Chapter 4 - Psychopharmacology

Question 1

FUNCTIONAL CLASSES of NEUROCHEMICALS

Answer 1

Neurochemicals fall into three general categories: NEUROTRANSMITTERS, NEUROMODULATORS, and NEUROHORMONES. Many of the same chemicals take on these different roles depending on the mode of their release and the type of receptors with which they interact.

Question 2

NEUROTRANSMITTERS

Answer 2

NEUROTRANSMITTERS are neurochemicals engaged in WIRING TRANSMISSION - they act on neurons in their own immediate vicinity. Neuro­transmitters are typically released from an axon terminals and cross the synaptic gap to interact with either fast ionotropic receptors or slow metabotropic receptors. At metabotropic receptors, neurotransmitter effects might last as long as several hours.

Question 3

NEUROMODULATORS

Answer 3

NEUROMODULATORS are neurochemicals engaged in volume transmission - they diffuse away from their site of release.

1) They are restricted to interactions with METABOTROPIC receptors and they produce longer-lasting changes in a neuron’s metabolic processing for periods up to several weeks - they’re often found in reward systems.
2) They can interact with both presynaptic and postsynaptic cells:
- in PRESYNAPTIC cells, they alter their rate of synthesising, releasing, reuptake, or enzyme-initiated breakdown of neurochemicals;
- in POSTSYNAPTIC cells, they adjust sensitivity to neurochemicals by influencing the production of receptors.
3) Unlike neurotransmitters, they are released by varicosities located along very thin, unmyelinated axons.

Question 4

NEUROHORMONES

Answer 4

NEUROHORMONES are neurochemicals produced by special neurons and released directly in the BLOOD SUPPLY. Neurohormones might travel long distances, for they interact only with cells that have specialised receptor sites to receive them.

Question 5

TYPES OF NEUROCHEMICALS - CHEMICAL CLASSES

Answer 5

Neurochemicals fall into three classes:

1) SMALL MOLECULES;
2) NEUROPEPTIDES;
3) GASOTRANSMITTERS.

Question 6

SMALL MOLECULES

Answer 6

SMALL MOLECULES transmitters are synthesised in axon terminals and the vesicles that encapsulate them’ are recycled. The class of small molecules can be further divided in:

1) ACETYLCHOLINE;
2) 6 MONOAMINES;
3) 3 AMINO ACIDS;
4) ATP and its byproducts.

Question 7

ACETYLCHOLINE

Answer 7

ACETYLCHOLINE is a neurochemical of the class of SMALL MOLECULES. Neurons that use ACh as their major neurochemical are referred to as CHOLINERGIC NEURONS.
Cholinergic neurons are primarily found:
1) at NEUROMUSCULAR JUNCTIONS - synapses between a neuron and a muscle fiber;
2) in the AUTONOMIC NERVOUS SYSTEM - all preganglionic synapses in the autonomic nervous system are cholinergic;
3) in NEUROMODULATION SYSTEMS which originate in the BASAL FOREBRAIN and BRAINSTEM and project to the LYMBIC SYSTEM and CEREBRAL CORTEX - they participate in learning and memory.

There are 2 subtypes of cholinergic receptors:
NICOTINIC RECEPTORS - fast ion­otropic receptors that respond to both ACh and nicotine - are found at neuromuscular junctions;
MUSCARINIC RECEPTORS - slower metabotropic receptors that respond to both ACh and muscarine -are found in hearth muscle.

Question 8

6 MONOAMINES

Answer 8

The six monoamines - SMALL MOLECULES - are further divided into subgroups, the CATECHOLAMINES (dopamine, norepinephrine, and epinephrine), the INDOLEAMINES (serotonin and melatonin), and HISTAMINE.

Question 9

CATECHOLAMINES

Answer 9

CATECHOLAMINES are MONOAMINES, part of the class of SMALL MOLECULES. They include DOPAMINE, EPINEPHRINE and NOREPINEPHRINE. Catecholamines share a common synthesis pathway.

