Behavioral Neuroscience..

Lecture 1.

Philosophical Background

  1. Neuroscience and Behavior
    1. Physiological basis of mind? Modern dualism?
    2. Neural bases of behavior? The key philosophical theme of modern neural science is that all behavior is a reflection of brain function
    3. Kandel, Schwartz, and Jessell (Principles of Neural Science), describe 5 sciences as important to the neurosciences: Anatomy, Physiology, Biochemical Pharmacology, Embryology, and Behavior.
    4. Brain/behavior looks at interaction. As with all correlations, causation might be tried in different directions.
    5. None is most important but all are important, including research and application
    6. Nothing in the nervous system makes sense except in light of behavior!
  2. Multidisciplinary experimental and explanatory approaches to behavior: Why do birds sing?
    1. "Why?" is always a hard question to answer. Perhaps rephrase?
    2. First--make the observation more precise.
    3. Then, redefine question--under what conditions do they sing?
    4. Physiological account--the mechanics of it.
    5. Ontogenic (how it develops or comes to be)
    6. Functional
    7. Evolutionary. Probably has evolutionary function, but can be inferred.
    8. Environmental/learning. plasticity within a lifetime..
  3. Dualism
    1. Rene Decartes (1591-1650)
    2. Was invented dualism to keep free will alive?
    3. This form of dualism not taken seriously now. But there are modern forms not too different.
  4. Monism.
    1. Physical. All is material.
    2. All is mental?
  5. Reductionism
    1. C. Lloyd Morgan: "In no case is an animal activity to be interpreted as the outcome of the exercise of a higher psychical facility if it can be fairly interpreted ass the outcome of one that stands lower on the psychological scale."
    2. Homogeneous. Deduction from a general theory of implications in which there is a commonality of terms.
    3. Heterogeneous. Any explanation of a fact that takes place somewhere else, at some other level of observation, described in different terms, and measured, if at all, in different dimensions.
    4. Avoid psuedo reduction: hypothetical devices for which there is no evidence.
  6. Consciousness. The "split-brain" studies.
    1. Symmetry (left/right).
    2. Slight asymmetry in function.
    3. Right brain: left half of body (except olfaction). Mostly mute in right-handed people
    4. Left brain: right half of body (except olfaction). This half talks.
    5. Split brain operation for treating severe epilepsy (Sperry, 1966, Gazzaniga, 1970).
    6. Sever corpus callosum.
    7. Patient can talk about what it's right half (left brain) experiences, but not the other half.
    8. Consciousness lies in actions, what we think of as consciousness lies in language.
  7. This course is about brain behavior relationships.
    1. Behavior.
    2. Physiology (anatomy biochemistry)
    3. Neither is cause--equal partners.
  8. Experimental Physiology.
    1. Last two hundred years. Successful. Different from classical biology (e.g., Darwin) which described, botinized, and looked at correlations.
    2. Experimental means manipulate. Change one thing and look to see what happens. A theory must direct action.
  1. Consequences of Not Using Animals
    1. Malaria. India. 1951. 75 million cases (800,000 deaths)
    2. 1961. 50,000 cases (533 deaths, if proportions are same).
    3. Due to eradication of mosquito with DDT (a separate story).
    4. How was it known that the mosquito was the culprit? Ultimately, give malaria to a human.
  1. One western culture has banned animal studies.
  2. Recent uses of humans in ethically questionable manner.
    1. Tuskeegee syphilis study, Into the 60's. Let syphilis run its course in black men. Supported by the PHS.
    2. Madrazo and Mexico studies of patients with P.D. Surgical intervention. Implants of adrenal glands. Successful temporally, Monkey studies designed from what he discovered.
    3. Early Parkinson's Disease work. Give MPTP to patients with PD.
    4. U.S. Radiation research.
  1. How Animals are Used.
    1. Animal Welfare Act
    2. PHS
    3. IACUC
    4. Pain and distress
    5. Number of animals
    6. Three R's: Reduce, refine, replace.


  1. Analog to circulatory system?
    1. Galen and Harvey
    2. The neuromuscular junction was first identified in 1860's under light microscopy. Not thought to apply to neural cells, though.
    3. Cajal noted discontinuities in cerebellar cells.
    4. Camillio Golgi (staining) and Santiago Ramón Y Cajál (1852-1934, anatomy)
    5. Ramón Y Cajál developed neural doctrine: the principle that the nervous system is made up of many individual, communicating neurons. Suggested that flow was from axon to dentrite.
    6. Sherrington (1897) coined "synapse"
  2. All cells (neural or otherwise) have;
    1. Membrane.
    2. Nucleus (red-blood cells do not).
    3. Mitochondria (maternal lineage).
    4. Microtubule and filaments.
    5. Ribosomes. sites where cell synthesize new protein. contains raw material and "docking site" for RNA. some free floating, others in endoplasmic reticulum.
    6. Lysosomes, contain enzymes that break down many chemicals into component parts.
    7. Golgi complex--network of vesicles preparing hormones for secretion.
  3. Structure of neuron.
    1. Cell body or soma. Contains stuff described above.
    2. Dendrites and axons.
    3. Myelin.
    4. Terminal (presynaptic)
    5. synapse.
    6. New neuron or motor.
    7. Processes (fibers) coming off of them. (table on board)
    8. Dendrites(input to cell)
    9. Axons (output)
    10. Unidirectional information flow.
  4. Types:
    1. unipolar: One primary process, many branches. some branches may be dendrites, others axons.
    2. Bipolar. Soma, one process at each end. One is dendrite. Other is axon. Axon always heads toward NS. Bipolar cells in eye, e.g.
    3. Multipolar. Predominate in vertebrate. One or more dendritic process, only one axon. . A spinal motor cell, receives about 10,000 contacts (and this is moderate), a Purkinje cell in cerebellum receives a/b 150,000 contacts.

Simple organization of NS.

  1. Draw simple NS, sensory afferent to motor efferent.
    1. o-----< o------< o----<
    2. Demonstration of speed (undergrad).
  2. Sensory -< motor (unidirectional flow, afferent->efferent). No exchange of fluids.
  3. Sensory1 -< interneuron-< motor


sensory2 -< interneuron -< motor

  1. Where we are going:
    1. A neuron is either at rest or discharging an "action potential," which is a brief electrical discharge. This discharge causes the release of neurotransmitter at a structure called the synapse, located at the neuron's terminal. The neurotransmitter causes the post-synaptic" neuron to be either more likely to fire an action potential, or less-likely to do so.
    2. And that is the neural basis of everything that we do.
  2. Afferent/efferent relative to position.
  3. Glia cells. ('glue') nonneural, still active. important.
    1. Myelin-providing
    2. Waste-removing.
    3. Guidance.
  4. Blood-brain barrier.
    1. Lining of endothelial (basically, lining of organs) cells that line capillaries. Out of brain, widely spaced.
    2. In brain, closely spaced together, form tight junctions. Large molecules cannot pass but certain gasses can.
    3. Lipids pass readily (heroin, nicotine, some gasses). Water soluble compounds do not.
    4. Active transport for essential amino acids, nutrients, water-soluble glucose.

The Resting Potential

  1. Voltage, Current, and Potential.
    1. Voltage (V) is electrical potential: separation of charge. (Analog to water pressure)
    2. Current (I) is flow of charge. (Analog to water flow).
    3. Resistance (R) is constant of proportionality: V = R I
    4. Conductance (G) is 1/R, also a constant of proportionality: I = VG.
    5. Example: Attach a hose to a water tower.
  2. Turn on a hose. Water is driven by pressure. A constant amount of water/unit time is delivered. Place a small restriction in the hose--same amount/unit time goes through the hose.
    1. Metaphor for Ohm's law: (ignore formulas for undergrad).
    2. Water tower provide pressure (potential). Water flows through an opening (current). Size of opening (resistance/conductance) and pressure influence current of water providing current. A pump that moves water to the tower is the energy input.
    3. Consider a closed hydraulic circuit. Pump, and constriction. Pump adjusted to maintain a constant pressure. The flow rate must depend upon the width of the pipe. If there is a constriction in the pipe (an increase in resistance) then flow rate must decrease. I=E/R = EG. The pump could pump less water to maintain the same pressure. Conversely, open up the gate and the pump must pump more water to maintain the same pressure. Pressure can be conceived as a potential difference--say in the height of a water tank.
    4. Current is flow of charge. For our purposes it is the flow of ions.
  3. All this requires the input of energy: pump water up, pump charge out.
    1. by elevating a water tower, pumping water, or adding a battery to the circuit. The system's tendency is to flow to a state of no potential difference.
  4. Draw axon.
    1. Lipid bilayer (phospholipids, hydrophilic head, hydrophobic tail.
    2. Heads attracted to polar medium, tails to each other to form a sheet that folds over into a tube.
    3. Na+ Cl- out (a/b concentration of seawater), K+ A- inside. resting potential.
    4. Maintains resting potential -55 mV.
    5. ion channels Na+, Cl-, K+
    6. Na+, K+ Channels are normally closed.
    7. Measurement of voltage (giant squid axon-large axon, small squid)
    8. The axon contains a membrane that maintains separation in the concentrations of Na+, Cl-, K+. The extracellular fluid, like seawater, is rich in Na+ and Cl-.
    9. Slight permeability to Na+ (some channels are open).
    10. There is free flow of Cl- (These channels become important in benzodiazepines, barbiturates, and ethanol). Ignore for now, will return to them later.
    11. The Na channels are activated by voltage. Some are open at resting potential, more are open as membrane becomes depolarized.
    12. With small depolarization, there is some influx of Na. and corresponding efflux of K+. Ultimately this would result in no change in potential.
    13. Energy separates the charge by maintaining the different concentrations in Na and K+ (3 Na+ out for 2 K+ in).
Ion Concentration gradient pushes: Electrostatic gradient pushes: Net flow at resting potential
Na+ In In In (equilibrium at +55 mv)
K+ Out In Usually out: equilibrium at -75 mv
Cl- Out In Depends. Equilibrium at -60 mv

Action Potential.

