La Trobe University PSY1BNA Lecture 8: The Chemistry of Behaviour 2 Neuropharmacology PDF

latrobe.edu.au PSY1BNA Lecture 8: The Chemistry of Behaviour 2 Neuropharmacology Week 8 La Trobe University CRICOS Provider Code Number 00115M latrobe.edu.au Overview Key knowledge and understanding Basic neuropharmacology, binding affinity, efficacy and dose response Drug effects on synaptic transm...

latrobe.edu.au PSY1BNA Lecture 8: The Chemistry of Behaviour 2 Neuropharmacology Week 8 La Trobe University CRICOS Provider Code Number 00115M latrobe.edu.au Overview Key knowledge and understanding Basic neuropharmacology, binding affinity, efficacy and dose response Drug effects on synaptic transmission Antipsychotic, antidepressant, and anxiolytic Some common recreational drugs latrobe.edu.au Readings for Neuropharmacology Recommended reading: Breedlove, S.M., & Watson, N.W. (2023). Behavioral Neuroscience (10th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 111-134). Breedlove, S.M., & Watson, N.W. (2020). Behavioral Neuroscience (9th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 106-126). Breedlove, S.M., & Watson, N.W. (2017). Behavioral Neuroscience (8th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 103-121). Part 1 Summary of Week 7 Content latrobe.edu.au Introduction Neurochemistry focuses on the basic chemical composition and processes of the nervous system. Focus of Week 7 lecture Neuropharmacology is the study of compounds that selectively affect the nervous system. Focus of Week 8 lecture latrobe.edu.au Neurotransmitter pathways - animations  Neurotransmitter pathways: Acetylcholine Neuroscience 6e Animation 6.1 - Neurotransmitter Pathways: Acetylcholine (oup.com)  Neurotransmitter pathways: Glutamate Neuroscience 6e Animation 6.2 - Neurotransmitter Pathways: Glutamate (oup.com)  Neurotransmitter pathways: Dopamine Neuroscience 6e Animation 6.3 - Neurotransmitter Pathways: Dopamine (oup.com)  Neurotransmitter pathways: Norepinephrine Neuroscience 6e Animation 6.4 - Neurotransmitter Pathways: Norepinephrine (oup.com)  Neurotransmitter pathways: Serotonin Neuroscience 6e Animation 6.5 - Neurotransmitter Pathways: Serotonin (oup.com) latrobe.edu.au Binding affinity and drug effectiveness latrobe.edu.au Receptor regulation latrobe.edu.au Receptor regulation latrobe.edu.au Drug effects on presynaptic mechanisms latrobe.edu.au Drug effects on postsynaptic mechanisms Part 2 Neuroactive Drugs 1 latrobe.edu.au Antipsychotics relieve schizophrenia Antipsychotics (neuroleptics): A class of drugs used to treat schizophrenia. Typical antipsychotics are selective dopamine D2 antagonists (reduce the positive symptoms of schizophrenia, such as delusions and hallucinations). Chlorpromazine, haloperidol, loxapine Atypical antipsychotics typically block some serotonin receptors and seem to reduce negative symptoms (such as social withdrawal and blunted emotional responses) of schizophrenia. Clozapine Third generation antipsychotics target novel synapses such as glutamate. latrobe.edu.au Antidepressants treat depression Monoamine oxidase (MAO) inhibitors prevent the breakdown of monoamines at the synapses. Accumulating monoamines and prolonging their activity is a major feature of antidepressants. Tricyclic antidepressants increase norepinephrine and serotonin at the synapses by blocking their reuptake into presynaptic axon terminals. Selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft allow serotonin to accumulate in the synapses, with fewer side effects than tricyclics. latrobe.edu.au Anxiolytics combat anxiety Anxiolytics, or tranquilizers, are depressants—drugs that reduce nervous system activity. Benzodiazepine agonists act on GABAA receptors and enhance the inhibitory effects of GABA. Example: Barbiturates latrobe.edu.au GABA receptors GABA receptors have several binding sites that enhance or inhibit GABA’s effects. Benzodiazepines bind at an orphan receptor—no known endogenous ligand. Allopregnanolone, a steroid, is elevated during stress and is calming. Other neurosteroids (steroids produced in the brain) may act on GABAA sites. latrobe.edu.au Designer Receptors Exclusively Activated by. Designer Drugs (DREADDs) latrobe.edu.au Opiates relieve pain Opium (extracted from poppy seeds) contains morphine, an effective analgesic, or painkiller. Morphine and heroin are related and are both highly addictive. These opiates bind to opioid receptors in the brain, especially in the locus coeruleus and the periaqueductal gray. latrobe.edu.au Opioid receptors in the rat brain latrobe.edu.au Endogenous opiates Endogenous opiates—peptides produced in the body that bind to opioid receptors and