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Chapter 4. Psychopharmacology. Principles of Psychopharmacology. Drug effects The changes a drug produces in an animal’s physiological processes and behavior. Sites of Action
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Chapter 4 Psychopharmacology
Principles of Psychopharmacology • Drug effects • The changes a drug produces in an animal’s physiological processes and behavior. • Sites of Action • The locations at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells. • Pharmacokinetics • The process by which drugs are absorbed, distributed within the body, metabolized, and excreted.
Figure 4.1 Cocaine in Blood Plasma. The graph shows the concentration of cocaine in blood plasma after intravenous injection, inhalation, sniffing, and oral administration.
Figure 4.2 A Dose-Response Curve. Increasingly stronger doses of the drug produce increasingly larger effects until the maximum effect is reached. After that point, increments in the dose do not produce any increments in the drug’s effect. However, the risk of adverse side effects increases.
Figure 4.3 Dose-Response Curves for Morphine. The dose-response curve on the left shows the analgesic effect of morphine, and the curve on the right shows one of the drug’s adverse side effects: its depressant effect on respiration. A drug’s margin of safety is reflected by the difference between the dose-response curve for its therapeutic effects and that for its adverse side effects.
Principles of Psychopharmacology • Drug Effectiveness • There are two reasons drugs vary in their effectiveness. • First, different drugs—even those with the same behavioral • effects—may have different sites of action. • The second reason that drugs vary in their effectiveness has to • do with the affinity of the drug with its site of action. • Affinity • The readiness with which two molecules join together.
Principles of Psychopharmacology • Effect of Repeated Administration • Tolerance • A decrease in the effectiveness of a drug that is administered repeatedly. • Sensitization • An increase in the effectiveness of a drug that is administered repeatedly.
Principles of Psychopharmacology • Drug Effectiveness • Withdrawal symptom • The appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken. • Withdrawal symptoms are caused by the same mechanisms that are responsible for tolerance.
Principles of Psychopharmacology • Placebo Effects • When experimenters want to investigate the behavioral effects of drugs in humans, they must use control groups whose members receive placebos, or they cannot be sure that the behavioral effects they observe were caused by specific effects of the drug. • Placebo • An inert substance given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug.
Figure 4.4 Drug Effects on Synaptic Transmission. The figure summarizes the ways in which drugs can affect the synaptic transmission (AGO =agonist; ANT = antagonist; NT = neurotransmitter). Drugs that act as agonists are marked in blue; drugs that act as antagonists are marked in red.
Sites of Drug Action • Effects on Receptors • Direct agonist • A drug that binds with and activates a receptor. This drug mimics the effects of a neurotransmitter. • Indirect agonist • A drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site of the principal ligand.
Sites of Drug Action • Effects on Receptors • Direct antagonist • Synonym for a receptor blocker. • Indirect antagonist • A drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding of the principal ligand. • Noncompetitive binding • Binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand.
Figure 4.5 Drug Actions as Binding Sites. This figure shows (a) competitive binding (direct agonists and antagonists act directly on the neurotransmitter binding site) and (b) noncompetitive binding (indirect agonists and antagonists act on an alternative binding site and modify the effects of the neurotransmitter on opening of the ion channel.
Sites of Drug Action • Effects on Reuptake or Destruction of Neurotransmitters • The next step after stimulation of the postsynaptic receptor is termination of the postsynaptic potential. • Two processes accomplish that task: • 1. Reuptake • 2. Enzymatic deactivation
Neurotransmitters and Neuromodulators • There are several dozen different neurotransmitters. • In the brain most synaptic communication is accomplished by two neurotransmitters: one with excitatory effects (glutamate) and one with inhibitory effects (GABA). • In fact, there are probably no neurons in the brain that do not receive excitatory input from glutamate-secreting terminal buttons and inhibitory input from neurons that secrete either GABA or glycine.
Neurotransmitters and Neuromodulators • Acetylcholine • The primary neurotransmitter secreted by the efferent axons of the central nervous system. • All muscular movement is accomplished by the release of acetylcholine. • Acetylcholine is involved in regulating REM sleep, perceptual learning, and memory.
Figure 4.7 Destruction of Acetylcholine (ACh) byAcetylcholinesterase (AChE)
Neurotransmitters and Neuromodulators • Acetylcholine • Botulinum toxin • An acetylcholine antagonist; prevents release • by terminal buttons. • Black widow spider venom • A poison produced by the black widow spider • that triggers the release of acetylcholine. • Neostigmine • A drug that inhibits the activity of AChE
Neurotransmitters and Neuromodulators • Acetylcholine • Nicotinic receptor • An ionotropic acetylcholine receptor that is • stimulated by nicotine and blocked by curare. • Muscarinic receptor • A metabotropic acetylcholine receptor that is • stimulated by muscarine and blocked by atropine.