  1. The shape of the action potential.
    1. Draw Potential vs time: threshold, hyperpolarization, depolarization, action potential, refractory period.
    2. All or none, frequency constrained, partly, by refractory period.
  2. Na channels open.
    1. Voltage gated.
  3. How do we know? (From. Nichols et al.)
    1. A.P. first described in 1849, understanding began in 1949
    2. "Soup vs sparks" characterized debate in early half of century (from Gordon Shepard, auvetmed, 17 feb 98.).
    1. Hodgkin and Huxley, Hodgkin and Katz.
  1. Depolarization causes voltage-gated Na channels to open.
    1. Slight depolarization->only a few open. Then returns to resting potential.
    2. Larger depolarization-> many open->more depolarization->more open-> more depolarization-> more open and so forth.
  2. Na channels close, stopping the Na influx. (Voltage gated)
    1. At peak, other voltage-gated Na channels (on inside) close, blocking Na+
    2. The inside channels are unaffected by TTX and STX: receptor specificity.
    3. Na involved in peak of A.P., and in rate at which the peak is approached.
  3. Meanwhile K+ channels open more.
    1. K+ to flow out, seek K+ equilibrium potential.
    2. Remain open through absolute refractory period
    3. Thus, voltage-gated K channels have been opening slowly and the peak time to open is shortly after the Na channels have been opening, and about the time the Na channels have closed.
    4. Meanwhile, Cl flows in because channels have not changed. This helps re-establish resting potentials.
    5. Na channels are closed by a separate gate that maintains the absolute refractory period.
    6. Return toward resting potential, and beyond (K+.)
  4. Refractory period. (absolute, relative)
    1. allows travel in one direction
    2. makes rate of firing related to intensity. (more intense stimuli can overcome relative, but not absolute, refractory period).
    3. Propagation. Influx of Na+ diffuses along axon bidirectionally, refractory period behind prevents back propagation.
  5. Role of myelin
    1. Insulation.
    2. Saltatory conduction.


  1. Draw simple NS, sensory afferent to motor efferent.
    1. o-----< o------< o----<
  2. Combination of APs.
    1. Excitatory post-synaptic potential. EPSP, (Na+)
    2. Inhibitory post-synpatic potential., (K+, Cl-)
    3. temporal summation, spatial summation
  3. Different classes of receptor action.
    1. Iontropic. Attach directly to an ion channel.
    2. Metabotropic. Ion channel removed from receptor.
  4. Properties and examples of ionotropic.
    1. Fast, short lasting, and simple. (msec resolution)
    2. Glycine, glutamate, GABA, nicotinic ACH
  5. Metabotrobic or (sometimes: second messenger.) Slower, longer lasting, more comlex.
    1. "first messenger" is the neurotransmitter.
    2. This stimulates adenylate cyclase (through guanine triphosphate), and adenylate enzyme that facilitates the formation conversion of ATP (adenosine triphosphate) to cyclic AMP.
    3. Cyclic AMP is the second messenger. As long as it is available, it activates a protein kinase that opens an ion channel and produces a post-synaptic potential.
    4. Cyclic AMP is broken down by enzymes called phosphodiesterase inhibitors.
    5. Some receptor subtypes are adenylate cyclase inhibitors, and therefore inhibit the metabotropic.
    6. Caffeine inhibites phosphodiesterase.
  6. Properties and examples of metabotropic
    1. Seconds to minutes to operate
    2. Modulators.
    3. More complex.
    4. May be involved in rf pathways, e.g. (KSJ)
    5. Muscarinic ACH, epinephrine,

Anatomy I

  1. Principles of organization
    1. High degree of order
    2. Modularity
    3. Structure and function interact
  2. Nervous system
  3. Central: Brain and spinal cord.
    1. Brain
    2. Spinal Cord
  4. Peripheral
    1. Autonomic
    1. Somatic
  1. Terms:
    1. rostral/caudal, dorsal/vental, etc.
    2. Views: sagittal, coronal, horizontal, etc.
  2. Spinal Cord
    1. Cenral gray, peripheral white.

Dorsal root (sensory)

    1. Ventral root (motor)
    2. Discovery of distinction between dorsal/ventral roots.
  1. Blood and fluid.
    1. General picture. Brain sits in fluid, bathed by CSF which flows around and through the brain. Sits on top of spinal cord and cortex envelops it. Protected by skull and meninges.
    2. Blood fed through two principle arteries (vertebral/caudal, internal carotid/rostral).
    3. Veinous drainage. Driven by pressure. Some veins can be bidirectional..
  2. Menenges (singular=meninx).
    1. Figure 4.6 Connnective tissue in CNS.
    2. Dura mater (hard mother.) protective
    3. Arachnoid membrane membrane. wedlike apperasnce. Provides some structure. CSF circulates through here. Cerebral arteries also flow through this area.
    4. Pia mater (pious, or delicate mother). More flexible, follows all convolutions.
    5. Peripheral nervous system only has the dura mater and pia mater. Arachnoid membrane not there.
  3. Cerebral spinal fluid and ventricular system.
    1. Fig. 4.7 CSF and ventricular system. Brain floats in this. Fluid cushion. Also regulated ionic environment.
    2. Choroid Plexus. Dense network of capillaries that secretes a/b liter cerebral spinal fluid. In all the ventricles. Weak place for BB barrier.
    3. There is a blood-CSF barrier that is usually synonomous with blood-brain barrier since CSF is in equilibrium with extracellular brain material.
    4. CSF formed in lateral ventricles (1 and 2), flows into 3rd, then through cerebral aquaduct into 4th ventricle. Leaves 4th ventricle through subarachnoid space, (1,2-->3-->4-->blood) flows through herniations in the dura mater into superior sagittal sinus and drains into veins.
    5. Half-life of replacement is 3 hrs.
    6. Hydrocephalus. Blockage of CSF. Can be treated by inserting a shunt and draining into Anatomy II: The brain abdominal cavity.


  1. Development. Neural tube, then forebrain/midbrain/hindbrain surrounding what becomes ventricles. Then further detail.
  2. Some details from Thompson, 1993.
    1. Over the nine months of development the human embryonic brain gains neurons at the rate of 250,000/min. Note, begins with a single split into two from the fertilized eg.
    2. There are upwards of 100,000 genes in human DNA and about 50,000 are active in the CNS
  3. Events important for the development of the brain:
    1. Induction is the general principle believed to underlie development.
    2. Neurons initially develop within neural plate and multiply rapidly.
    3. At some point they stop dividing and migrate to their ultimate destination. Migration triggered, somehow, by the termination of mitosis. Radial glia guide this.
    4. Early in development one can see beginning of forebrain, midbrain, and hindbrain forming around three chambers, which will become ventricles 1,2,3 (forebrain), cerebral aquaduct (midbrain), and hindbrain (4th ventrical).
    5. forebrain -> telecephalon (endbrain), diencephalon (interbrain)
    6. midbrain-> mesencephalon (midbrain)
    7. hindbrain->metencephalon (afterbrain), myelencephalon (marrowbrain).
    8. further differentiation takes place through develoment.
  4. Variation and selection in neural development
    1. axonal growth is guided by physical and chemical factors.
    2. Growth cones
    3. chemotaxis permits a terminal button to find the appropriate receptor to form a synapse.
    4. Selection and pruning. In order to survive, a synapse needs to be active. Importance of early experience, since this pruning takes place throughout childhood.
  5. cerebral cortex:
    1. begins as a single layer, a few cells thick. the "geminal zone." When a cell stops dividing it moves up to another layer.
    2. Some of these cells them move up another layer.
    3. This appears to move in waves.
    4. Radial glia cells appear to guide this. (Mercury damages it)
  6. To find each other:
    1. Chemical guidance. Growing end of an axon has a special structure called a growth cone.
    2. To sort out connections. Many more connections are present initially than ultimately. Sorting out takes place by death.
  7. Experimental design.
    1. Describe events in normal animal
    2. Describe events after experimental manipulation
    3. Analyses of events in vitro
  1. Forebrain
    1. Telecephalon.
    2. diencephalon. Between mesencephalon (midbrain) and telencephalon. Thalamus and hypothalamus. .
  1. Mesencephalon (Midbrain, surrounds cerebral aquaduct)
    1. Tectum, (roof)
    2. Tegmentum (Covering)
  2. CNS Hindbrain, Surrounds 4th ventricle.
    1. Metencephalon (behind brain).
    2. Medulla, (some books also call myelencephalon). Most caudal portion of brain stem. Lower portion is rostral end of spinal cord.
  3. MRIs to show brain sitting in the head.?
  4. Cortex Transparency 20
    1. Longitudinal fissure
    2. Corpus callosum
    3. Central Fissure
    4. Lateral Fissure
    5. Precentral Gyrus (motor). Motor homunculus
    6. Postcentral Gyrus (sensory) Sensory homunculus.
    7. Frontal, parietal, temporal, occipital lobes.
    8. Transparency #1 to show evolution of cortex.
    9. Transparency from Graphics book to show relationship of brain/body mass.
  5. Laminar structure of cortex
    1. Layer I. Superficial, few neuronal bodies, glial cells,, axonal processes, parallel to pia mater
    2. Layer II Outputs. Densely cellular. mostly small, pyramidal
    3. Layer III. Outputs. Larger pyramidal.
    4. Layer IV. Stellate cells, afferents from thalamus, big in sensory areas.
    5. Layer V. Largest pyramidal. Outputs to striatum, brain stem, spinal cord. Betz in motor areas.
    6. Layer VI. Project back to thalamus.
  6. Columnar structure.
  7. Lateralization of Function.
    1. Longitudinal symmetry
    2. Brain lobes, connection by corpus callosum
    3. Connection of eyes. left visual field to right brain
    4. Speech is driven in right-handed people is driven by left hemisphere.
    5. Experiments with split-brain.

  1. Anatomic, functional, and neurochemical distinctions.

Autonomic Nervous System

Structure or Function
Sympathetic Reaction (fight or flight) Parasympathic Reaction(vegetative)
Pupil of Eye Dilate Constrict
Heart Rate


Increase (faster rate of contraction) Decrease (slower rate of contraction)
Lungs Fast and shallow respiration, dilate bronchi Slow and deep respiration, constrict bronchi.
Stomach and Intestinal Glands Inhibit Activate
Stomach and Intestinal Wall No motility (no movement of food) Motility (muscles move food)
Lacrimal glands Secretion of tears no effect
Liver Release glucose no effect
Sweat Glands Secretion No effect
Blood vessels Abdominal: constrict

Muscle: dilate

Dilate (reduces blood pressure)
Bladder Inhibition of contraction Contraction
Penis Ejaculation Erection
Vagina Orgasm Secretion of lubricating fluid
Location of Ganglia Bilateral chain parallel to spinal cord (sympathetic chain). Permits spreading and diverse action. Near effector organ. Focused, specific action.
Neurotransmitter at ganglion. Acetylcholine Acetylcholine
Neurotransmitter at Effector Organ Norepinephrine (noradreline) Acetylcholine (muscarinic, second messenger)
Drugs that stimulate Cocaine, amphetamine, LSD Nerve Gas (Soman) Some Pesticides. Muscarine from pilocarpus plant (increases salivation). Some Mushrooms.
Drugs that inhibit "Beta-blockers" (propanolol) Atropine (from deadly nightshade, Atropa belladona.)