Question 10

DOPAMINE

Answer 10

DOPAMINE is a CATECHOLAMINE, a MONOAMINE, and a SMALL MOLECULE.
Dopamine systems are involved with (1) MOVEMENT and (2) processing of REWARD - ADDICTION to drugs is especially influenced by activity of dopamine circuits.
There are 2 main dopaminergic systems:
1) the MESOSTRIATAL PATHWAY, from the SUBSTANTIA NIGRA to the BASAL GANGLIA - it is involved in movement.
2) the MESOLIMBIC PATHWAY, from the VENTRAL TEGMENTUM to the NUCLEUS ACCUMBENS and FRONTAL CORTEX - it is involved in processing of reward and addiction.
There are five types of dopamine receptors, all METABOTROPIC, named D1 through D5:
-D1 and D5 produce excitation;
-D2, D3 and D4 produce inhibition.

Question 11

EPINEPHRINE

Answer 11

EPINEPHRINE - formerly adrenaline - is a CATECHOLAMINE, a MONOAMINE, and a SMALL MOLECULE.
Epinephrine is an important NEUROHORMONE but plays a limited role as a CNS neur­ochemical - the “adrenalin rush” results from the release of epinephrine from the adrenal glands into the blood supply.
Epinephrine is mainly produced by areas of the MEDULLA and it participates in basic functions such as regulation of blood pressure.
Its receptors - which also respond to norepinephrine - are METABOTROPIC and classified as α or β receptors.

Question 12

NOREPINEPHRINE

Answer 12

NOREPINEPHRINE - formerly noradrenaline - is a CATECHOLAMINE, a MONOAMINE, and a SMALL MOLECULE.
Norepinephrine is mainly produced by the LOCUS COERLUS of the PONS which projects to every major part of the brain. Activity of these circuits results in increased arousal and vigilance - norepinephrine is found at the postganglionic synapses of the SYMPATHETIC NERVOUS SYSTEM (responsible of arousal).
Its receptors - which also respond to epinephrine - are METABOTROPIC and classified as α or β receptors.

Question 13

HISTAMINE

Answer 13

HISTAMINE is a MONOAMINE and a SMALL MOLECULE. All histamine is produced by the TUBEROMAMMILLARY NUCLEUS of the HYPOTHALAMUS, which projects to nearly every brain area where it acts on METABOTROPIC receptors. The main effect of this neuromodulating system is to increase alertness.

Question 14

INDOLEAMINES

Answer 14

INDOLEAMINES are MONOAMINES, part of the class of SMALL MOLECULES. They include SEROTONIN and MELATONIN, which share a common synthesis pathway.

Question 15

SEROTONIN

Answer 15

SEROTONIN is a INDOLEAMINE, a MONOAMINE and a SMALL MOLECULE.
95% of the body’s serotonergic neurons are located in the ENTERIC NERVOUS SYSTEM - in the brain, most of them are in the RAPHE NUCLEI of the BRAINSTEM, which projects to the CEREBRAL CORTEX, CEREBELLUM, SPINAL CORD and LIMBIC SYSTEM. At least 15 types of serotonergic receptors have been iden­tified, and all - but one - function as METABOTROPIC receptors.
Serotonergic activity is correlated to appe­tite, sleep, mood, and aggression.

Question 16

MELATONIN

Answer 16

MELATONIN is a INDOLEAMINE, a MONOAMINE and a SMALL MOLECULE. It is synthesised from serotonin and mostly produced by the PINEAL GLAND. It participates in the control of sleep.

Question 17

3 AMINO ACIDS

Answer 17

Although several amino acids - SMALL MOLECULES - participate as chemical messengers, 3 are especially significant: GLUTAMATE, GABA, and GLYCINE.

