PSYC 377 Physiological Psychology Exam 3 Study Guide

 Basic Pharmacology
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 --must be able to cross the Blood-Brain Barrier ;most used to manage/treat psychopathology; some used recreationally.

Drug Naming Conventions
Example: 7-cloro-1,3-dihydro-1-methyl-5-phenyl-2H-benzodiazepin-2-one


Example: diazepam

Example: Valium

Drug Doses: mg/kg (body weight)

Needed to standardize concentration of drug across subjects when measuring:
Dose Response Curves (DRC)

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.



DRCs and Drug Safety:





Drug Interactions

Pharmacokinetics

How drugs get into, around and out of the body.


Parenteral (injection) Administration Routes

Diffusion:

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.

Oral administration: (p.o.):
Digestive system --lipid barrier between food and blood; lipid solubility determines absorption partition coefficient
Factors that determine lipid solubility
Determinants of ionization:

1. pH of solvent

2. acidity/alkalinity of drug

3. pKa of drug 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).

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).
The equilibrium constant K is defined as the fraction of H+ and A-  to the HA.
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.
[H+] = Ka ([HA]/[A-] )
Taking the logarithm of each side gives:
log [H+]  = log Ka  + log ([HA]/[A-] )
Now we can multiple by -1.
-log [H+]  = -log Ka  - log ([HA]/[A-] )
Which is the same as:
-log [H+]  = -log Ka  + log ([A-] /[HA])
Traditionally, -log is substituted with a lower case p, so the equation becomes (known as the Henderson-Hasselback equation:
pH = pKa + log ([A-] /[HA])
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.
[A-] /[HA] = exp (pH -  pKa)
This means that when pH is equal to  pKa , [A-] = [HA], or that the acid is 50% ionized.
Drug, acid, pKa=3.5

Side A, pH=3.5,

ionization=50%, i.e, 1/2

Side B, pH= 7.5

ionization= .00001 i.e, 1/10,000

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.
epidermis packed with keratin EG: nicotine patch

Distribution - where drugs go in the body.

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

Barriers:


Transport mechanisms:

Excretion and metabolism:
enzymes:
Factors altering rate of metabolism:

1. Induction and blocking of enzymes

(antabuse blocks acetaldehyde dehydrogenase)

2. age

3. species
Pharmacodynamics - Drug Effects and Sites of Action


The Dopamine Reinforcement Pathway
The Four Figures Below depict the site of action of drugs of abuse from different perspectives. 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).The fourth figure depicts the "reinforcement circuit" in a human brain.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.

drugsynapsevta-nac3

The following list is an summary of the known effects of selected drugs.

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 activity. 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.

The following substances are not "addictive" in the typical sense--it has been hypothesized that their serotonergic (5-HT) effects may modulate the changes in the VTA-NAcc dopamine system.
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.
OPERANT LEARNING
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!