  1. Lesion and ablation (intentional and accidental).
    1. Logic: render neurons inactive, look for alterations in behavior.
    2. Approach: Position brain precisely. Make surgical knife cut, or insert cannula and deliver lesion.
    3. Control: sham lesion.
  2. Permanent techniques.
    1. Knife cut
    2. Electrolytic lesions
    3. Chemical lesion
  3. Temporary lesions.
    1. KCl (not in book, not covered)
    2. Colchicine (slow down axoplasmic transport of NT).
    3. Cryogenic cooling.
  4. Histological techniques
    1. Goal: locate site of lesion, or study structure of a region of the nervous system.
    2. Steps:
  5. Stains.
    1. myelin (Weil stain)
    2. cell body (cresyl violet gets nissl substance in cytoplasm.)
    3. membrane: golgi stain. outlines full cell, but only a fraction of them.
    4. Methelene blue (DNA/RNA in Nissl substance, so gets cell bodies. Not specific to neurons. )
    5. Golgi stain. Outlines full cell, but only a fraction of them.
    6. Nissl stain. Attracted only to Nissl substance, containing RNA, DNA, that encircles nucleus. So highlights cell bodies. Useful for doing cell counts. Not selective for neural cells.
    7. Autoradiography.
  6. Tracing neural connections: Anterograde.
    1. From dendrites toward cell body and toward terminal button. (Moving forward, efferent to site of administration).
    2. Apply close to dendrites or cell bodies. Transported toward axon. Takes a few days.
    3. Phaseolus vulgaris leukoagglutinin (PHA). A kidney lectin (lectin is a protin that binds to a specific cell in immune system. )
    4. Immunocytochemical methods.
  7. Tracing neural connections: Retrograde, from nerve terminal toward cell body (afferent to site of administration).
    1. Apply label (e.g., flurogold/flourescent) close to terminal button . Wait a few days. Look for cell bodies under microscope.
    2. Horseradish peroxidase. Taken up in terminal button, migrates to cell body.
  8. Recording and stimulating neural activity.
    1. Electrophysiological recording.
    2. Localizing neuron activation.
    3. Microdialysis. (measure extracellular levels of neurotransmitter).
    4. Chemical stimulation, e.g., reverse microdialysis. cannulae injection.
    5. Electrical stimulation of section of brain.
  9. Neurochemical methods.
    1. Localize transmitters in brain.
  10. Imaging techniques.
    1. CAT
    2. MRI
    3. PET (uses 2-DG).
  11. Genetic studies.
  12. Behavior-chemical interactions-at the whole animal level.

Comparative and Evolutionary Perspectives.

  1. What is the problem that must be solved?
    1. There are many different types of organisms on the planet. Many look somewhat alike: Sparrows look like other sparrows and snails look like other snails. Others look very different. Sparrows look kind of like finches but not at all like snails. Moreover, on close examination, individual sparrows differ slightly in coloration, beak size, weight, ....The similarities and the differences must be accounted for.
  2. A scientific account will accommodate all that we know.
    1. The similarities among dogs are found in many elements of structure (legs, snout, brain, spinal cord, tail) and function (social, carnivores, live birth, nurse). Nevertheless, individual dogs differ, sometimes subtly, from one another.
    2. There are systematic ways of classifying these into
  3. There are at least three general principles that must be accounted for by a general theory. Note: Amer Heritage. Theory: 1) Systematically organized knowledge applicable in a wide variety of circumstances, esp, a system of assumptions, principles, and rules of procedure devised to analyze, predict, or otherwise explain the nature or behavior of specified phenomena. . . . 4) an assumption baed on limited information or knowledge; a conjecture. < Greek: theoros, spectator; probable from thea, a viewing and oros, seeing. Note the empirical derivation!
    1. Individuals of a given species are not identical. This was a problem to solve, but now variation is a crucial component of natural selection. Indeed, variation itself may have been selected.
    2. Some of this variation is heritable. Height for example or the ability to speak. But the ability to speak English is not.
    3. Not all offspring survive (says Rosen..., perhaps "leave descendents" is better): some die, some reproduce. Note the distinctions: we survive long after our offspring have produced offspring. But spiders are eaten by their offspring and, in the case of some males, by their mate. What matters is leving offspring.
  4. Two broad forms of evolution have been identified.
    1. Convergent evolution: a process that produces a resemblance due to convergence rather than common "analogy".
    2. Homology. Resemblance based on common ancestry, but while serving different functions. e.g., simmilar forelimb structures serving as an arm, foreleg of a dog, flipper of a seal, and wing of a bat. All contain similar bones: humerus, radius and ulna, and the bones forming hands and fingers.
  5. Structure and function are often correlated.
    1. But note, with correlation, causation is hard to determine.
  6. Be able to list the commonalities among vertebrate nervous systems:
    1. Development from a hollow, dorsal tube, bilateral symmetry, segmentation (pairs of spinal nerves from each level of cord), hierarchical control (from brain), separate systems (e.g, central/peripheral, symp/parasymp), localization of function.
  7. Be able to compare and contrast N.S. of vertebrates with that of molluscs and insects.
    1. basic plan: both have one and most invertebrates have some sort of central n.s....but not all
    2. Brain. Not all invertebrates have one, but evolution tends to press toward central control.
    3. Number of neurons. Vertebrate: many devoted to info processing. Invertebrate brains have fewer, more complicated, and larger ones. So some info processing takes place in the neuron.
    4. Identifiable neurons: found in invertebrates, very few cases in vertebrates.
    5. Ganglion structure. more reliance on distributed ganglia in inverebrates. The structure is that of a outer rind consistingof monopolar cell bodies and an inner core consisting of the extensions of cell bodies forming a "neuropil" (network of axons and dendrites.
    6. Axons and neuronal conduction. Many mammalian axons have myelin --> faster. Perhaps b/c mammals are so big. Many invertebrates have a few giant axons (squid, crawfish) mediating escape responses.
    7. Structural changes. Invertebrates undergo impressive, large changes (metaphorphosis). Vertebrates changes are less impressive.
    8. Location. Vertebrate--in bony skull. Inveterbrate--in many, in stomach (note Abdominal nervous system in mammals).
  8. Note similarities in brain structure. transparency.
  9. Note brain weight/body mass ratios among diferent vertebrates.
    1. Slope describes relationship between body mass and brain mass.
    2. Intercept: encephalization factor. Larger factor --> larger relative brain size.
    3. The following encephalization factors come from Schmidt-Nielson. They were originally reported for a regression of brain mass in kg vs body mass in kg. The factors used in the text gives wrong answers for brain size...for example. it says that the human brain is 0.71*(body mass).69 = 13.3 kg or 13.3 grams (they are not clear as to what units they are using) either is incorrect. 13.3 kg = 29 lbs. 13.3 gm is about 14 paper clips.
    4. Note that there is a basic amount of brain function req'd just to function. So over that provides additional senses, motor control, plasticity.


  1. Dose/effect curve.
    1. ED50, LD50, Margin of safety/therapeutic index
    2. LD50/ED50 vs LD1/ED99
  2. Tolerance and sensitization.
    1. Sensitization.
    2. Tolerance. Decreased sensitivity to a drug due to repeated administration.
    3. Behavioral tolerance.
    4. Withdrawal. Closely linked to tolerance and to drug abuse.
  3. Placebo effect,
    1. Placebo: an inert substance given in lieu of a physiologically active drug.
    2. Used experimentally as a control. Often used as a control used when testing for therapeutic effects of a new drug.
    3. Can be a large effect.
  4. Time course curve. Intensity of effect (or amount, or concentration) vs time.
    1. Plot ascending and descending curve with horizontal line showing threshold for effect.
    2. T0 = time of administration
    3. T1 = onset of action
    4. T2 = peak effect
    5. T3 = offset of action (mention acute tolerance here).
    6. Absorption, distribution (can include the ascending and first phase of the descending curve) , elimination.
  5. Kinetics.
    1. Pharmacokinetics. "the factor influencing the magnitude of drug effect by determining the amount of drug at various sites in the body as a function of time" (Levine).
    2. The half life.
  6. Routes of administration.
    1. Note time course for i.v., inhalation, and oral.

  1. Major events in neurotransmission
    1. Synthesis of neurotransmitter, formation of vesicles
    2. Transport down axon
    3. Storage in vesicles
    4. Release of NT by action potential (Ca++ )
    5. Interaction with a receptor (excite or inhibit)
    6. Separation of NT from receptors
    7. Stop action
    8. Autoreceptors.
    9. Presynaptic receptors.
    10. Pharmacodynamic tolerance.
  2. Neurotransmitters
    1. Acetylcholine
    2. Biogenic amines (or monoamines)
    3. Amino acids.
    4. Adenosine
  3. All action described in terms of receptor.
    1. Agonist vs antagonist
    2. Direct vs indirect.
  4. Affinity.
  5. The effect of a drug is related to the amount of a drug at a site of action. The proportion of a dose actually contributing to a drug's effect is influenced by:
    1. The rate and extent of absorption from the site of application
    2. The rate and extent of tissue distribution (e.g., lipophillicity)
    3. The rate of biotransformation to active or inactive metabolites
    4. The rate of excretion.

  6. Norepinephrine receptor and stimulants (cocaine/d amphetamine).
    1. Alpha methyl para tyrosine (AMPT). Blocks synthesis of dopa from tyrosine.
    2. Reserpine. Inhibits storage (makes vesicles "leaky").
    3. d-amphetamine. stimulates release of NE (and DA). increases alertness and arousal. Rebound depression, b/c not replaced rapidly enough. One evidence for role of catecholamines in depression.
    4. Haloperidol. blocks receptor.
    5. cocaine. Tricyclic antidepressants. Block reuptake.
    6. MAO inhibitors. Block degradation
    7. Clonidine. Stimulate presynaptic receptor. Acts like a lot of NT is there, therefore acts as an antagonist postsynaptically since inhibits release. Attempted in treating cocaine (unsuccessful)
  7. Book mentions nicotine, lsd, Ergot (grain mold) as serotonin agonist, Salem.