Question 18

GLUTAMATE

Answer 18

GLUTAMATE is an AMINO ACID and a SMALL MOLECULE - it is the most common EXCITATORY neurochemical in the CNS, used by as many as 90 percent of the synapses in the human brain. Once released, it is cleared quickly by both neurons and astrocytes. Glutamate has several receptors:

• 3 types of IONOTROPIC receptors - NMDA, AMPA and KAINATE receptors;
• 8 types of METABOTROPIC receptors called MGLURS.

Question 19

GABA

Answer 19

GABA is an AMINO ACID and a SMALL MOLECULE - it is the most common INHIBITORY neurochemical in the CNS, used by as many as 40 percent of the synapses in the human brain. There are three types of GABA receptors:

• GABAa and GABAc receptors, which are IONOTROPIC CHLORIDE CHANNELS that allow chloride ions in the cell;
• GABAb receptors, which are METABOTROPIC POTASSIUM CHANNELS that allow potassium ions out of the cell.

GABAa receptors contain binding sites that interact with many drugs, which depress nervous system activation by increasing the inhibition produced by GABA.
BENZODIAZEPINES, ALCOHOL and BARBITURATES can activate GABAa receptors.

Question 20

GLYCINE

Answer 20

GLYCINE is an AMINO ACID and a SMALL MOLECULE - it has an INHIBITORY effect for it opens IONOTROPIC CHLORIDE receptors which allow negatively charged chloride ions to enter the cell, therefore polarising it. Glycine is found primarily in synapses formed by SPINAL CORD INTERNEURONS.
Glycine’s interactions with NMDA glutamate receptors in the SUPRACHIASMATIC NUCLEUS of the hypothalamus produces the lower body temperatures typical of sleep.

Question 21

ADENOSINE TRIPHOSPHATE (ATP) and ADENOSINE

Answer 21

ATP, and its byproduct ADENOSINE, are SMALL MOLECULES - they act as neuromodulators in the CNS.
There are three types of receptors for adenosine, namely A1, A2 and A3.
A1 receptors inhibit the release of glutamate, acetylcholine, norepinephrine, serotonin, and dopamine.

Question 22

NEUROPEPTIDES

Answer 22

NEUROPEPTIDES, unlike small molecules, are produced in the cell body and require active transport to the axon terminal. Unlike small molecules, their vesicles are not recycled and they activate only METABOTROPIC RECEPTORS. Furthermore, the only way in which they are deactivated is removal from the synapse by DIFFUSION - there is no reuptake or enzymatic digestion.
One of the most important groups of neuropeptides are ENDORPHINS - opioids associated with pain relief and a sense of euphoria - naturally produced by the HYPOTHALAMUS and PITUITARY GLAND.

Question 23

GASOTRANSMITTERS

Answer 23

GASOTRANSMITTERS are gasses that transfer information from one cell to another. Since gaseous molecules dissolve in lipids, they diffuse through membranes without needing vesicles - they also act on receptors located within cells rather than on receptors embedded in the membrane.
They include CARBON MONOXIDE (CO), and NITRIC OXIDE (NO). NO is involved with neural communication, the maintenance of blood pressure, and PENILE ERECTION.

Question 24

AGONISTS and ANTAGONISTS

Answer 24

Drugs can boost or reduce the activity of a neurochemical. AGONISTS are drugs that enhance the activity of a neurochemical, whereas ANTAGONISTS reduce the activity of neurochemical. The final outcome of the action of an agonist or antagonist depends on whether the neurochemical it influences excites or inhibits the cell.

Question 25

MECHANISMS of NEUROPHARMACOLOGY

Answer 25

Drugs can produce their psychoactive effects on 5 different levels, by influencing:

1) SYNTHESIS OF NEUROCHEMICALS;
2) STORAGE OF NEUROCHEMICALS;
3) RELEASE OF NEUROCHEMICALS;
4) REUPTAKE OR ENZYME ACTIVITY;
5) PRESYNAPTIC and POSTSYNAPTIC RECEPTORS.