relieve pain—are also addictive. Enkephalins Endorphins Dynorphins There are three main types of opiate receptors (all are metabotropic): Delta (δ) Kappa (κ) Mu (μ) latrobe.edu.au Cannabinoids Marijuana is derived from Cannabis sativa—its active ingredient is Δ9-tetrahydrocannabinol (THC): Effects vary—include relaxation, mood alteration, stimulation, hallucination, and paranoia Sustained use can cause addiction The brain contains cannabinoid receptors to mediate the effects of THC and other compounds. Cannabinoid receptors are concentrated in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex. latrobe.edu.au Cannabinoid receptors in the brain latrobe.edu.au Cannabinoids There are two kinds of cannabinoid receptors (both are G protein-coupled metabotropic receptors). CB1 receptors are only found in the CNS and mediates the rewarding properties of cannabinoids. CB2 receptors are prominent in the immune system. Endocannabinoids—homologs of marijuana produced in the brain—act as retrograde messengers and may influence neurotransmitter release from the presynaptic neuron. Anandamide is an endocannabinoid with many effects: Alters memory formation Stimulates appetite Reduces pain sensitivity Protects from excitotoxic brain damage Lowers blood pressure Combats nausea Lowers eye pressure from glaucoma latrobe.edu.au Chronic use of marijuana Chronic or heavy marijuana use has negative effects Transient amnesia Stimulation and paranoia are possible Respiratory problems Addiction Cognitive decline Psychiatric disorders Use of marijuana in adolescence is correlated with development of psychosis in adulthood. Part 3 Neuroactive Drugs 2 latrobe.edu.au Stimulants Stimulants increase nervous system activity and have an alerting, activating effect. Many naturally occurring and artificial stimulants are widely used, including amphetamine, nicotine, caffeine, and cocaine. Khat, or qat, is an African shrub that acts as a stimulant. Amphetamine-like stimulants, called cathinones, are released when khat is chewed. latrobe.edu.au Nicotine Nicotine (from tobacco) Increases heart rate, blood pressure, hydrochloric acid secretion, and bowel activity. Acts as an agonist on nicotinic ACh receptors in the body and brain. Rewarding effects are mediated by receptors in the ventral tegmental area. Nicotine in one cigarette can occupy 88% of the brains nicotinic receptors. latrobe.edu.au Cocaine Leaves from the coca shrub alleviate hunger, promote endurance, and enhance sense of well-being. Cocaine is the purified extract. Can be used as an anesthetic Increases catecholamine stimulation Is highly addictive Crack cocaine is smoked and enters the brain more rapidly. Cocaine blocks monoamine transporters—especially dopamine—slows reuptake of neurotransmitters, enhancing their effects. Dual dependence is addiction to the effects of the interaction of two drugs. For example, cocaine metabolized in the presence of ethanol (alcohol) yields an active metabolite called cocaethylene, to which the user may develop an additional addiction. latrobe.edu.au Cocaine binding sites in the brain latrobe.edu.au Amphetamine Amphetamine and methamphetamine are synthetic stimulants that resemble catecholamine transmitters (norepinephrine, epinephrine, and dopamine) in structure. They cause the release of neurotransmitters even in the absence of action potentials and potentiate release with action potentials. Amphetamine enhances activity in two additional ways: By blocking the reuptake of catecholamines into the presynaptic terminal By providing an alternative target for the enzyme (monoamine oxidase) that normally inactivates catecholamines latrobe.edu.au Effects of amphetamine use Short-term effects of amphetamines include alertness, euphoria, and stamina. Long-term use leads to sleeplessness, weight loss, and general deterioration of mental and physical condition. Prolonged use of amphetamine may lead to symptoms that closely resemble those of paranoid schizophrenia: compulsive, agitated behavior and irrational suspiciousness. latrobe.edu.au Alcohol Alcohol’s effects are biphasic—an initial stimulant phase followed by a depressant phase. Alcohol activates GABAA receptors and increases inhibitory effects. This contributes to social disinhibition and loss of motor coordination. Alcohol also stimulates dopamine pathways, causing euphoric effects. Alcohol abuse damages nerve cells; the frontal lobes are the most affected by chronic alcohol use, yet some effects are reversible. Periodic overconsumption, or bingeing, may cause brain damage and reduces neurogenesis. Fetal alcohol syndrome is the result of pregnant women abusing alcohol, with