Some synthetic pathways.

    1. Acetyl CoA + Choline CAT--> ACh + CoA
    2. ACh AChE-> Choline + Acetate
    3. Tyrosine -> l DOPA -> Dopamine -> Norepinephrine-> Epinephrine.
  1. ACh synapse .
  2. Dopamine synapse
    1. D1: post-synaptic, increase 2nd messenger cAMP
    2. D2: pre and post-synaptic, decrease 2nd messenger cAMP
  3. Glutamate
    1. Ionotropic
    2. Metabotropic
    3. Require both A.P. AND receptor occupation.
    4. Four properperties:
  4. GABA (Gamma-aminobutyric acid).
    1. GABAA receptors. different sites of action
    2. benzodiazepines (and alcohol?): book narrative says these are linked. figure suggests barbiturate.

Sensory Systems: General

  1. General layout
    1. Reception--Physical interaction with receptor-- e.g., odorant molecule, audition, pressure.
    2. Transduction--physical energy to electrical energy.
    3. Coding--frequency and difference.
  2. Transducers convert some form of energy into electrical energy that the N.S. can use.
    1. Mechanical (hair cells, pressure)
    2. Acoustic (also hair cells)
    3. Chemical
    4. Thermal
    5. Electromagnetic
  3. Example: Pacinian Corpuscle.
    1. Bare nerve fiber, specially designed so that bending it opens ionic (Na+) channels
    2. Onionlike layers around free-nerve ending to cushion.
    3. depolarize--generate action potentials.
    4. Record from fiber
    5. Physical structure (not neural circuitry) makes it more sensitive to slow, transient touch.
  4. Receptive field.
    1. neuron in somatosensory cortex connects to that Pacinian corpuscle. Receptive Field for that neuron is the area of skin serving that P. C.
    2. Sensitivity or two-point threshold is related the density of pacinian corps--or nerves which, in turn, is related to amount of cortical surface area devoted to area of skin.
  5. Texture.
    1. Pacinian: highest sensitivity: 250-300 Hz (rapidly adapting, pressure, vibration).)
    2. Vibration sensitivity.
    3. Detect texture by moving finger.


  1. Physical stimulus is "light".
    1. Part of E.M. spectrum--show transparency
    2. Varies in amplitude and frequency (wavelength)
    3. Visible light, about 400 to 750 nanometers
    4. High energy = high frequency = short wavelength
    5. quantal (photon) vs wave.
Perception Quantal characteristic Wave characteristic

(red -> violet)

low energy -> high energy long wavelength ->

short wavelength


(dim -> bright)

few quanta -> many quanta small amplitude -> large amlitude.

  1. Characteristics
    1. Intensity
    2. contrast
    3. color (hue, saturation, brightness).
    4. Dynamic range (photopic, scotopic)
    5. Detection of form.

  2. General layout of visual system. Eye-> optic nerve -> chiasm -> tract -> LGN -> occipital cortex.
  3. Eye.
    1. Iris (muscle forming a hole called pupil)
    2. Lens
    3. Eye muscles Rapid. No afferents.
    4. Cornea. Clear covering
    5. Photoreceptors on fovea: rods and cones
    6. Blind spot.
    7. Choroid Plexus: black lining, nutrition. Holds photoreceptors. Provides photopigment.
  4. Transduction at photoreceptor..
    1. Rod cells contain a photopigment. Rhodopsin (rose opsin). Unbleached (in dark) had deep purple hue. In light turns pale.
    2. Rhodopsin consists of 11 cis retinal and (rod) opsin. Light causes retinal to straighten out and detach from opsin, producing all trans retinal and opsin.
    3. Causing hyperpolarzation from -35 mV to -55 mV (K+ Nernst potential).
    4. Graded potential of rods and cones discovered by Tomita.
  5. Structure of the Retina and the visual pathways.



| Horizontal

Bipolar Cells


| Amacrine

Ganglion Cells

  1. Intermezzo: series of stages for vision:
    1. Light absorbed by rhodopsin
    2. Isomerization of retinal
    3. Block Na channels
    4. hyperpolarize rod or cone
    5. Release synaptic vesicles
    6. Graded (generator) potentials in amacrine, bipolar, horizontal
    7. Action potentials in ganglion cells:
    8. Integration to produce contrast center/surround RF. Physical stimulus.
    9. Light. Wave (amplitude, frequency/wavelength)
    10. Quantum. packet of some energy, corresponding to wavelengtn.

  2. Color
    1. Trichromatic/Young-Helmholtz
    2. Note experiment.
    3. Hering. Opponent processing.
  3. Single unit recording in the visual system.
    1. Use electrode, monitor firing rate, then find receptive field, then find optimal stimulus.
  4. Optimal stimulus in LGN, center-surround.
  1. Cell types in LGN. X, Y. Transparency.
  2. Parvo/magnocellular distinction.

Parvo ganglion cells Magno ganglion cells
Anatomical differences small cell body

dense branching

short branching

majority of cels

large cell body

sparse branching

long branching

minority of cells

Physiological differences slow conduction rate

sustained response

small receptive field

low-contrast sensitivity

color sensitive

rapid conduction rate

transient resonse

large receptive field

high-contrast sensitivity

color blind

Possible behavioral consequences detailed form analysis

spatial analysis

color vision

motion detection

temporal analysis

depth perception.

  1. Visual processing in visual cortex.
    1. Feature detectors: isolate features of vision.
    2. Simple cells. Stationary bar or edge at particular angle in particular part of RF
    3. Complex. Larger RF, particular pattern moving in a particular way at a particular speed or stationary bar anywhere in R.F. .
    4. Hypercomplex. Similar to complex, but with strong inhibitory region.
    5. Grandmother cell
    6. Visual agnosias. See table in KSJ..
  2. Structure of primary visual cortex.
    1. Orientation columns
    2. Laminar structure.
  3. Pull together the visual pathways.
    1. As Carlson points out, there are separate areas for color (in primates and some other species), form, position, and movement.
  4. Dorsal stream.
    1. Both (dorsal and ventral streams) originate in striate cortex, diverge in extra-striate cortex.
    2. Dorsal stream is 'where' system.
    3. Turns upward (dorsally) ending in ctx of posterior parietal lobe.
    4. mostly magnocellular input, but some parvocellular too.
  5. Ventral stream
    1. "What" system.
    2. Also originates in striate ctx, diverges in extra-striate ctx.
    3. about magno, parvo.
  6. Pull together parallel visual pathways.
    1. Parvo- and magnocellular both go to Layer 4C of area V1 (Vee-one) (primary visual cortex) and there the pathway branches into 3.
    2. In general they handle the following features: color (originating from parvo); fine detail (originating mostly from parvo); broad form (originating largely from magno); and motion, depth, location (mostly from magno).
  7. Lesion studies
    1. V1: lose color sensitivity. Also responsible for orientation, eye dominance.
    2. V4: color and form perception. Lesions diminish color perception.
    3. V5. movement.
    4. Inferotemporal ctx. (ventral stream)
  8. Lateral inhibition.

Motor systems

  1. Motor system. General picture.
    1. Motor system. Efferent side. What questions would one want to ask:
    2. General Organization of sensorimotor system organized so as to initiate a motor act (ctx), orchestrate the contraction of muscles to pull it off (basal ganglia, "motor" loops), send those instructions to the appropriate neuron in the primary motor cortex, which sends instructions down spinal tracts, with a branch to the cerebellum stating the intent, monitor the muscles to ensure that they do as they are told at the level of the spinal cord and in the cerebellum. The consequences of motor acts figure in, too, through midbrain structures close to the substantia nigra and that probably make contact with the "cognitive" loop of the basal ganglia.
  2. Muscles
    1. Smooth, internal organs.
    2. cardiovascular, heart.
    3. Striated, Slow-twitch, slow, little fatigue, less vigorous contraction.
    4. Striated, fast-twitch, rapid, fatigue readily, vigorous.
  3. neuromuscular junction.
    1. motor unit--neuron and muscles it innervates.
    2. eyes, one neuron, only a few fibers.
    3. biceps, one neuron, hundred fibers.
  4. Acetylcholine receptor at the neuromuscular junction
    1. Nicotinic cholinergic receptor.
    2. Stimulated by nicotine.
    3. Ionotropic
    4. Release of Ach is promoted by alpha bungarotoxin (a snake venom), black widow spider venom.
    5. Release of Ach blocked by botulinum toxin.
    6. Nicotinic receptors blocked by rabies virus, curare.
    7. Acetylcholinesterase is inhibited by soman (irreversibly) or physostigmine (irreversibly).
  5. Myesthenia Gravis
    1. Automimmune
    2. Decrease ACh receptors--weakness
    3. Rx--replacement, ACHE (a pesticide)/discuss mechanism
  6. Stretch reflex/reflx arc.
    1. Starting at muscle spindle, aferent impulses are conducted to termnal buttons in gray matter of spinal cord. These terminal buttons terminate on alpha motor neuron that innervate extrafusal muscle fibers of same muscle. Maintain position of limb, postural control. Gastrocnemius muscle (large calf muscle) that goes behind the knee. When stretched, stretch reflex contracts to maintain posture.
    2. Another reflex, from golgi tendon organ. Some detect amount of stretch and go central. Another forms a second spinal reflex except through a glycine (inhibitory) neurron that inhibits the efferent alpha motor neuron.. {this was the first discovery of inhibition).
    3. Unilateral deafferentation (Taub). Diminished use. Preference for intact limb. Force use-> learn to use it. Application to stroke victims.
  7. Descending pathways. Two types: dorsolateral and ventromedial. Named for where cell bodies lie in the spinal cord.
    1. Traditional distinction: pyramidal vs extrapyramidal.
    2. General picture: Current distinctions involve dorsolateral and ventromedial tracts. Each has a corticospinal component and a cortico-brainstem-spinal ( "extrapyramidal") component.
Name/Function Dorsolateral (contralateral descent, unilateral control, specific spinal segment, distal limbs) Ventromedial ( ipsilateral descent, diffuse branching( bilateral, across several spinal segments) proximal limbs)
Cortico-brainstem-spinal posture/locomotion/balance. From cortex to brainstem nucleus, then to motor neuron in spinal cord digits as a cluster (mitten), wrist, distal arm all as pertains to posture. Also feet and lower legs.