Question 26

drug effects on SYNTHESIS OF NEUROCHEMICALS

Answer 26

Manipulating the SYNTHESIS of a neurochemical will affect the amount available for release.
AGONISTS provide larger quantities of precursors - neurochemical building blocks - which boosts synthesis.
ANTAGONISTS interfere with the synthesis path­ways of neurochemicals.

Question 27

drug effects on STORAGE OF NEUROCHEMICALS

Answer 27

Certain drugs have an ANTAGONISTIC effect by interfering with the storage of neurochemicals in vesicles within the neuron. For instance, RESERPINE - used to reduce blood pressure - blocks the uptake of monoamines into synaptic vesicles.

Question 28

drug effects on RELEASE OF NEUROCHEMICALS

Answer 28

Drugs often modify the release of neurochemicals in response to the arrival of an action potential
METHAMPHETAMINE - a variant of amphetamine - acts as a dopamine agonist by (1) entering the presynaptic cell trough dopamine transporters and (2) disrupting vesicles containing dopamine and releasing it in the intracellular fluid. The presence of large amounts of dopamine outside of vesicles activates transporters which begin to work in reverse, releasing dopamine even in absence of action potentials.

Question 29

drug effects on REUPTAKE OR ENZYME ACTIVITY

Answer 29

At this levels, drugs can either (1) influence the reuptake of neurochemicals or (2) act on enzymes that break down released neurochemicals.
REUPTAKE INHIBITORS include COCAINE, AMPHETAMINE (dopamine agonists) and PROZAC (serotonin agonist and antidepressant)

Question 30

drug effects on POSTSYNAPTIC RECEPTORS

Answer 30

The greatest number of interactions between drugs and natural biochemistry occur when drugs interfere with the activity of receptors.
AGONISTS mimic natural neurochemicals and activate receptor sites;
ANTAGONISTS occupy receptor sites without activating them.

CURARE - a South American drug - acts as a cholinergic antagonist by blocking NICOTINIC receptors.
GABAa receptors can be activated by agonists such as BENZODIAZEPINES, BARBITURATES, and ALCOHOL.

Question 31

INTER-INDIVIDUAL VARIABILITY IN RESPONSES TO DRUGS

Answer 31

Drug effects experienced by individuals are influenced by:

1) BODY WEIGHT : larger bodies have more blood than smaller bodies and therefore require larger quantities of a drug to reach an equiv­alent concentration;
2) GENDER: alcohol, for instance is diluted by water in muscle tissue - since generally males have more muscle tissue than females of the same weight, they require more alcohol to reach the same concentration.
3) GENETICS: genetics affect a liver enzyme, ALDH, which participates in the metabolism of alcohol - lack of the gene for ALDH enzyme leads to unpleasant symptoms associated with drinking.

Furthermore, concentration of a drug in the blood supply strictly depends on its method of administration.

Question 32

TOLERANCE

Answer 32

TOLERANCE is the process by which a drug’s effects are lessened as a result of repeated administration and thus, more of a drug is needed to produce the same effect. Tolerance effects can result from changes in enzymes, changes in RECEPTOR DENSITY (more receptors require more neurochemicals) and LEARNING. CLASSICAL CONDITIONING associated with drug use can also produce tolerance. The body’s efforts to compensate for drug administration become conditioned, or asso­ciated, with the stimuli involved with drug administration - this is why overdoses are likely to occur in environments unfamiliar to the user.

Question 33

WITHDRAWAL

Answer 33

WITHDRAWAL is the syndrome of symptoms that follow discontinuance of an addicting drug. In general, with­drawal effects are the opposite of the effects caused by the discontinued drug - a person in withdrawal from a sedative will become agitated, whereas a person in withdrawal from a stimulant will become lethargic. Withdrawal symptoms are likely cause by the same compensation mechanisms that are responsible for tolerance - drug effects and compensation mechanisms cancel each other out, but when the former are absent the latter become apparent.

