Hecht GS PSYC 377 Exam 3 Study Guide

an exogenous chemical not necessary for normal cellular function that significantly alters the function of certain cells when taken in fairly low doses.

drugs that alter mood, thought, or behavior --most used to manage/treat psychopathology; some used recreationally.

A Cartesian Plot in which the X-axis plots concentration of a drug or hormone. The Y-axis plots response, which could be almost anything. For example, the response might be enzyme activity, accumulation of an intracellular second messenger, membrane potential, secretion of a hormone, heart rate or contraction of a muscle. Remember that the term "dose" strictly only applies to experiments performed with animals or people, where you administer various doses of drug. However, the term "dose-response curve" is also used more loosely to describe in vitro experiments where you apply known concentrations of drugs. Dose-response experiments typically use 10-20 doses of drug, approximately equally spaced on a logarithmic scale. For example doses might be 1, 3, 10, 30, 100, 300, 1000, 3000, and 10000 nM. When converted to logarithms, these values are equally spaced: 0.0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0. Note: The logarithm of 3 is actually 0.4771, not 0.50. The antilog of 0.5 is 3.1623. So to make the doses truly equally spaced on a log scale, the concentrations ought to be 1.0, 3.1623, 10.0, 31.623 etc.

Routes of Administration: The first phase (step) in the study of pharmacokinetics

vehicle: Must be inert and compatable with the tissues being "invaded" by the needle.

s.c.: subcutaneous or "sub-q"-- the needle (and drug/vehicle bolus) is placed under the most superficial layers of skin but above the underlying muscle tissues-- results in slow, sustained pharmacokinetic absorbtion profiles.

i.m.: intramuscular -- the needle (and drug/vehicle bolus) is placed into the belly of large striated muscle tissues-- results in more rapid pharmacokinetic absorbtion profiles than sub-q.

i.p.: intraperitoneal -- the needle (and drug/vehicle bolus) is placed into peritoneal cavity containing all of the abdominal organs-- results in more rapid pharmacokinetic absorbtion profiles than sub-q or i.m.-- very rarely used in humans because of our unique abdominal musculature.

i.v.: intravenous --the needle (and drug/vehicle bolus) is placed directly into a vessel of the venous circulatory system-- results in extremely rapid pharmacokinetic profiles --in a sense absorbtion is "bypassed". In animal research a permantly inplanted i.v. catheter may be employed to examine behavioral phenomena such as drug self- administration (yes animals will use drugs recreationally and will even "pay" more for drugs they really "like").

substances tend to move from areas of high concentration to areas of low concentration until concentration is equal in both areas.

Diffusion works between liquids and gasses --lungs are an efficient gas exchange system: oxygen in-CO2 out --Smoke and solids --snuff - tobacco, cocaine, heroin, etc.

Digestive system --lipid barrier between food and blood; lipid solubility determines

The tendency for acid drugs to get trapped on the basic side of a membrane and basic drugs to get trapped on the acid side of a membrane. Only nonionized molecules can diffuse through membrane. They reach equal concentration on both sides. The law of diffusion only applies to the nonionized molecules.Thus, only the concentration of nonionized molecules will be equal on both sides of a membrane.

This section is for those in class (and you know who you are) who needed to know "the mystical numbers" and how one obtains them -- you must not use this knowledge to harm your fellow earthlings or there will be retribution (I'll make you do the calculations on the exam without giving you the formulae --insert evil laughter here).

Acid/base chemistry is a very simple proton transfer equilibrium. A generic example where AH is any acid and A- is the conjugate base is given below.

When we measure the pH of a solution, we are measuring the concentration of hydrogen atoms (actually H3O+) in solution. Strong acids will increase the number of hydrogen atoms and strong bases will decrease the number of hydrogen atoms. By definition a strong base is a weak acid (just look at the equilibrium above).

K = ([H+] [A-] ) / [HA] , for this equilibrium K is called Ka for acid dissociation constant.

Since we are interested in the amount of H+ we need to arrange the equation to just have [H+] in one side.

Traditionally, -log is substituted with a lower case p, so the equation becomes (known as the Henderson-Hasselback equation:

So if we know the pH of a solution and the pKa the acid we can determine how much [A-] and [HA] we have in solution, using the rearranged equation below.