Carlson: corticorubralspinal

(tectum/ sup. colli, reticular formation, vestibular, motor nuclei of cranial nerves.). Coordinate body/eye movement, motor programs like walking and swimming, balance.
Corticospinal (pyramidal). from cortex to motor neuron in spinal nerve. other movements such as reaching, picking, manipulation, dexterity digits independently (primates, hamsters, raccoons) forearm in reaching descend, branch diffusely, control of proximal limbs in reaching movement.

  1. General picture: linear



CTX --------------------------------> spinal cord --------> muscle, voluntary.

CTX----------> red nucleus------>spinal cord ---------> muscle, locomotion, balance

Ventromedial (Ventral in Carlson)


CTX --------------------------------> spinal cord ----------> muscle, voluntary

CTX ------------> brainstem -----> spinal cord -----------> muscle, locomotor, balance

  1. Some notes.
    1. DL and VM pathways similar in that each has two major tracts. One direct from ctx to muscle (with a couple of synapses in between). The other makes a stop at the brainstem first.
    2. "Voluntary" designation after the corticospinal is traditional. All are "voluntary" in a sense (i.e., not strictly reflexive) and all originate in cortex and susceptible to operant control
    3. VM: more diffuse, axons inneverate bilaterally and across spinal segments.
    4. DL: contralateral descent, unilateral control, specific spinal segments, distal limbs.
    5. Carlson (and most others) makes some finer distinctions in the Ventromedial pathways. Note these are in the Ventromedial cortico-brainstem-spinal tracts. .
    6. Corticobulbar (bulbar=medulla). similar to corticospinal, but for cranial nerves.
  1. Ventromedial pathways. "maintenance of erect posture, to integrated movements of body and limbs such as orienting movements, to synergistic movements of individual limbs and to directing the course of progression." (Kuypers, 1985, copied from Shepard's text.)
    1. Ventromedial cortico-brainstem-spinal tract.
    2. Ventromedial pathways involved with posture. Lesions --> postural deficits. Loss of control over trunk and proximal limb muscles. Monkeys could stand only with great difficulty.
    3. Ventralmedial corticospinal. ipsilateral. orignate in trunk and upper leg regions of primary motor cortex. descend to appropriate regions of spinal nerve and emerge to muscles in trunk. These pathways are responsible for trunk, neck, proximal limb muscles.
    4. dorso lateral tracts: finer control. Control of extremities..
  2. How do we know this? Anatomy had been described for some time. Function described in series of experiments involving lesions of descending corticospinal pathways (ipsilateral and contralateral).(Lawrence and Kuypers, 1968).
    1. Lesion dorsolateral corticospinal tract (left and right) in medullary pyramids. V-M. remained intact.
    2. Then, 1/2 monkeys, unilateral lesion of dorsolateral corticorubral spinal tract.
    3. Other half. lesion all ventromedial pathways, only corticorubral spinal intact.
  3. Basal ganglia.
    1. Input to striatum (caudate/putamen)
    2. Outputs are globus pallidus and substantia nigra.
    3. Interconnections are inhibitory
    4. Motor loop (motor/sensory ctx->putamen->GPi (caudal-ventral), Snpr -> thalamus). Lesion-> motor effects. (Parkinson's disease)
    5. Cognitive loop (frontal assn ->caudate->GPi (rostral/caudal), Sn/pr (rostro-medial.) Lesion: reversal learning, sequences, Huntington's disease.)
  4. Linear approach, to help think about disorders of motor loop. Note, does not strictly map onto above figure, b/c a nigral/striatal loop is represented here:

Inhibit Inhibit Inhibit Excite

Substantia Nigra -> caudate/putamen -> Globus/pallidus -> thalamus -> cortex -> muscle tone, bradykinesia.

    1. Remove globus/pallidus: remove inhibition on thalamus, increase muscle tone, increase bradykinesia.
    2. Remove caudate/putamen: remove inhibition on GP. Decrease muscle tone, decrease bradykinesia (too much movement).
    3. Remove SN. Like removing GP (on first approximation).
  1. Huntington's Chorea
    1. Genetic disorder/dominant gene, 50% chance of inheir.
    2. Doesn't appear until after 40's (after age of reproduction, usually.)
    3. Damage to caudate and putamen. Cholinergic and GABAergic.
    4. Motor incoordination/spasticity/involuntary muscle movements (involuntary is characteristic of B.G.), cognitive loss-retardation, dementia. death within 15-20 yrs. about 10,000 cases in US.
  2. Parkinson's disease
    1. Resting tremor, slow movement, rigidity, little cog. loss, but difficulty doing more than one thing at a time.
    2. Loss of DA neurons, esp in S.N., in nigra/striatal loop.
    3. Appears when 60-90% of S.N. is depleted. This may occur through life. Insult in youth may lead to earlier onset.
    4. Rx is replacement therapy--l DOPA. precursor to dopamine. Get nigral-straital connection going again.
    5. Neurolepetics. Block DA. Causes parkinsonian symptoms. Alleviated with benzotropine (cholinergic agonist).
    6. Chronic blockade of DA: receptor supersensitivity. Over-activity of SN. Too much movement. Tardive dyskinesia.
  3. MPTP methylphenyltetrahydropyridine
    1. 30-40 Y.O. drug addicts on West Coast
    2. Detective story. A group suddenly came down with P.D in 1983. Traced to one source of supply and ultimately to one underground chemist.
    3. Produces signs and symptoms identical to P.D. in all primates.
    4. Points to environmental cause.
    5. Research prompted by it.
    6. MPTP --> MPP+ in presence of MAO.
  4. Tardive Dyskinesia/nigral-striatal loop.
    1. Halopridol: blocks DA receptors. Note: benztropine-> anticholinergic. Blocking Da releases inhibition on the Ach--they become overactive, benz inhibits instead.
    2. P.D.: Da neurons die.
    3. Huntington's: ACh neurons die. Decreases inhibitory output b/c of GABA. S.N. becomes too active.
    4. Tardive dyskinesia. Increases dopamine sensitivity through denervation supersensitivity.

  5. Cerebellum
    1. Among the oldest structures phylogenetically.
    2. Overall structure:
    3. Draw on board:
    4. Lateral zone, intermediate zone, vermis, flocculonodular lobe. Now the structures. Carlson does this anatomically, I'll do it functionally (from Neurobiology of Disease book)
    5. Vestibulo-cerebellum (flocculonodular in Carlson).
    6. Cerebrocerebellum. Poorly discharged ballistic movement. Impairment in highly trained movements. Poor aim.

Functional group Cerebellar loci Location Afferents Efferents Function Damage


Flocculonodular Lobe Caudal end vestibular system vestibular nuclei oculomotor, coordination of gaze smooth visual pursuit

disordered gaze, vertigo, nystagmus, oculomotor reflex (to compensate for head mvts)
Vermis Midline -- auditory visual from tectum

-- cutaneous and kinesthetic from spinal cord

Fastigial nucleus and then to

-- vestibular nucleus

- reticulo-spinal tract (Ventro-medial cortical Brainstem-spinal/flexor and extensor of legs).

posture, walking. Impaired antigravity, alternating limb mvts when walking. Drunken gait.


Intermediate Zone, interposed nucleus cerebellar cortex, intermediate lobe. -- Motor ctx.

-- Spinal: GTO, spindle.

-- alpha & gamma motor neurons

-- thalamus

-- red nucleus--> dorsalateral, cortico-brainstem-spinal.

Initiate movement, control motor neurons in walking.

relate actual movement to plans

limb rigidity.

Cerebellar tremor

Slow/impede modulation of muscle mvt in response to velocity or position,

Impaired repetition flexion/extension



Lateral zone Lateral cortex. from motor cortex (note: none from spinal cord), via pontine nucleus, to motor cortex via dentate (deep cerebellar) nucleus smoothness of skilled movement

program ballistic movements.

C: weakness, decomposition of movement (short and jerky, rather than smooth) Long reaction time, impaired ballistic movements


  1. All species, some more than others,
  2. Note amount of energy and behavior devoted to finding a safe place to sleep.
  3. Transparency. Stages of sleep.
  4. Resting and awake.
    1. Alpha waves. Regular oscillations. about 8-12 Hz. .
    2. Beta waves. irregular, low-amplitude, high-frequency.
  5. NREM Sleep.
    1. Stage 1. Transition stage. If awakened, sometimes report that they weren't asleep. Theta waves(3.5-7.5 Hz). irregular, jagged, low in voltage.
    2. Stage 2. K complex. (abrupt high-magnitude, low-frequency waveform (like an electric sigh).
    3. Stage 3 and 4 (Slow-wave sleep/SWS). Can be hard to distinguish from one another, but stage 4 is much more dominated by delta activity (very high amplitude, low-frequency (< 3 Hz) activity. This period may permit brain to rest.
    4. Sleep spindles. Short-bursts of activity (low-magnitude, 12-14 Hz) at all stages.
  6. REM sleep
    1. Eugene Aserinsky and Nathaniel Kleitman. Studying EEG and alertness in children. 1953.
    2. EEG like awake. ("desynchronized").
    3. Muscles limp. Lack of muscle tonus.
    4. Rapid eye movement.
    5. Vaginal secretion/penile erection.
    6. Narrative, vivid dreams. (During slow-wave can be more static, sometimes nightmares).
    7. all mammals and birds.
    8. deprivation and rebound.
    9. Sleeping pills (barbiturates, benzodiazepines).
    10. Clinical depression-> too much REM, little stage 4. (see end of book).
  7. Basic rest-activity cycle (BRAC).
    1. Cycling between REM and NREM.
    2. Kleitman (1961) pointed out others, including performance on vigilance tasks, eating, drinking, heart rate, oxygen consumption, stomach motility, urine production.
  8. Dreams
    1. Housekeeping: sorting and organizing? (narrative aspect is a secondary byproduct).
    2. Secret desires? (narrative is of primary importance.)
    3. Flushing the synapses?
  9. Sleep as restorative process? Human studies.
    1. Sleep deprived humans.
    2. Little difficulty with physical activities.
    3. No change in physiological stress (i.e.changes in cortisol and epinephrine which result from chronic stress).
    4. With severe deprivation, e.g. staying awake for 264 hours (11 days) in order to set a record, only slept for 15 hours and he was fine.
  10. Animal studies.
    1. Yoked control procedure.
  11. Exercise and sleep.
    1. Even bed-ridden individuals sleep, similarly to normals.
    2. A relationship may exist between body-temp. elevation and sleep-and exercise elevates both temp. Any elevation in body temp during the day increases sleep that night. (note experiment in book, do not cover in class).
    3. Mental activity. Cortical activity, even that produced by applying a vibrator to a finger, produced more delta activity in that portion of the brain at night.
  12. Chemical control of sleep.
    1. Benzodiazeines.
    2. aspirin or ibuprofen.
  13. Neural control of arousal.
    1. Brain stem reticular formation: general arousal (NE).
    2. Basal forebrain. (ACh)
  14. Cycling of REM/NREM sleep. Control in Pons (predator/prey?).
    1. Note figures 8.11, 8.13, 8.15.
    2. Stack them up.
  15. Acetylcholine.
    1. Paribrachial area of pons
    2. Active just before and during REM sleep. may trigger onset of REM sleep and efferents may inhibit ARAS. or cortical structures. Activity leads to PGO waves, REM, cortical activation.
    3. ACh activity from magnocellular regions produces paralysis of descending motor fibers.
    4. ACH also inhibits Dorsal raphe and Locus Coeruleus.
  16. Norepinephrine and Serotonin.
    1. Dorsal raphé.Raphé contains much serotonin.. Once thought to be primary NT involved in onset of sleep. Health food stores sold tryptophan, precursor to serotonin. Not real effective. Tryptophan also in milk products (warm milk before bed?).
    2. Raphé means seam. System is located medially in brain stem, close to a line joining halves of the hindbrain.
    3. Locus Coeruleus. catecholamine. efferents go widely to brain. Apparently suppresses sleeep. Activity falls to zero (actively inhibited) during REM sleep.
  17. General points.
    1. Cycling of sleep/arousal and of REM/NREM sleep is distributed across the brain.
    2. No central executive mechanisms, probably, but rather interactions of excitation and inhibition.
    3. Neurochemical processes account for actions of drugs.
    4. Such an elaborate process, that occurs across many species has to be important.
  18. Neurochemistry.
    1. 5-HT agonists.
    2. 5-HT antagonists.
    3. NE. Active when awake, less active when asleep.
    4. Acetylcholine.
    5. Caffeine decreases stage 4 a lot.
    6. Aging. Decreases acetylcholine and REM
    7. Depression.
    8. Amphetamine withdrawal (REM rebound).

