Chapter Four Psychopharmacology

Neurotransmitters, Neuromodulators, and Neurohormones Participate in directed synapses by acting on neurons in their own immediate vicinity Neuromodulators and neurohormones Participate in nondirected synapses by acting on more distant neurons Neuromodulators communicate with target diffuse away from the point of release Neurohormones travel in the blood supply to reach their final targets

Neuromodulators and Neurohormones Figure 4.1 Neurotransmitters, Neuromodulators, and Neurohormones. Neurotransmitters typically influence cells across a synaptic gap, while neuromodulators diffuse away after being released to affect cells at a distance. Neurohormones are often released into the bloodstream to travel to their ultimate destinations. (Cengage Learning, 2016)

Identifying Neurochemicals Substances released by one cell that produce a reaction in a target cell The substance: Must be present within a presynaptic cell. Is released in response to presynaptic depolarization Interacts with specific receptors on a postsynaptic cell

Types of Neurochemicals Figure 4.2 Categories of Neurochemicals. Major categories of neurotransmitters, neuromodulators, and neurohormones. (Cengage Learning, 2016)

Features of Small-Molecules and Neuropeptides Table 4.1 Features of Small-Molecules and Neuropeptides

Small-Molecule Neurochemicals: Acetylcholine Produced in cholinergic neurons Two receptor types: Nicotinic receptors Muscarinic receptors Figure 4.4 Amanita muscaria. Muscarinic cholinergic receptors get their name in recognition of their response to both acetylcholine (ACH) and muscarine, derived from the deadly Amanita muscaria mushroom. (Vitaly Ilyasov/Shutterstock.com)

The Distribution of Cholinergic Systems in the Brain Figure 4.3 The Distribution of Cholinergic Systems in the Brain. In addition to playing important roles at the neuromuscular junction and in the autonomic nervous system, cholinergic neurons are widely distributed in the brain. Important systems originate in the basal forebrain and brainstem and form projections to the limbic system and cerebral cortex. These systems participate in learning and memory and deteriorate in patients diagnosed with Alzheimer’s disease. (Cengage Learning, 2016)

Small-Molecule Neurochemicals: Monoamines Catecholamines Dopamine, norepinephrine, epinephrine Synthesized from tyrosine Indoleamines Serotonin, melatonin Serotonin is synthesized from tryptophan

Catecholamines Share a Common Synthesis Pathway Figure 4.5 Catecholamines Share a Common Synthesis Pathway The catecholamines, including dopamine, norepinephrine, and epinephrine, are synthesized from the substrate tyrosine. Tyrosine is converted into L-dopa by the action of tyrosine hydroxylase. L-dopa is converted into dopamine by dopa decarboxylase. The action of dopamine β-hydroxylase on dopamine produces norepinephrine. When norepinephrine reacts with phenylethanolamine N-methyl-transferase, epinephrine is produced.

Dopaminergic Systems in the Brain Dopaminergic neurons in the midbrain form connections with other neurons Dopamine activity is associated with motivated behavior and reward processing

Dopaminergic Systems in the Brain (cont’d.) Figure 4.6 Dopaminergic Systems in the Brain. Dopaminergic neurons in the midbrain project to the basal ganglia, the limbic system, and the frontal lobes of the cerebral cortex. These systems appear to participate in motor control, reward, and the planning of behavior. (Cengage Learning, 2016)

Noradrenergic Systems in the Brain Norepinephrine Noradrenergic neurons Increases arousal and vigilance Primary neurotransmitter in the sympathetic nervous system Epinephrine Adrenergic neurons Regulation of eating, blood pressure

Noradrenergic Systems in the Brain (cont’d.) Figure 4.7 Noradrenergic Systems in the Brain. Neurons releasing norepinephrine are found in the pons, medulla, and hypothalamus. Released norepinephrine goes to nearly every major part of the brain and spinal cord, producing arousal and vigilance. (Cengage Learning, 2016)

Indoleamines: Serotonin Synthesized from tryptophan Regulates mood, sleep, and appetite Figure 4.8 The Synthesis of Serotonin. Serotonin synthesis begins with dietary tryptophan, which is converted into 5-HTP by the action of tryptophan hydroxylase. 5-HTP is converted into serotonin by the action of 5-HTP decarboxylase. (Cengage Learning, 2016)

