Pharmacology Chapter 4

Lecture Preview Principles of Psychopharmacology Sites of Drug Action Neurotransmitters and Neuromodulators

Principles of Psychopharmacology Pharmacokinetics The process by which drugs are absorbed, distributed within the body, metabolized, and excreted. Routes of Administration Intravenous (IV) Injection – injection of a substance directly into a vein. Intraperitoneal (IP) Injection – injection of a substance into the peritoneal cavity, the space that surrounds the stomach, intestines, liver, and other abdominal organs.

Principles of Psychopharmacology (Continued) Intramuscular (IM) Injection – injection of a substance into a muscle. Subcutaneous (SC) Injection – injection of a substance into the space beneath the skin. Oral Administration – administration of a substance into the mouth so that it is swallowed. Sublingual Administration – administration of a substance by placing it beneath the tongue. Intrarectal Administration – administration of a substance into the rectum. Inhalation – administration of a vaporous substance into the lungs.

Principles of Psychopharmacology (Continued) Topical Administration – administration of a substance directly onto the skin or mucous membrane. Intracerebral Administration – administration of a substance directly into the brain. Intracerebroventricular (ICV) Administration – administration of a substance into one of the cerebral ventricles.

Principles of Psychopharmacology (Continued) Distribution of Drugs Within the Body Lipid Solubility – ease with drug molecules are soluble in fat. Depot Binding – binding of a drug with various tissues of the body or with proteins in the blood. Albumin – a protein found in the blood; serves to transport free fatty acids and can bind with some lipid-soluble drugs. Inactivation and Excretion Enzymes deactivate drugs (e.g., liver). Drugs are eventually excreted (e.g., kidneys).

Figure 4.2 Depot Binding with Blood Albumin Protein

Principles of Psychopharmacology (Continued) Drug Effectiveness Dose-Response Curve – a graph of the magnitude of an effect of a drug as a function of the amount of drug administered. Many drugs have more than one effect, which should be taken into consideration when determining the effect dose for treatment.

Figure 4.3 A Dose-Response Curve

Figure 4.4 Dose-Response Curves for Morphine

Principles of Psychopharmacology (Continued) Therapeutic Index – the ratio between the dose that produces the desired effect in 50% of the animals and the dose that produces toxic effects in 50% of the animals. Effects 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 (Continued) 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. Placebo Effects An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug.

Sites of Drug Action Antagonist Agonist A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell. Agonist A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell.

Sites of Drug Action (Continued) Effects on Production of Neurotransmitters Drugs may exert their agonistic or antagonistic effects by influencing the production of neurotransmitters. Effects on Storage and Release of Neurotransmitters Drugs may exert their agonistic or antagonistic effects by influencing the storage and release of neurotransmitters.

Figure 4.5 Drug Affects on Synaptic Transmission

Sites of Drug Action (Continued) Effects on Receptors Drugs may exert their agonistic or antagonistic effects by influencing receptors. Direct Agonist – a drug that binds with and activated a receptor. Direct Antagonist – a drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor.

Sites of Drug Action (Continued) Noncompetitive Binding – binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand. 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 site for the principal ligand.

Figure 4.6 Drug Actions at Binding Sites

Sites of Drug Action (Continued) Presynaptic Heteroreceptor – a receptor located in the membrane of a terminal button that receives input from another terminal button by means of an axoaxonic synapse; binds with the neurotransmitter released by the presynaptic terminal button.

Figure 4.7 Presynaptic Heteroreceptors

Figure 4.8 Dendritic Autoreceptors

Sites of Drug Action (Continued) Effects on Reuptake or Destruction of Neurotransmitters Drugs may exert their agonistic or antagonistic effects by influencing the reuptake or destruction of neurotransmitters.

Neurotransmitters and Neuromodulators (Continued) Acetylcholine Primary neurotransmitter secreted by efferent axons of the PNS. Major concentrations of ACh in the CNS include: Dorsolateral Pons (role in REM sleep) Basal Forebrain (role in learning) Medial Septum (role in memory)

Neurotransmitters and Neuromodulators (Continued) Botulinum Toxin – an ACh antagonist; prevents release by terminal buttons. Black Widow Spider Venom – a poison produced by the black widow spider that triggers the release of acetylcholine. Hemicholinium – a drug that inhibits the uptake of choline. Neostigmine – a drug that inhibits the activity of acetylcholinesterase.

Figure 4.10 Biosynthesis of Acetylcholine

Figure 4.11 The Acetylcholine-Choline Cycle

Neurotransmitters and Neuromodulators (Continued) Nicotinic ACh Receptor – an ionotripic ACh receptor that is stimulated by nicotine and blocked by curare. Muscarinic ACh Receptor – a metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine.