Neurotransmitters and Neuromodulators • The Monoamines • Dopamine, norepinephrine, epinephrine, and serotonin are four chemicals that belong to a family of compounds called monoamines. • Because the molecular structures of these substances are similar, some drugs affect the activity of all of them to some degree.
Neurotransmitters and Neuromodulators • The Monoamines • The first three, dopamine, norepinephrine, and epinephrine belong to a subclass of monoamines called catecholamines. • The monoamines are produced by several systems of neurons in the brain. Monoaminergic neurons thus serve to modulate the function of widespread regions of the brain, increasing or decreasing the activities of particular brain functions.
The Monoamines • Nigrostriatal system • A system of neurons originating in the substantianigra and terminating in the neostriatum (caudate nucleus and putamen of the basal ganglia);appears to play a role in the control of movement. • Mesolimbic system • A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus; appears to play a role in the reinforcing effects of drugs that are commonly abused. • Mesocorticalsystem • A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex; appears to influence formation of short-term memories, planning, and preparing strategies for problem solving.
The Monoamines • Reserpine • A drug that interferes with the storage of monoamines in synaptic vesicles; serves as a monoamine antagonist. • Methylphenidate • A drug that inhibits the reuptake of dopamine; also known as Ritalin; used to treat children with attention deficit disorder. • Monoamine oxidase (MAO) • A class of enzymes that destroy the monoamines: dopamine, norepinephrine, and serotonin • Chlorpromazine • A drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors
Indolamines • Serotonin • Also called 5-HT or 5-hydroxytryptamine. Thought to play a role in the regulation of mood, the control of eating, sleep, dreaming, and arousal. Also thought to be involved in the regulation of pain. The amino acid tryptophan is the precursor of serotonin.
Figure 4.10 Biosynthesis of Serotonin (5- hydroxytryptamine, or 5-HT).
The Monoamines • Fluoxetine (Prozac) • A drug that inhibits the reuptake of 5-HT.Used to treat depression, obsessive-compulsive disorder and some anxiety disorders. • PCPA • A drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT and serves as a serotonergic antagonist. • LSD • A drug that stimulates 5-HT2A receptors. • MDMA • A drug that serves as a noradrenergic and serotonergic agonist, also known as “ecstasy”; has excitatory and hallucinogenic effects.
Amino Acids • Three of the at least 8 amino acids are especially important because they are the most common neurotransmitters in the CNS: glutamate, gamma-aminobutyric acid (GABA), and glycine. • Glutamate • An amino acid; the most important excitatory neurotransmitter in the brain. • GABA • Gamma-aminobutyric acid is an amino acid. GABA is the most important inhibitory neurotransmitter in the brain and spinal cord
Figure 4.12 GABAA Receptor. This schematic illustration of a GABAA receptor, with its binding sites.
Amino Acids • Glycine • It appears to be the most important inhibitory neurotransmitter in the lower brain stem and spinal cord. • Strychnine • A direct antagonist for the glycine receptor. Causes convulsions and death even in small doses.
Peptides • Peptides consist of two or more amino acids linked together by peptide bonds. • Endogenous opioid • A class of peptides secreted by the brain that act as opiates; drugs that effect opioid receptors reduce pain. Enkephalin: One of the endogenous opioids. • Naloxone • A drug that blocks opioid receptors; often used to treat heroin overdose.
lIPIDS • Endocannabinoid • A lipid; a ligand for receptors that bind with THC, the active ingredient of marijuana. • Anandamide • The first cannabinoid to be discovered and probably the most important one.
nUCLEOSIDES • A nucleoside is a compound that consists of a sugar molecule bound with a purine or pyrimidine base. One of these compounds, adenosine, which serves as a neuromodulator in the brain. • Adenosine • A combination of ribose and adenine. Released by glial cells and neurons. Dilates blood vessels and increases supply of cellular nutrients. • Caffeine • A bitter-tasting alkaloid drug that blocks adenosine receptors.
Soluble Gases • Recently, investigators have discovered that neurons use at least two simple, soluble gases—nitric oxide and carbon monoxide—to communicate with one another. • Nitric oxide (NO) • A gas produced by cells in the nervous system; used as a means of communication between cells. Nitric oxide synthase is the enzyme responsible for production of nitric oxide.