Serotonergic Pathways in the Brain Figure 4.9 Serotonergic Pathways in the Brain. Most serotonergic neurons are found in the raphe nuclei of the brainstem. Serotonin released by these neurons affects the spinal cord, cerebellum, limbic system., and cerebral cortex. These systems participate in the control of mood, sleep, social status, aggression, and appetite. (Cengage Learning, 2016)

Histamine Synthesized from histidine Associated with wakefulness Figure 4.10 Location of Histamine Receptors in the Brain. Histamine activity in the brain is associated with wakefulness. Older versions of antihistamines crossed the blood-brain barrier and produced drowsiness. (Courtesy of Laura Freberg)

Amino Acid Messengers: Glutamate Major excitatory neurotransmitter in the CNS Subtypes of glutamate receptors: NMDA, AMPA, and kainate Figure 4.11 The NMDA Glutamate Receptor. The NMDA receptor has two unusual qualities. First, it requires both the binding of glutamate and sufficient depolarization before it responds. At the resting potential, the ion channel is blocked by a molecule of magnesium (Mg2+). Depolarization ejects the Mg2+. If glutamate now binds with the receptor, the channel will open and ions will be allowed to pass. Second, the receptor allows both sodium and calcium ions to enter the neuron. These features make the NMDA glutamate receptor a prime candidate for having a significant role in learning at the cellular level. (Cengage Learning, 2016)

Amino Acid Messengers: GABA Major inhibitory neurochemical in the CNS Synthesized from glutamate GABAA and GABAB receptors GABAA receptors interact with psychoactive drugs Figure 4.12 The GABAA Receptor Interacts with Several Drugs. In addition to binding sites for GABA itself, the GABAA receptor also contains binding sites that interact with benzodiazepines, barbiturates, and ethanol (alcohol). These drugs depress nervous system activity by increasing the inhibition produced by GABA. Combining any of these drugs can produce a life-threatening level of neural inhibition. (Cengage Learning, 2016)

The GABAA Receptor Interacts with Several Drugs Figure 4.12 The GABAA Receptor Interacts with Several Drugs. In addition to binding sites for GABA itself, the GABAA receptor also contains binding sites that interact with benzodiazepines, barbiturates, and ethanol (alcohol). These drugs depress nervous system activity by increasing the inhibition produced by GABA. Combining any of these drugs can produce a life-threatening level of neural inhibition. (Cengage Learning, 2016)

Amino Acid Messengers: Glycine Major inhibitory neurochemical in spinal cord interneurons Excitatory function with glutamate at NMDA receptors Synthesized from serine Figure 4.13 Glycinergic Neurons. Glycine is a major inhibitory neurotransmitter in spinal cord interneurons and in smaller numbers of neurons located elsewhere in the central nervous system (CNS). Glycine plays an excitatory role at the NMDA glutamate receptor and also contributes to the management of sleep-waking cycles. (Albert Tousson/Phototake)

ATP and Adenosine Act in the CNS and in connections between autonomic neurons and the vas deferens, bladder, heart, and gut ATP is associated with pain perception and sleep-waking cycles Adenosine inhibits the release of many neurochemicals Figure 4.14 Caffeine and Adenosine Share Similar Structure. Because of their similar structures, caffeine and adenosine (shown here) compete at binding sites of postsynaptic receptors for adenosine. Because adenosine activity is correlated with drowsiness, caffeine’s ability to block adenosine at the receptor contributes to alertness. (PASIEKA/Science Photo Library/Getty Images)

Neuropeptides Substance P (pain perception) Endorphins act on same receptors as opioids and heroin Insulin and cholecystokinin function in digestion and as neuromodulators and neurohormones Oxytocin and vasopressin act as neuromodulators and neurohormones

Distribution of Endorphin Receptors in the Human Brain Figure 4.15: Distribution of Endorphin Receptors in the Human Brain. This PET scan identifies areas of the brain rich in endorphin receptors, which appear in red and yellow. These receptors respond both to our naturally occurring endorphins and to externally supplied opioids, including heroin and morphine. (Philippe Psalia/Science Source)

Gasotransmitters Diffuse through membranes and interact with intracellular receptors Transmits information from the postsynaptic to the presynaptic neurons Nitric oxide (NO) Neural communication, maintenance of blood pressure, erection (target of Viagra)