Neurotransmitters and Neuromodulators (Continued) The Monoamines A class of amines that includes indolamine, such as serotonin; and catecholamines, such as dopamine, norepinephrine, and epinephrine. Dopamine A catecholamine synthesized from L-DOPA. Major CNS dopaminergic systems include: Nigrostriatal System (role in movement) Mesolimbic System (role in reinforcement/reward) Mesocortical System (role in short-term memory, planning, and problem solving)

Neurotransmitters and Neuromodulators (Continued) AMPT – a drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines. Reserpine – a drug that interferes with the storage of monoamines in synaptic vesicles. Apomorphine – a drug that blocks dopamine autoreceptors at low doses; at higher doses, blocks postsynaptic receptors as well.

Figure 4.14 Effects of Low and High Doses of Apomorphine

Neurotransmitters and Neuromodulators (Continued) Methylphenidate – a drug that inhibits the reuptake of dopamine. Monoamine Oxidase (MAO) – a class of enzymes that destroy the monoamines. Deprenyl – a drug that blocks the activity of MAO-B; acts as a dopamine agonist. Chlorpromazine – a drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors.

Figure 4.15 Role of Monoamine Oxidase

Neurotransmitters and Neuromodulators (Continued) Norepinephrine (and Epinephrine) Norepinephrine – one of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the ANS. Epinephrine – one of the catecholamines; a hormone secreted by the adrenal medulla; serves also as a neurotransmitter in the brain.

Neurotransmitters and Neuromodulators (Continued) Moclobemide – a drug that blocks the activity of MAO-A; acts as a noradrenergic agonist. Locus Coeruleus – a dark-colored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle. Axonal Varicosities – an enlarged region along the length of an axon that contains synaptic vesicles and releases a neurotransmitter or neuromodulator. Most norepinephrine is released in this way. Idazoxan – a drug that blocks presynaptic noradrenergic 2 receptors. Facilitates the synthesis and release of NE.

Neurotransmitters and Neuromodulators (Continued) Serotonin An indolamine neurotransmitter; also called 5-hydroxytryptamine. PCPA – a drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT.

Figure 4.17 Biosynthesis of Serotonin (5-Hydroxytryptamine, or 5-HT)

Neurotransmitters and Neuromodulators (Continued) Fluoxetine (Prozac) – a drug that inhibits the reuptake of 5-HT. Fenfluramine – a drug that stimulates the release of 5-HT. MDMA – a drug that serves as a noradrenergic and serotonergic agonist, also known as “ecstasy”; has excitatory and hallucinogenic effects.

Neurotransmitters and Neuromodulators (Continued) Amino Acids Glutamate An amino acid; the most important excitatory neurotransmitter in the brain. NMDA Receptor – a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; has several other binding sites. AMPA Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA.

Figure 4.19 NMDA Receptor

Neurotransmitters and Neuromodulators (Continued) Kainate Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by kainic acid. Metabotropic Glutamate Receptor – a category of metabotropic receptors that are sensitive to glutamate. AP5 – a drug that blocks the glutamate binding site on NMDA receptors. PCP – phencyclidine; a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist.

Neurotransmitters and Neuromodulators (Continued) GABA An amino acid; the most important inhibitory neurotransmitter in the brain. Produced from glutamic acid by the action of an enzyme called GAD. Allylglycine – a drug that inhibits the activity of GAD and thus blocks the synthesis of GABA. Muscimol – a direct agonist for the GABA binding site on the GABAA receptor. Bicuculline – a direct antagonist for the GABA binding site on the GABAA receptor.

Figure 4.20 GABAA Receptor

Neurotransmitters and Neuromodulators (Continued) Benzodiazepine – a category of anxiolytic drugs; and indirect agonist for the GABAA receptor. Anxiolytic – an anxiety-reducing effect. Glycine An amino acid; an important inhibitory neurotransmitter in the lower brain stem and spinal cord. Strychnine – a direct antagonist for the glycine receptor.

Neurotransmitters and Neuromodulators (Continued) Peptides Endogenous Opioids A class of peptides secreted by the brain that act as opiates. Enkephalin – one of the endogenous opioids. Naloxone – a drug that blocks opiate receptors. Lipids Endocannabinoid A lipid and endogenous ligand for cannabinoid receptors, which also binds with THC, the active ingredient of marijuana.

Neurotransmitters and Neuromodulators (Continued) THC – the active ingredient in marijuana; activates CB1 receptors in the brain. Anandamide – the first cannabinoid to be discovered. FAAH – fatty acid amide hydrolase, the enzyme that destroys anandamide after it is brought back into the cell by anandamide transporters. Rimonabant – a drug that blocks CB1 receptors. MAFP – a drug that inhibits FAAH; prevents the breakdown of anandamide. AM1172 – a drug that inhibits the reuptake of anandamide.

Neurotransmitters and Neuromodulators (Continued) Nucleosides Compounds that consist of a sugar molecule bound with a purine or pyrimidine base. Adenosine – a nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain. Caffeine – a drug that blocks adenosine receptors.

Neurotransmitters and Neuromodulators (Continued) Soluble Gases Nitric Oxide – a gas produced by cells in the nervous system; used as a means of communication between cells. Nitric Oxide Synthase – enzyme responsible for the production of nitric oxide. Sildenafil (Viagra) - binds with the enzyme that destroys cyclic GMP, the longer lasting byproduct of nitric oxide.