This means that when pH is equal to pKa , [A-] = [HA], or that the acid is 50% ionized.

Now, only the nonionized molecules will be in equilibrium. This means that for each nonionized molecule on side A there will be only one ionized

molecule, but for each nonionized molecule on side B there will be 10,000 ionized molecules. Thus, there will be 10,000 more molecules on side B than side A.

Lipid solubility - highly lipid soluble drugs tend to concentrate in the lipids and water soluble drugs concentrate in body water.

Kidneys: filter everything out and reabsorb what is needed and what is lipid soluble. Reabsorption is altered by pH.

Time course for drug concentration determined by rate of absorption and rate of excretion.

Different for different routes of administration. Half-life: time taken to reduce drug concentration by ½

Therapeutic window: Drug concentration above the therapeutic level and below the toxic level.

The first figure shows the anatomy of the "reinforcement pathway" in a rat brain.

The second and third figures show an exaggerated "close-up" view of a hypothetical synapse between the VTA and the Nucleus Accumbens (The Nucleus Accumbens has different abbreviations in the different figures--so be careful when you are studying--it can have either of the following abbreviations: Acc, NAcc

vtanaimg

Schematic diagram of the brain-reward circuitry of the mammalian (laboratory rat) brain, with sites at which various abusable substances appear to act to enhance brain-reward and thus to induce drug-taking behavior and possibly drug-craving. ICSS, descending, myelinated, moderately-fast-conducting component of the brain-reward circuitry that is preferentially activated by electrical intracranial self-stimulation., DA subcomponent of the ascending mesolimbic dopaminergic system that appears preferentially activated by abusable substances: Raphé brain stem serotonergic raphé nuclei LC, locus coeruleus; VTA ventral tegmental area; Acc, nucleus accumbens; VP, ventral pallidum; ABN, anterior bed nuclei of the medial forebrain bundle; AMYG, amydala; FCX frontal cortex: 5HT, serotonergic (5-Hydroxytryptamine) fibers, which originate in the anterior raphé nuclei and project to both the cell body region (ventral tegmental area) and terminal projection field (nucleus accumbens) of the DA reward neurons; NE, noradrenergic fibers, which originate in the locus coeruleus and synapse into the general vicinity of the ventral mesencephalic DA cell fields of the ventral tegmental area; GABA, GABAerqic inhibitory fiber systems synapsing upon the locus coeruleus noradrenergic fibers, the ventral tegmental area, and the nucleus accumbens, as well as the GABAergic outflow from the nucleus accumbens; Opioid, endogenous opioid peptide neural systems synapsing into both the ventral tegmental DA cell fields and the nucleus accumbens DA terminal projection loci; ENK, enkephalinergic outflow from the nucleus accumbens; DYN, dynorphinergic outflow from the nucleus accumbens; GLU, glutamatergic neural systems originating in frontal cortex and synapsing in both the ventral tegmental area and the nucleus accumbens.

It is now known that the reinforcement or reward system of the brain is mediated by one of the major dopaminergic pathways followed by the Medial Forebrain Bundle (MFB). The MFB sends fibres from neurons of the Ventral Tegmental Area (VTA) to the other forebrain nuclei including the septum and the prefrontal cortex and (importantly) to the Nucleus Accumbens. Animals (including humans) will do a lot of work to receive stimulation to the MFB.

A laboratory preparation can be constructed in which an electrode delivers microlitres of a drug to specific brain regions when an animal presses a lever. Animals will press the lever at extremely high rates for delivery of drugs directly into different parts of the reinforcement pathway (usually VTA or nucleus accumbens) - this is usually accompanied by an increase in DA release at the nucleus accumbens.

All drugs with a potential for abuse appear to (directly or indirectly) increase DA activity in this pathway. Such drugs include: alcohol, cocaine, amphetamine, nicotine, morphine, methadone, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA or ecstasy), phencyclidine (PCP or angel dust) and cathinone. The specific role of DA in this pathway appears to be to decrease activity in the Nucleus Accumbens.

Act on the MFB via opiate receptors on cells of the Ventral Tegmental Area. These opiate receptor containing cells themselves inhibit GABA-ergic neurons which synapse onto the DA pathway. The removal of GABA-ergic inhibition allows the DA cells to fire at a higher frequency thus inhibiting the NA. When the activity of a brain under the influence of morphine is viewed by positron emission tomography (PET), the cerebral cortex shuts down but underlying centres associated with emotion remain active.