Basic Rest/Activity cycles.

  1. First different diurnal cycles, then about sleep.
    1. Circadian rhythms (daily)
    2. Ultradian (faster than a day).
    3. Zeitgeber.
    4. Importance
  2. measurement.
    1. Simply note when go to sleep or awaken.
    2. Activity. running wheel, attach an actimeter, etc.
    3. Type of information. Gross activity. Elevator example. Look at photocell breaks on elevator to get activity of Haley Center.
    4. Could get daily rhythms, hourly rhythms (ultradian) rhythms.
    5. Then ask what causes them. How can we produce or eliminate them?
    6. Endogeneous or exogeneous? remove or add cues.
  3. How does sun (light) act?
    1. through eyes?
    2. Curt Richter. blind rats. Then ask further, blind along optic tract. note eliminate by blinding anterior but not posterior of chiasm. Suprachiasmic nuclei is important. Fibers come from optic nerve up to SCN. not tract.
    3. but still a rhythm. in humans 25 hours (recent data, more slightly more than 24 hrs). Sun marks the time but is not the whole.
  4. Jet lag.
    1. Going west is easier because one can sleep late.
    2. Stay in the sun.
  5. Shift work. Rotate through later shifts (day, evening, night) takes less time to adjust than other direction. Also lots of lights in the room.


  1. Feedback system
    1. Open loop (no feedback) vs closed loop (feedback).
    2. Negative feedback: Control signal minus output results in a new command.
    3. Examples:
    4. Positive feedback. Explosive.
  1. Body temp maintained at a constant level. 37o C or 98.6o F. this set point can vary with time of day. (Drops when asleep)
  2. Sensors
    1. peripheral temp. receptors in skin
    2. Hypothalamus
    3. Homeostasis. (Walter Cannon)
  3. Controlled by hypothalamus. important areas are preoptic area (heat dissipation) and posterior (head conservation). Separate controls. Sources of influence are from peripheral temperature detectors and local (hypothalamic) detectors.
    1. Mechanisms of warming up: behavioral (moving to warm place), shivering to generate energy, vasoconstriction to get blood away from skin and embedded in fat.
    2. mechanisms of cooling off, behavioral, vasodilation, spreading out (dog on porch), panting, sweating.
    3. Local control.
    4. hypothalamus. Afferents from peripheral temp receptors embedded in skin. There are separate ones for warmth and cold. Efferents to autonomic, endocrine, and skeletomotor responses.
Stimulate Lesion Local warming Local Cooling

(responsible for keeping cool)

Dilate blood vessels



hyperthermia cool air is reinforcing cool air not reinforcing.

(responsible for keeping warm

Constrict B.V.




  1. Fever. (Kluger, M.J. 1979) Iguana (ectotherm).
    1. Place iguana on a thermal gradient, cool on one end, warm on the other.
    2. Places itself in middle: 98o
    3. Infect with flu virus: positions self in warm part of gradient: gives self a fever.
    4. Prevent this from happening: Ill longer, more likely to die
Core Temperature Set point Difference Response
98 101 +3 conserve heat, warmth is a reinforcer.
101 101 0 maintain status quo
101 98 -3 give off heat, sweat, cool is reinforcing.

  1. Drinking
    1. Note, to maintain homeostasis need detector, setpoint(s), and effector
    2. Homeostatic. Maintain constant, 0.15 M solution of solutes (isotonicity).
    3. Hypovolemic
  1. Starting and stopping appear to be controlled separately.
  2. Note problems to be solved.
    1. Food needs to be controlled and selected
    2. Glucose not lipid soluble, membranes are not.
    3. Food must be stored.
    4. Meals neet to start and stop.
    5. No way of knowing body weight.
    6. Food has multiple functions: glucose, nutrients, etc.
  3. Peripheral factors
    1. Flavor
    2. Aversions (and proclivities) show plasticity through life.
    3. Respondent. Pair flavor with distress, then distress elicited by flavor. (me and gin).
  4. Stomach: two stimuli
    1. distention. Test, (Deutsch).
  5. Duodenum
    1. secretes cholecystokinin (CCK). Secretes as hormone into bloodstream when food released. Is this relevant?
  6. Glucose/insulin cycle.
    1. Eat --> food digested --> glucose absorbed in blood

insulin -----> enters cells (if insulin is present) and converted to fat or glycogen.

    1. As glucose declines, glucoreceptors pick it up, and get hungry. Note also that glucose can no longer enter cells, BUT CAN enter CNS.
    2. Glucagon. Hormone released by pancreas (e.g., during food deprivation). Stimulates liver to convert STORED glycogen
    3. diabetes mellitus:
  1. Storage of energy:
    1. Shortterm
    2. Long term
    3. Multiple rules of insulin
  2. Central mechanisms
    1. Lateral Hypothalamus.
    2. Ventromedial. Damage. eat a lot, gain wait, less responsive to glucose, finicky eaters, will not work as hard to get food.. Normal meal size the same, buteat more frequently. So not because of interference with offset of eating (as wth CCK)
    3. Cause may be that ventromedial damage produces increased insulin production. Cauuses greater storage of food as fat. They eat because they store so much fat.
    4. Neurotransmiters. 5 HT, decreases carbohydrate intake.
  3. Discrimination of satiety: Corwin, Woolverton, and Schuster, 1992
    1. Interest in internal cues to decrease eating. Also, roles of CCK, 5-HT (via fenfluramine) and NE (via d-amphetamine).
  1. Emotions.
    1. Behavior is multiply determined.
    2. Has been noticed for some time now that there is a correlation between emotional states and autonomic arousal. Anger, fear, and intense emotions associated with sympathetic arousal (goose bumps from piloerection, autonomic stimulation, porcupine quills and cat fur).
    3. This is a correlation of A and B. Question: Does A cause B, B cause A, or something else cause both A and B?
    4. Ulcers. Holes in stomach. formed by acid and breaks in lining. Perhaps formed by parasympathetic rebound after arousal, not during arousal. Because that is when stomach secretions, and acidity, is greatest.

Learning and Memory.

Behavior change, learning.

  1. Types of behavior change
    1. Evolutionary change (doesn't act on an individual)
    2. Changes within a lifespan.
    3. Habituation, sensitization
    4. Respondent conditioning,
    5. Operant conditioning (instrumental conditioning)..
  2. Lashley, search for engram, neural pathways responsible for learning. many brain slices, could find none, equipotentiality.
  3. Hebb synapse. (1949)
    1. If a (weak) synapse is active at the same time a post-synaptic neuron is active, then that synapse becomes strengthened.
    2. Permits formation of an association.
    3. Could only be speculation in 1949. An attempt to identify a set of conditions that could give rise to learning.
  4. Memory
    1. Control by a previously presented stimulus.
    2. Some techiques for studying.
    3. matching-to-sample.
    4. radial arm maze
    5. passive avoidance/active avoidance, consolidation.
  5. Long-term potentiation.
    1. Prolonged change (depolarization) in the resting potential of a neuron due to some event--such as tetanic stimulation or a pairing of two events.
    2. Note, long-term depression would be similar, but a hyperpolarization.Requires: 1) activation of synapse and 2) post- synaptic depolarization.
    3. Tetanic stimulation. Show transparency.
    4. Associative long-term potentiation. LTP due to simultaneous occurrence of 1) activation of strong synapse and 2) activation of a weaker synapse.
  6. Associative conditioning in hippocampus. (Associative LTP)
    1. Hippocampus circuit.
    2. See figure in Carlson.
    3. Kelso and Brown (1986)
  1. NMDA receptor. (n-methyl-d aspartate)
    1. Participants include magnesium, NMDA/Glutamate receptors, and some other receptor. Also, K and Ca.
    2. NMDA receptor sits close to a channel that normally has magnesium blocking it. An excitatory amino acid stimulates it, but because of the magnesium nothing happens.
    3. Depolarization ejects the magnesium, but the channel closes if the receptor is not stimulated.
    4. Simultaneous depolarization AND stimulation opens the channel, ejects the magnesium, and permits the inrush of positive ions, which makes tends to keep it depolarized.
    5. This does not occur IF an NMDA antagonist is administered prior to the pairing.
    6. If the nmda antagonist is administered after the pairing then no effect.
  2. Summary:
    1. Glutamate opens channel.
    2. A.P. ejects magnesium
    3. Glutamate + A.P. opens channel and expels Mg. Ca++ enters, acts as second messenger and initiates long-term changes responsible for potentiation.
    4. Postsynaptic change: Calcium activates protein kinases. (postsynaptic change)
  3. Mechanisms of post-synaptic strengthening.
    1. Increase number of receptors.
    2. Increase communication betweeen postsyaptic membrane and rest of neuron-> greater effect of EPSP. Increased sensitivity.
    3. Kinase: a class of enzymes capable of adding a phosphate group to certain proteins. Activated by Ca. Induces relatively permanent change.
  4. Mechanisms of pre-synaptic strengthening.
    1. Presynaptic (retrograde)/nitric oxide

Dopamine and the Neural Substrate of Primary Reinforcement/Instrumental conditioning and Motor Learning.