permanent damage to the fetus. latrobe.edu.au The effects of alcohol on the brain latrobe.edu.au Hallucinogens Hallucinogens alter sensory perception and produce peculiar experiences. LSD (acid), mescaline (peyote), and psilocybin (magic mushrooms) have mainly visual effects. Hallucinogens have diverse neural actions, including those on the noradrenergic (e.g., mescaline), serotonergic (e.g., mescaline, psilocybin, and LSD), Ach (e.g., muscarine), and opiate (e.g., Salvia) systems. LSD acts as a serotonin agonist or partial agonist, especially on 5HT2A receptors, found in high concentrations in the visual cortex. latrobe.edu.au Perceptual alteration with LSD latrobe.edu.au Functional classes of drugs Ketamine (Special K) blocks NMDA receptors in the prefrontal cortex. It is classified as a dissociative: Produces detachment and depersonalization at moderate doses Produces transient hallucinogenic effects and psychotic symptoms at high doses MDMA (Ecstasy) is a hallucinogenic amphetamine derivative; its major actions are increases in serotonin levels and changes in dopamine and oxytocin levels. Effects are positive emotions, empathy, sense of well-being, colorful visual phenomena. Chronic use causes depression, memory disturbances and alters the structure and function of serotonergic neurons. latrobe.edu.au Clinical applications Part 4 Drug Abuse and Addiction latrobe.edu.au Drug abuse and addiction Substance abuse and addiction afflicts many millions of people and disrupts the lives of their families, friends, and associates. Important social costs include: Huge expenses for medical and social services Millions of hours lost in the workplace Elevated rates of crime associated with illicit drugs Scores of children who are damaged by their parents’ substance abuse behavior latrobe.edu.au Substance related disorders Substance-Related Disorders: Dependence (addiction) is the desire to self-administer a drug of abuse—criteria include patterns of consumption, craving, time and energy, and impact on one’s life. It is a more severe disorder than substance abuse, which is a pattern of use that does not fully meet the criteria for dependence. Many addictive drugs cause dopamine release in the nucleus accumbens. Some axons that terminate here originate in the ventral tegmental area (VTA) and are involved in the reward pathway. The addictive power of drugs may come from stimulating this pathway. Another pathway may involve the insula, a brain region within the frontal cortex. People with damage to this area have been able to stop smoking effortlessly. Reciprocal connections between the VTA and the insula suggest that these two regions normally interact to mediate addiction. latrobe.edu.au Neural pathway implicated in drug abuse latrobe.edu.au Dopaminergic pathways in the brain latrobe.edu.au Factors in susceptibility to addiction Biological—sex, genetic predisposition Family situation—family breakup, poor relationships, sibling drug users Personal characteristics—aggressiveness, emotional control Environmental factors—peer pressure, social factors Environmental stimuli can become associated with the effects of drugs. Cue-induced drug use is the increased likelihood of using a drug because factors are present that were also present when the drug was last used. latrobe.edu.au Medications to treat drug abuse Lessening the discomfort of withdrawal—benzodiazepines and drugs that suppress central adrenergic activity to help ease withdrawal symptoms or cravings Providing alternatives to the addictive drug—agonist or partial agonist analogs partially activate the same pathways, such as methadone or nicotine patches Directly blocking the actions of the addictive drug—blocks effects of the abused drug but may produce harsh withdrawal symptoms Altering the metabolism of the abused drug—changing breakdown of drug can change, reduce, or reverse its rewarding properties Antabuse causes nausea-inducing metabolites to be formed from alcohol in the body Blocking the brains reward system—blocks rewarding effects of the abused drug, but may produce a lack of all pleasurable feelings latrobe.edu.au The cutting edge Vaccination may be effective for prompting the immune system to reject and remove targeted drugs. latrobe.edu.au The cutting edge latrobe.edu.au Concluding remarks The effects of a drug depend on its site of action and dose Drugs affect each stage of neural conduction and synaptic transmission Antipsychotic, antidepressant, and anxiolytic drugs Opiates are potent painkillers The effects of stimulant drugs Hallucinogens alter sensory perception Substance abuse and addiction are major health problems Treating drug abuse