Question 34

ADDICTION

Answer 34

ADDICTION is the compulsive need to use the drug repeatedly in spite of negative consequences to the user.

Most addictive drugs have the ability to stimulate our natural neural SYSTEMS OF REWARD - by inducing more intense and longer-lasting dopamine release - which we experience as feelings of pleasure. These systems are responsible of promoting behaviours that aid our SURVIVAL or the survival of the species, such as eating, drinking and engaging in sexual behaviour. These behaviours produce activity in dopamine systems such as the MESOLIMBIC PATHWAY, the MESOSTRIATAL PATHWAY and in the NUCLEUS ACCUMBENS.
Drugs that do not stimulate dopamine pathways - such as LSD - do not cause the compulsive cravings of addiction.

Question 35

PLACEBO and NOCEBO EFFECTS

Answer 35

A PLACEBO effect is a beneficial effect produced by a fake treatment - drug effects are often influenced by a user’s expectations, experiences, and motivations. Placebo effects work on symptoms modulated by the brain, such as pain perception, stress-related insomnia and depression, yet it does not act on their physical correlates.
Placebo effects are CONTEXT-DEPENDENT - meaning they are enhanced by specific contexts - yet they occur even when the patient is aware that they are getting a placebo. Researchers speculate that the simple ritual of taking a pill is enough to trick the brain into thinking that the body is being healed.

NOCEBO effects are negative effects produced by fake treatment caused by negative expectations of such treatment.

Question 36

STIMULANT DRUGS

Answer 36

STIMULANT DRUGS share the ability to increase alertness and mobility. They include CAFFEINE, NICOTINE, COCAINE and AMPHETAMINE, and ECSTASY (MDMA).

Question 37

CAFFEINE

Answer 37

CAFFEINE increases blood pressure and heart rate, improves concentration, and wards off sleepiness.
It is an ADENOSINE ANTAGONIST - it produces its behavioral effects by blocking adenosine receptors, reduc­ing the normal inhibitory activity of adenosine. Caffeine assumption can be slightly ADDICTIVE for it leads to increased release of dopamine in the NUCLEUS ACCUMBENS.
Furthermore, caffeine crosses the PLACENTA easily, and the fetus and breastfed newborn are relatively unable to metabolize caffeine, leading to reduced rates of growth and other complications.

Question 38

NICOTINE

Answer 38

NICOTINE increases heart rate and blood pressure, promotes the release of adrenaline into the circulation, reduces fatigue,produces muscular relaxation and heightens cognitive performance.
Nicotine has its primary effect as an AGONIST at the NICOTINIC CHOLINERGIC receptors - which are not found only at neuromuscular junctions, but also in several areas of the brain.
Nicotine’s action on the cholinergic systems of the BASAL FOREBRAIN is responsible for increased alertness and cognitive performance.
Nicotine produces ADDICTION by stimulating cholinergic receptors in the MESOLIMBIC PATHWAY.

Question 39

COCAINE and AMPHETAMINE

Answer 39

At lower doses, COCAINE and AMPHETAMINE produce alertness, elevated mood, confidence, and a sense of well-being. At higher doses, they produce schizophrenia-like symptoms, such as hallucinations - often tactile sensations - and delusional paranoia.
Both drugs - the most addictive drugs known - are powerful DOPAMINE AGONISTS, but act in different ways:
- COCAINE prevents dopamine reuptake by blocking dopamine transporters on the presynaptic membrane, which results in abnormal amounts of dopamine in the synaptic gap.
- AMPHETAMINE mimics dopamine by (1) entering the presynaptic cell trough dopamine transporters and (2) disrupting vesicles containing dopamine and releasing it in the intracellular fluid. The presence of large amounts of dopamine outside of vesicles activates transporters which begin to work in reverse, releasing dopamine even in absence of action potentials.