  1. Definition of operant conditioning.
  2. Basal ganglia.
    1. Controls movements.
    2. Controls sequences of behavior.
    3. Afferents from cortex (sensory association/motor association ctx)
    4. Returns processes to cortex, closer to motor ctx.
    5. Processes also contact midbrain dopamine pathways involved in reinforcement.
    6. Assembles sequences of movements. As movements become automatic, become managed by basal ganglia.
    7. Parkinson's disease. Substantia nigra (in B.G.) dies. movements become controlled again.
  3. Electrical Brian Stimulation. Review definition of reinforcement.
    1. Olds and Milner, 1954. Implanted small electrode to brain. Attempting to identify sources of arousal in the midbrain. Neil Miller had recently reported aversive effects of electrical brain stimulation in regions in the midbrain. They experimented with electrode placement, and discovered that, instead of being aversive (or even generally arousing) that rat kept going to place where stimulus train was delivered.
    2. Replicated with lever. permitted finer control over deliver, response and contingencies.
    3. Pressed lever to do this. Almost to the exclusion of all else.
    4. Can be done successfully when electrode is in olfactory bulb, prefrontal ctx, nucleus accumbens, caudate, putamen, some thalamic nuclei, reticular formation amygdala, VTA, SN, LC, MFB.
  4. Dopamine
    1. A common link to all of these areas is dopamine. Three pathways are present. Two pathways are important to reinforcement, the third to movement.
    2. Remember that the reinforcer acts on the response, not the organism!
Nigral/striatal (movement, some learning?) Meso-limbic Meso-cortical
Afferents {inputs from basal ganglia} {inputs from cortex, hypothalamus, pre-optic areas.}
Source (cell bodies) Substantia Nigra

Ventral Tegmental Area

Destination (Terminals)

Note: Fibers found in MFB

Amygdala Hippocampus
Striatum Septum Limbic cortex
Nucleus Accumbens Prefrontal cortex
olfactory tubercle

  1. SN and VTA are midbrain (tegmental) areas.
    1. MFB particularly sensitive to EBS.
    2. VTA receives afferents from lateral hypothalamus and preoptic areas (close to hypothalamus, important in temp regulation, among other things), cortex, and amygdala. (Establishing operation?)
    3. These afferents also go through MFB to other areas, including nucleus accumbens.
  2. To tease all this apart. Experimental strategies follow.
  3. Link to hippocampus. Stein, L, Belluzzi, J.D. (1987). Reinforced activity in a single hippocampal cell with infusion of dopamine.
    1. Hippocampus slice.
    2. Recorded from single neuron in CA1 (output region) of hippocampus.
    3. These neurons contains dopamine receptors so cell bodies lay elsewhere.
    4. When there was a 0.5 second ( sec) burst of firing, they applied a small amount of DA thorough a small pipette.
    5. Conditions for dopamine. Baseline, contingent DA, noncontingent DA (so it wasn't that DA was nonspecifically stimulatory).
    6. Then repeated with cocaine (equally effective) and saline (ineffective).

Modification of EBS:

  1. Systemic self-administration of dopamine agonists. As described above, with S.A. will elaborate on this later.
  2. Systemic administration of DA ANtagonists.
    1. Rolls et al., 1974. Rats pressed a lever for food, water, or EBS. Spiroperidol (systemically) suppressed responding.
  3. Dopamine antagonists in N.A.
    1. Stellar et al. Response contingent electrical stimulation in media forebrain bundle suppressed by application of dopamine antagonist in N.A.
  4. Dopamine agonists serve as reinforcers when administered directly in these regions.
    1. SA of dopamine agonist into nucleus accumbens, VTA is possible (e.g., of cocaine or d-amphetamine).
    2. Antagonist studies. To see which part of MFB is rf.
    3. Agonist studies. Cocaine decreases amount of current required for EBS.
    4. Note! Administration of glutamate antagonist into VTA also blocks intracranial stimulation.
  5. Microdialysis.
    1. Note figure 12-22. EBS -> release of dopamine in N.A..
    2. Natural reinforcers increases dopamine release in VTA. (water, food, sex)
    3. Cocaine increases lever pressing and release of dopamine.
    4. Under conditions of fluid deprivation, drinking water provokes release of DA into NA. But not under other conditions.(this is done in behaving animals, microdialysis.)
    5. Conditioned reinforcement (stimuli paired with a primary reinforcer) provoke release of dopamine in nucleus accumbens.
    6. So, release can be specific to what is established as a rf. by the hypothalamus, pre-optic areas, etc. (note, cocaine or drug abuse bypasses these modulators of reinforcement).
  1. Summary.
    1. In general, structures behavior according to prior consequences. Permits structure in behavior to reflect structure in a changing environment.
    2. Inputs from VTA (which receives inputs from hippocampus, hypothalamus), help organize what contexts are reinforcing.
    3. Outputs to cortex send the results and guide behavior.
    4. Dopamine is a player in reinforcement
    5. Suspect drugs that influence dopamine as reinforcers.
    6. Central pathways seem to mediate reinforcement, but these pathways have fingers distributed into many other areas of the brain.
    7. Potential links to events that establish reinforcement stimuli.
    8. Potential links to hippocampus, seat of memory, among other things.


  1. Neurons that mediate a delay interval.
    1. Delayed MTS procedure.
    2. Manipulation of DMTS responding.
    3. Identify a neuron that responds when a red light, but not a green light, is presented during a delay interval. (Fuster and Jervey, (1981) / desc. In Carlson).
    4. Administer electrical stimulus to ctx. This is similar to stopping rehersal. severe disruption. (Covner and Starmm, 1972).
  2. Human anterograde amnesia.
    1. Korsakoff's syndrome. Anterograde amnesia (inability to recall events that occur after an injury). Associated with heavy drinking. Thiamine deficiencies.
    2. Removal of temporal lobes.
  3. H.M.
    1. Severe epileptic
    2. Temporal lobes and hippocampus removed.
    3. Hippocampus. no effect on iq. moderate retrograde amnesia (immediately before surgery). Complete anterograde amnesia. could not store/consolidate certain events.
    4. Model of memory: sensory information-> short-term memory -> (consolidation) -> long-term memory.
    5. many procedural tasks could be accomplished.
    6. Declarative memory
    7. Nondeclarative meory.
    8. Concluded from this and others that
    9. pretty much limited to talking about things. new tasks could be acquired, but could not say that they were acquired.

Day Room Experimental Group Control goup
1 Food Haloperidol (systematic) Saline
2 no food Haloperidol sal
3 food Haloperidol sal
4 nofood Haloperidol sal


. repeat for 8 days.

TEST Choice no room preference chose "food" room

    1. Conclusion. HAL interfered with the acquisition of place preference. With acquisition of that stimulus having reinforcing properties.

To nail down need: dose effect, other drugs, better quantification.

  1. Drug discrimination.
    1. Powerful demonstration of reinforcing stimulus properties of cocaine.
    2. Wood and Emmett-Oglesby. (1989) Rats trained to discriminate systematic cocaine and saline. During test days cocaine adminstered to NA, caudate, prefrontal. Cocaine lever only pressed when administered to NA.
  2. Intracranial stimulation.
    1. SA of dopamine agonist into nucleus accumbens, VTA is possible (e.g., of cocaine or d-a).
    2. Antagonist studies. To see which part of MFB is rf.
    3. Agonist studies. Cocaine decreases amount of current required for EBS.
  3. Microdialysis.
    1. Reinforcement increases dopamine release in VTA. Cocaine increases lever pressing and release of dopamine.
  1. Summary

  1. Korsakoff. severe thiamine (vitamin B1) deficiency. Thiamine required to metaboloze glucose. retrograde and anterograde amnesia.
  2. Learning in Aplysia.
    1. Transparency of aplysia.
    2. Flaps, and siphon
    3. Stimulate siphon, gill withdraws.
  1. Substance Abuse.
  1. Old definition of addiction: physical addiction.
    1. Based on heroin withdrawal.
    2. Associated with tolerance.
    3. Withdrawal symptoms always the opposite of the drugs' effects.
    4. Heroin->euphoria, constipation, relaxation, analgesia.
    5. Heroin withdrawal-> dysphoria, diarrhea/cramping, agitation, sensitivity to pain
    6. Alcohol/tranquilizers--> sedation, hypnotic actions, diminished seizures.
    7. Alcohol/tranquilizer withdrawal-> anxiety, sleeplessness, enhanced seizures (potentially fatal).
    8. Neither necessary nor sufficient.
    9. Cannot explain first use.
    10. Drug addicts undergo repeated withdrawal.
  2. Current definition. Focus on common features.
    1. Reinforcing properties of drugs. animal and human studies.
    2. Negative reinforcement. e.g., avoidance of withdrawal.
    3. Tolerance.
    4. Craving/relapse.
  3. Commonly abused drugs.
    1. Common feature is dopamine. Necessary, but not sufficient.
    2. amphetamine, cocaine, opiates, nicotine, alcohol, sedative/hypnotics, barbiturates PCP, cannabis release dopamine.