Drug Actions at the Synapse Agonists enhance the activity of a neurotransmitter Antagonists reduce the activity of a neurotransmitter

Mechanisms of Drug Actions at the Synapse Neurochemical production Manipulating the synthesis of a neurotransmitter may affect the amount available for release Neurochemical storage Interfering with the storage of a neurotransmitters in vesicles within a neuron Neurochemical release Can be modified in response to the arrival of an action potential by drugs

Mechanisms of Drug Actions at the Synapse: Receptor Effects Mimic the action of a neurotransmitter at the site Block the synaptic activity by occupying a binding site Influence the activity of the receptor

Drug Interactions at the Cholinergic Synapse Figure 4.16 Drug Interactions at the Cholinergic Synapse. Drugs can interact with many ongoing processes at a synapse. Agonists at the cholinergic synapse, which appear in green, include black widow spider venom, nicotine, and dietary choline. Spider venom enhances acetylcholine (ACh) release, and nicotine activates ACh receptors. Increased intake of dietary choline can increase production of ACh. Antagonists, which appear in red, include botulin toxin, curare, and organophosphates. Botulin toxin blocks the release of ACh, and curare blocks nicotinic ACh receptors. Organophosphates break down the enzyme acetylcholinesterase (AChE), so they technically serve as ACh agonists. Although a reduction in AChE activity might initially boost ACh activity, it eventually has a toxic effect on ACh receptors. (Cengage Learning, 2016) Figure 4.17 Cobra venom, shown in red and orange, interacts with cholinergic receptors. (Laguna Design/Science Source)

Drug Interactions at the Dopaminergic Synapse Figure 4.18 Drug Interactions at the Dopaminergic Synapse. L-dopa, prescribed in cases of Parkinson’s disease, serves as a dopaminergic agonist by promoting increased dopamine synthesis, and amphetamine increases the release of dopamine. Cocaine, amphetamine, and methylphenidate are dopamine reuptake inhibitors. Apomorphine activates dopaminergic receptors. Reserpine exerts an antagonistic effect by interfering with the uptake of monoamines into synaptic vesicles. Traditional medications used to treat schizophrenia, such as the phenothiazines, block dopaminergic receptors. (Cengage Learning, 2016)

Drug Interactions at the Serotonergic Synapse Figure 4.19 Drug Interactions at the Serotonergic Synapse. Agonists at the serotonergic synapse include tryptophans, MDMA (ecstasy), headache remedies, monoamine oxidase (MAO) inhibitors, and selective serotonin reuptake inhibitors (SSRIs), including Prozac. Antagonists for serotonin include reserpine and some medications used to treat schizophrenia. (Cengage Learning, 2016)

Reuptake Effects and Enzymatic Degradation Cocaine, amphetamine, and Ritalin inhibit dopamine reuptake SSRIs (e.g., Prozac) inhibit serotonin reuptake Enzymatic degradation Organophosphates interfere with AChE Deactivation of neurotransmitters

Basic Principles of Drug Effects Administration of drugs Method of administration leads to different effects on nervous system; blood-brain barrier Individual differences Drug effects influenced by body weight, gender, and genetics Placebo effects User expectations influence drug effects Double-blind experiment

Concentration of a Drug in the Blood Supply Depends on the Method of Administration Figure 4.20 Concentration of a Drug in the Blood Supply Depends on the Method of Administration. Drug effects are dependent on the concentration of the drug in the blood supply, and some methods of administration produce effective concentrations faster than others. In the case of nicotine, smoking a cigarette produces a much faster increase in blood nicotine concentration than chewing an equivalent dose of tobacco. However, chewing tobacco produces higher sustained concentrations of nicotine than smoking does. (Adapted from Bennett, 1983)

Tolerance, Withdrawal, and Addiction Lessened effects as a result of repeated administration Withdrawal Occurs when substance use is discontinued; opposite of the effects caused by the discontinued drug Addiction Compulsive need to use the drug repeatedly despite harm to the user

Vaccinations Against Drugs of Abuse Figure 4.21 Vaccinations Against Drugs of Abuse. Psychoactive drugs would not be psychoactive at all if they were unable to cross the blood-brain barrier to interact with the central nervous system (CNS). By developing antibodies that link with molecules of particular drugs of abuse, the drugs can be prevented from passing through the blood-brain barrier. (National Institute on Drug Abuse)