Question 40

ECSTASY (MDMA)

Answer 40

MDMA increases heart rate, blood pressure, body temperature, and SOCIABILITY for a period of about three to six hours.
It is a synthetic relative of AMPHETAMINE and it acts in the same way - MDMA is taken up by transporters, causing them to reverse their action. Unlike amphetamine, it influences mainly SEROTONIN transporters and it stimulates OXYTOCIN release causing increased sociability - it is called the love drug. Nevertheless, MDMA stimulates norepinephrine and DOPAMINE transporters as well, causing addiction.

Question 41

OPIOIDS

Answer 41

OPIOIDS are substances that interact with endorphin receptors, whereas OPIATES is restricted to substances derived from the flower opium poppy. Opiates include CODEINE and MORPHINE (from which HEROIN is synthesized).
At low doses, opioids produce euphoria, pain relief, a lack of anxiety, muscle relaxation, and sleep (ENDORPHINS - neuropeptides and opioids produced by the hypothalamus and pituitary gland - are natural pain relievers).
At higher doses, opioids produce tremendous euphoria.

Opioids INHIBIT NEUROTRANSMITTER RELEASE.
They do so:
1) by inhibiting the entry of CALCIUM into the presynaptic terminal - calcium promotes EXOCYTOSIS,
2) by enhancing the outward movement of POTASSIUM, which in turn polarizes the cell and shortens the duration of action potentials.

Opioids are ADDICTIVE - they bind to cells that normally release GABA, which in turn inhibits dopamine release in the NUCLEUS ACCUMBENS. This inhibition of inhibitor cells results in higher dopamine activity in the mesolimbic pathway.

Question 42

CANNABIS

Answer 42

CANNABIS produces excitation and mild euphoria, but some individuals might experience depression and social withdrawal.
It contains more than 50 psychoactive compounds, known as cannabinoids, the most important of which is THC. THC acts as an AGONIST at receptors for ENDOGENOUS CANNABINOIDS.
THC has negative effects on memory formation, attention, and working memory because of the abundance of cannabinoid receptors in the HIPPOCAMPUS and PREFRONTAL CORTEX.

Question 43

LSD

Answer 43

LSD is a hallucinogen that shares a similar chemical composition with SEROTONIN. It acts as an AGONIST at SEROTONERGIC AUTORECEPTORS in the PREFRONTAL CORTEX, LOCUS COERLUS and RAPHE NUCLEI.
LSD produce tolerance but no withdrawal or addiction. A major - yet rare - negative consequence of LSD use is the experience of intrusive visual hallucinations, which can continue long after the person has stopped using the substance.

Question 44

ALCOHOL

Answer 44

At lower doses, ALCOHOL dilates blood vessels, reduces anxiety, promotes assertiveness, and reduces behavioral inhibitions.
At higher doses, assertiveness becomes aggression, disinhibition causes risky behaviour and motor coordination drops.
At even higher doses, coma and death can result from suppression of respiration or aspiration of vomit.

Alcohol produces its main effects by:

1) acting as an AGONIST at GABAa RECEPTORS, which normally produce neural inhibition;
2) acting as an ANTAGONIST at NMDA GLUTAMATE RECEPTORS, which results in memory problems;
3) stimulating DOPAMINERGIC PATHWAYS, which produce the euphoric and addictive qualities of alcohol.

Alcohol produces rapid TOLERANCE by:

1) increasing production of LIVER ENZYMES that eliminate alcohol from the system;
2) increasing the number of GABAa and NMDA glutamate receptors.

Alcohol as several detrimental effects on health:

1) it damages several brain areas, including the FRONTAL LOBES, responsible for higher-order cognitive functions;
2) it can lead to KORSAKOFF syndrome, in which the ability to form new memories is impaired;
3) it is dangerous for the developing fetus and for the vulnerable adolescent brain, especially to white matter.