Physiological and Behavioral Tolerance

  1. Tolerance
    1. Diminished effect of a drug as a result of repeated exposure to that drug.
    2. To understand sequence of events in drug action: administer->blood->site of action.
    3. Protracted.
    4. Acute (tachyphylaxis).
    5. Mention sensitization. Enhanced effect. Won't cover here.
  2. Metabolic (dispositional).
    1. Increase in rate of metabolism or elimination.
    2. Same dose->lower blood levels.
    3. Pentobarbital and sleeping duration in mice. (From H. Remmer as summarized in Julien).
  3. Pharmacodynamic tolerance.
    1. Changes at the synapse that result in diminished sensitivity to the same blood level.
    2. Same dose-> same blood level->diminished effect.
  4. Mechanisms for pharmacodynamic tolerance. (Examples come from opiate pharmacology in Feldman, Meyer, and Quenzar). Exemplary, not exhaustive.
    1. Down-regulation of peptide synthesis. With repeated exposure, less opiate peptide (or its precursor) is synthesized. The production by mRNA is reduced.
    2. Down-regulation of receptor number. Repeated administration->fewer receptors. Note: Julien defines this incorrectly.
    3. Reduced sensitivity of the receptor.
  5. Behavioral tolerance: respondent mechanisms.
    1. Repeat exposure in a particular setting. The setting becomes a CS that elicits a "compensatory" response.
    2. Room-> heroin -> core temp, respiration.
    3. Room -> compensatory response ( temp, respiration.
    4. Administer in absence of context, can be fatal.
    5. Siegel, S, Hinson, R.E., Krank, M.D., and McCully, J. (1982). Heroin "overdose" death: Contribution of drug-associated environmental cues. Science, 216, 436-437.
    6. Rats, daily i.v. injections in one of 2 rooms for 30 days. Even days, heroin, odd days, vehicle.
    7. Group 1. (Heroin->colony) Heroin in colony room, Vehicle in different room with constant white noise.
    8. Group 2. (Heroin-> noisy room) Heroin in second room, vehicle in colony room. Association between a room and heroin remained intact.
    9. Group 3. (Control) all vehicle injections: of vehicle injections in colony room, in noisy room.
    10. Then give a high dose. (15 mg/kg):
    11. Room-> heroin-> direct effect.

Room-> compensatory response.

    1. If compensatory response could not occur. Animals died.
    2. Tolerance related to withdrawal. Unclear how. But environment can elicit a compensatory response, then could induce cravings.
    3. Other drugs. Also other interventions: e.g., insulin.
  1. Behavioral tolerance, operant mechanisms. Adjustment to impairment..
    1. Behavioral augmentation of tolerance. From LeBlanc et al. See also Goldstein, Pharm. of Alcohol.
    2. Moving belt test. Before after design.
  2. Behavioral tolerance.
    1. Term introduced by Schuster (e.g., Schuster, Dockens, Woods, 1966. Behavioral variables affecting the development of amphetamine tolerance.
    2. Schuster et al.'s experiment 1. (not the best, but seminal).
    3. Reinforcers earned after before, during, and acute d amphetamine.
Rat 2 Rat 4 Rat 5
Pre-chronic (no drug) 55 29 55 26 55 31
Day 1 of chronic 54 9 41 19 55 16
Day 5 of chronic 54 20 54 23 54 30
Tolerance after DEC? no yes yes some no yes

    1. repeat dose-effect curve.
    2. Experiment 2. Sidman Avoidance.
    3. Experimental design. for tolerance.

Substance abuse.

  1. Some early (and in many quarters, still current) views on substance abuse.
    1. Early in century. Thought that only humans could become addicted to drugs. A. R. Lindesmith, a sociologist, argued that " . . . only those to whom the drug's effects can be explained can become addicts" and "certainly from the point of view of social science it would be ridiculous to include animals and humans together in the concept of addiction." (quotes from Laties, 1986, Hx of B. Pharm in Adv. Behav. Pharm. Vol 5). Among the reasons were that it was thought that only humans could feel pleasure, could associate pleasure with other events (such as a drug), and could come under the control of other pleasurable events (in a sense, only humans could sin).
    2. Weak character. In some quarters this thinking still exists, although in a more disguised form. "Not the toxic agent but the impulse to use it, makes an addict." "we feel impelled to regard all types of drug cravings as varieties of one single disease "The group of human beings who respond to frustration in life with a special type of emotional alteration which might be designated tense depression marked by great painful tension and at the same time by a high degree of intolerance to pain.' How does one treat this? and is it even true? and what is it based on but examining people who already have a hx of drug use. Does it predict that an animal could become addicted?
    3. Blame the mother.
    4. Pharmacological.
    5. Behavioral/ drug as reinforcer. Makes contact with both pharmacological, y focusing attention on the drug, and behavior, bu bringing in the 3-term contingency.
  2. Shirley Spragg, 1940, at Yerkes in Fla. (Described in Laties, Lessons from Behavior Pharm., Adv. in Beh. Pharm., Vol. 6).
    1. Administered morphine twice daily to a chimp.
    2. Then, during withdrawal, the chimp aggressively pulled Spragg to the room containing the syringe. Single counterexample is sufficient to show that nonhumans can be addicted. After withdrawal complete, chimp lost interest.
  3. Spragg thought only apes would be capable of addiction.
    1. "Lower" species could not form associations over time.
    2. Spragg did not have the conceptual framework, e.g., the three-term contingency, to understand his observations. (More of a demonstration than an experiment.)
    3. Results basically uninfluential.
  4. Three-term contingency.
    1. Stimulus (antecedent conditions), responses, and consequences and stimuli.
    2. Thompson and Schuster (1964)--morphine self-administration.
    3. (Pickens and Thompson, 1968). S.A. of cocaine.
    4. Identifying aversive consequences.
    5. Without first contact drug cannot exert control.
    6. With contact drug delivery (or other positive reinforcers) exert control.
  5. Note importance of mechanism.
    1. Two sorts of mechanisms are understood
    2. Certain drugs participate in behavior as reinforcing consequence. Generality from other reinforcers or aversive events (withdrawal).
    3. Certain pharmacological classes. So if a drug is a dopamine agonist, then can immediately infer how it should act, how abuse might be managed, etc.
    4. Contact with other research.
    5. Application of results from different lines of research.
    6. Permits identification of similarities and differences.
  6. Not all users become abusers. With the exception of nicotine, most users do not become abusers. Question, then, is how do we increase or decrease the liklihood that the reinforcer exerts control. That is: under what conditions is substance abuse more likely to occur.
    1. Note, drug-taking has behavioral and pharmacological influences.
  7. Pharmacological variables.
    1. Mechanisms of action (dopamine is important, but not the only player).
    2. Drug: note different pattern for ethanol and morphine self-administration by human and monkey.
    3. Dose
    4. Route
    5. Tolerance/withdrawal.
  8. Behavioral variables.
    1. Response Cost.
    2. Delay of Reinforcer (e.g., Lattal's work).
    3. Alternative reinforcers. (AA based on this?)
  9. Pharmacological variables have been discussed, behavioral variables are also important. ID drug as a reinforcer permits one to bring in all that is known about this type of behavioral control, from other reinforcers (just like understanding receptors allows one to bring in a lot of neuroscience).
    1. Importance of delay (weakness of delayed reinforcement)
    2. Importance of alternate activities.
    3. Ratio value, (show Moreton, 1977)
    4. Delay to rf. Contact with route
    5. alternate activities. b= kR/(R+Ro)
  10. General principles of pharmacology and of behavior together can be used to understand drug abuse at the individual level.
    1. Kinetics-describe how quickly a drug can be delivered to the site of action.
    2. Delay of reinforcement--shorten and have more powerful control.

  1. Discriminative Properties of drugs.
    1. Three-term contingency
    2. Definition of discriminative stimulus.
    3. Most work done with exteroceptive stimuli. Assertion that science applies to interoceptive stimuli, as well.
    4. General tactic.
  1. Sedative/hypnotics.
    1. Barbiturates, ethanol (and other alcohols), benzodiazepines.
    2. General effects
    3. Common effects:
    4. Five principles:
    5. Tolerance.
    6. Receptor actions.
  1. Ethanol is the active ingredient so as long as it is around, one is intoxicated.

New Drug Development.

  1. Goals
    1. Safety
    2. Efficacy
    3. (Profitability)
  2. Drug discovery
    1. Serendipity
    2. Natural products.
    3. Synthetic chemicals.
  3. Preclinical pharmacology/animal studies
    1. Screening, initial dose-effect determination.
    2. Initial evaluation of potential usefulness.
    3. Animal models of disorders
    4. Anti-punishment effect, hole-board-> sedative hypnotics
    5. Suppression of avoidance, but not escape-> neuroleptics
    6. DRL 72" -> antidepressants
    7. Drug discrimination.
  4. Toxicity testing.
    1. Assessment of lethality, toxic effects, margin of safety.
    2. End of preclinical psychopharmacology, beginning of clinical trials.
    3. IND (Investigational New Drug) requirements. (1987)
  5. Formulation.
    1. Other ingredients, absorption, kinetics, ability to tolerate, etc.
  6. Clinical trials.
    1. Figure showing time course.
    2. Time Course for the Clinical Trials portion of New Drug Development (From Levine, 1990)
Number of Patients Length Purpose Percent of Drugs Successfully Completing1
Phase 1 20-100 Several Months Mainly safety 70
Phase 2 Up to several hundred Several months to 2 years Some short-term safety, but mainly effectiveness 33
Phase 3 Several hundred to several thousand 1-4 years Safety, effectiveness, dosage 25-30%
1For example, of 100 drugs for which investigational new drug applications are submitted to FDA, about 70 will successfully complete phase 1 trials and go on to phase 2; about 33 will complete phase 2 and go on to phase 3; and 25 to 30 will clear phase 3 (and, on the average, about 20 of the original 100 will ultimately be approved for marketing.)

  1. Accelerated approval
  2. Approval
    1. FDA must respond within 180 days of submission.
    2. Postmarketing surveillance (phase 4).
    3. Patent protection.
    4. Off label use.
  3. Orphan drug act (1983).
    1. Rare diseases. Affects fewer than 200,000 Americans. About 2,000 of these.
    2. 2/3 of the cost of development may be deducted from taxes.
    3. Exclusive use permitted for 7 years.
    4. Priority can be granted for review.
    5. Funds can be provided to help develop them.
  4. Center for Drug Evaluation and Research. (CDER)
    1. Branch of FDA that guides this approval process.
    2. User fees. To ensure proper staffing so the process can continue.

  1. Schizophrenia
    1. Definition.
    2. Dopamine
  1. Depression.
    1. Unipolar. Only depressed.
    2. About 5% of population at some point in their life.
    3. Diagnosis: at least 5 of
    4. Bipolar. Above, but alternates with periods of mania. (manic depression).
    5. Exogeneous.
    6. Genetic?
    7. Endogenous, virus (e.g. Epstein-Barr, Borna?)
    8. Chemical changes.


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