Effects of Psychoactive Drugs: Stimulants Increase alertness and mobility Caffeine – adenosine antagonist Nicotine – nicotinic cholinergic receptor agonist Cocaine – dopamine reuptake inhibitor Amphetamine – stimulates release and inhibits reuptake of dopamine/norepinephrine Ecstasy (MDMA) – stimulates release of serotonin and oxytocin; toxic to serotonergic neurons

Caffeine Content of Common Products Figure 4.22 Caffeine Content of Common Products. (Adapted from Byer & Shainberg, 1995) (Cengage Learning, 2016)

Caffeine Content of Common Products (cont’d.) Figure 4.22 Caffeine Content of Common Products. (Adapted from Byer & Shainberg, 1995) (Cengage Learning, 2016)

Health Consequences of Methamphetamine Abuse Figure 4.23 Methamphetamine Abuse Leads to Multiple Health Consequences. Not only does methamphetamine abuse frequently lead to hallucinations and delusions similar to those caused by schizophrenia, but users experience additional health issues, including a characteristic pattern of dental decay known as “meth mouth.” This condition results from the mouth dryness and the clenching and grinding of teeth caused by the drug. (Michale Rubenstein/Redux)

Historical Use of Cocaine Figure 4.24 Cocaine Was an Ingredient in Many Widely used Products. Prior to World War I, many commercial products contained cocaine. Sigmund Freud originally believed that cocaine was an effective antidepressant. The ability of cocaine to produce rapid addiction eventually changed people’s minds about the safety of the drug. (Bettman/Corbis)

Ecstasy Damages Serotonergic Neurons Figure 4.25 MDMA (Ecstasy) Damages Serotonergic Neurons. Monkeys were given either MDMA twice per day for four days or saline (control). The image to the left shows the cortex of a control monkey, the middle image shows the cortex of one of the MDMA monkeys two weeks after the last dose, and the image on the right shows the cortex of one of the MDMA monkeys seven years after the last dose. (Dr. GA Ricaurte, Johns Hopkins University School of Medicine)

Opioids Interact with endorphin receptors Opiates Pain relief, relaxation, sense of euphoria Opiates Derived from sap of opium poppy Morphine, codeine Heroin Synthetic opiate Derived from morphine Figure 4.26 Opium is the Source of Several Psychoactive Substances. Opium is obtained from the opium poppy, Papaver somniferum. Afghanistan remains the world’s leading supplier of opium, where the crop makes up at least 15 percent of the country’s gross domestic product. (Frank and Helen Schreider/National Geographic Creative)

Marijuana (Cannabis) Active ingredient THC is an endogenous cannabinoid receptor agonist Cannabinoid receptors are in the hippocampus and prefrontal cortex Effects: mild euphoria, perceptual distortion, hallucination, and depression

Cannabis and the Risk of Psychosis Figure 4.27 Cannabis and the Risk of Psychosis. While the vase majority of people using cannabis will not experience psychosis, cannabis use, especially early, chronic use in adolescence, interacts with a person’s genetics to influence risk of developing psychotic symptoms. The COMT gene, which produces an enzyme that breaks down catecholamines in the synaptic gap, features two alleles, “Met” and “Val.” Individuals with the Val/Val genotype who use cannabis during adolescence are more likely to display psychotic symptoms. Among the catecholamines influenced by COMT is dopamine, which plays an important role in schizophrenia. (Adapted from Caspi et al., 2005)

LSD Serotonergic agonist No known medicinal value Hallucinogens Use results in tolerance, but not addiction or withdrawal Flashbacks with extended use

Alcohol GABAA receptor agonist Stimulates dopaminergic reward pathways Rapid tolerance Damaging effects on health

Alcohol and Mortality Figure 4.28 Alcohol and Mortality. Large meta-analyses demonstrate that people who drink moderately (about 20 grams of alcohol per day or about 1.4 servings) experience a relatively lower risk of death than people who drink either no alcohol or more than 75 grams (about 5 servings) per day. The exact reasons for these correlations are not well understood, nor do these data distinguish between people who spread out their drinking over time or binge drink on occasion). (Adapted from Corrao et al., 2000)