These substances both act on dopaminergic nerve terminals which synapse onto cells in the nucleus accumbens and septum. They increase release from the synapse by inhibiting re-uptake of dopamine - indeed amphetamine appears to actually reverse the re-uptake mechanism causing more DA to be released. Cocaine boosts the activity of the whole brain especially the primitive emotional structures. Long-term abusers of amphetamine and cocaine develop psychosis-like symptoms - hallucinations, paranoia, mood disturbances and repetitive behaviours which led to the proposal of the dopamine theory of schizophrenia.

Stimulates nicotinic receptors (a subclass of acetylcholine receptors) including the VTA dopaminergic cells which carry such receptors.. The reinforcing effect of nicotine is therefore believed to be due to its effect on the release of DA in the nucleus accumbens. Although nucleus accumbens neurons carry receptors for nicotine this region does not appear to be directly involved in nicotine's reinforcing effects. Interesting most other drugs of abuse actually decrease ACh activityAlcohol, benzodiazepines, barbiturates, inhaled solvents

In low doses, alcohol appears to act on the brain by stimulating the GABA-benzodiazepine receptor complex (inhibitory), and by becoming incorporated into all neuronal membranes and making them less excitable. In the DA reward pathway alcohol causes an increase in the firing rate of cells in the ventral tegmental area and a consequent increase in the release of DA at the nucleus accumbens. The precise mechanism involved in these effects is not clear at present.

D 9-tetrahydrocannabinol (THC), the active ingredient of marijuana, acts on cannabinoid receptors - the endogenous neurotransmitter which they bind is called anandamide (from the Sanskrit word "Ananda" meaning bliss), its role is not presently known. These are widespread through the brain with few receptors in the brain stem or and spinal cord (Herkenham et al., 1991). The receptors are particularly dense in the hippocampus (responsible for memory processing), the cortex (cognitive function) and the basal ganglia and cerebellum (structures involved in movement control). THC injection into the nucleus accumbens increases DA levels while injection into the VTA does not - this suggests that the reinforcing effects of cannabis are due to its effect on DA synapses - probably by binding to presynaptic heteroreceptors.

LSD acts on neurons which use the neurotransmitter serotonin (5-HT) largely because of its structural similarity to the neurotransmitter. It has a great affinity for the 5-HT2 receptor. Pathways which contain serotonergic neurons are involved in many aspects of behaviour including the control of eating, mood, sleep, arousal, the regulation of pain and in the control of dreaming. The relation to the DA reward system is unknown.

MDMA has both amphetamine-like (at lower doses) and hallucinogenic (at higher doses) properties. Its neurochemistry reflects this - lower doses stimulate the release of DA (including in the nucleus accumbens) and as the dose increases this is accompanied by serotonergic effects - in fact it inhibits the re-uptake of serotonin.

DEFINITION: OPERANT LEARNING– Behavior is a function of its consequences

A. Positive Reinforcement: strengthens learning by giving the subject something that increases its behavior (usually something desirable)

B. Negative Reinforcement:strengthens learning by removing something painful or aversive (note: also increases behavior)

C. Positive Punishment: weakens learning by giving the subject something that decreases its behavior (usually something painful)

D. Negative Punishment:weakens learning by taking away something that the subject finds reinforcing… (note: also decreases behavior).

E. BE PREPARED TO ANSWER QUESTIONS ABOUT THORNDIKE’S DISCRETE TRIALS OPERANT STUDIES AND SKINNER’S FREE RUNNING OPERANT STUDIES (SCHEDULES OF REINFORCEMENT, ETC)

F. KNOW THE PATTERNS OF RESPONDING THAT ARE TYPICAL OF FIXED RATIO (FR) AND FIXED INTERVAL (FI) SCHEDULES OF REINFORCEMENT

G. REINFORCEMENT "WORKS" BY INCREASING ACTIVITY IN THE VTA-NA CIRCUIT! THUS RECREATIONAL DRUG USE IS A TYPE OF LEARNING--THE BEHAVIOR THAT IS REINFORCED BY THE DRUG IS THAT OF OBTAINING AND ADMINISTERING THE DRUG!