Chapter 4: Neurotransmitters and Psychopharmacology> > > > > > Neurotransmitters and Neuromodulators Principles of Psychopharmacology Drug Actions The Classification of Psychoactive Drugs Agonists and Antagonists Drug Abuse Neurotransmitters and Neuromodulators > Neurotransmitters - endogenous, found in axon terminals, released by presynaptic neuron and bind to postsynaptic receptors - excitatory or inhibitory effects on postsynaptic neurons through receptor actions glutamate = principal neurotransmitter with excitatory actions GABA = principal neurotransmitter with inhibitory actions Glycine also important neurotransmitter with inhibitory actions > Neuromodulators - modify the release of a neurotransmitter adenosine modulates presynaptic dopamine release peptides may have neuromodulatory actions Neurotransmitters and Neuromodulators > Classes of neurotransmitters and neuromodulators acetylcholine indoleamines monoamines catecholamines amino acids melatonin serotonin dopamine norepinephrine epinephrine glutamate GABA glycine aspartate others Neurotransmitters and Neuromodulators > Classes of neurotransmitters and neuromodulators opioids neuropeptides non-opioids endorphins enkephalins dynorphins substance P neuropeptide Y others lipids anandamide nucleosides adenosine guanosine ATP others soluble gases nitric oxide others Neurotransmitters and Neuromodulators acetylcholine - released at all neuromuscular junctions - released at ganglia of sympathetic nervous system, and at target organs of parasympathetic nervous system - implicated in REM sleep, cognition and learning/memory Acetyl CoA + choline - synthesized from choline and acetyl CoA by choline acetyltransferase - degraded by acetylcholinesterase (AChE) - choline is reuptaken, and converted back to acetylcholine ChAT ACh + coenzyme A AChE choline + acetic acid Neurotransmitters and Neuromodulators acetylcholine nicotinic muscarinic - nicotinic receptors: ionotropic (rapid) found in neuromuscular junctions, junctions and CNS axoaxonic synapses agonist = nicotine; antagonist = curare - muscarinic receptors: metabotropic (slower) agonist = muscarine; antagonist = atropine released extensively throughout CNS from varicosities (beadlike swellings lli on axons)) that h do d not form f traditional di i l synapses (neuromodulation) .indoleamines synthesized from tryptophan indoleamine biosynthesis catecholamine biosynthesis Neurotransmitters and Neuromodulators monoamines catecholamines dopamine norepinephrine epinephrine > norepinephrine (noradrenaline) .Neurotransmitters and Neuromodulators acetylcholine Neurotransmitters and Neuromodulators melatonin serotonin dopamine norepinephrine epinephrine indoleamines monoamines catecholamines .locus coeruleus = cell body region of most extensive projection system .minor neurotransmitter released in the brain .norepinephrine implicated in vigilance > epinephrine (adrenaline) .hormone released by adrenal medulla .catecholamines synthesized y from tyrosine .released at target organs of sympathetic branch of ANS . motivation .also infundibular .behavioral effects of agonists are primarily excitatory Neurotransmitters and Neuromodulators monoamines catecholamines dopamine norepinephrine epinephrine . mesocortical.β1 and β2 = increase excitability of postsynaptic neurons .α2 are CNS autoreceptors .α1 = depolarization in CNS . attention.β3 adrenoceptors found only in periphery (especially adipose) . β1 and β2 adrenoceptors all found in CNS and periphery .α2 = hyperpolarization in CNS . through G proteins . and nigrostriatal systems are the major and most well-studied of the dopaminergic systems .all 5 types are metabotropic. α1 α2. α2 β1.all 5 types of adrenoceptors sensitive to EPI.Neurotransmitters and Neuromodulators norepinephrine Neurotransmitters and Neuromodulators α1 α2 β1 β2 β3 (peripheral) norepinephrine > norepinephrine .mesolimbic. learning. as well as norEPI .dopamine implicated in movement.α1. D1.some varicosities (M system from median raphe) form conventional synapses . D5: all postsynaptic. D4. and release is diffuse (neuromodulation) . D2. D3.D1. pain . feeding. D5 receptors all metabotropic .implicated in regulation of arousal.released from varicosities. D3.some varicosities (D system from dorsal raphe) do not appear to form synapses. D4: presynaptic and postsynaptic. sleep cycles > serotonin .implicated in regulation of mood. and decrease AC Neurotransmitters and Neuromodulators monoamines indoleamines melatonin serotonin > melatonin . and increase adenylate cyclase (AC) . sleep.D2.released from pineal gland .Neurotransmitters and Neuromodulators monoamines catecholamines dopamine norepinephrine epinephrine Neurotransmitters and Neuromodulators D1 D2 D3 D4 D5 dopamine . arousal. rather than axon terminals . Cl.5-HT3 .ubiquitous distribution. all metabotropic . 5-HT2C .Neurotransmitters and Neuromodulators monoamines indoleamines melatonin serotonin Neurotransmitters and Neuromodulators serotonin (5-HT) . 5-HT1D.5-HT2A. the predominant excitatory neurotransmitter in CNS .at least 14 different receptor subtypes . ionotropic.directly lowers threshold for excitatory effects on axons .5-HT1B and 5-HT1D are presynaptic autoreceptors 5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT1F 5-HT2A 5-HT2B 5 HT2C 5-HT 5-HT3 5-HT4 5-HT5A 5-HT5B 5-HT6 5-HT7 Neurotransmitters and Neuromodulators amino acids > glutamate GABA glycine aspartate others glutamate -g glutamic acid . 5-HT1E . 5-HT1B. all metabotropic t b t i .channel. 5-HT2B. 5-HT1F .5-HT1A. inhibitory input .excitatory effects through receptor actions on postsynaptic receptors . co-binding required Zn2+ .mGluR1. and postsynaptic depolarization. NMDA ion g2+.blocks Ca2+ conductance Neurotransmitters and Neuromodulators glutamate .activation of NMDA receptor-associated ion channels is dependent upon contiguous presynaptic and postsynaptic activity .binding decreases activity polyamine (molecules that promote growth and development) binding increases activity Mg2+. Ca2+ Mg2+ -70 mV .NMDA receptor. metabotropic (molecular switches and autoreceptors) Neurotransmitters and Neuromodulators glutamate .AMPA receptor. channels are blocked byy Mg .At the resting potential.multiple binding sites on NMDA receptor glutamate glycine . ionotropic (Ca2+ channel) . Na+ channel) . ionotropic (most abundant. ionotropic (Na+ channel) . w/ 7 types of mGluRs . Ca2+ Mg2+ Ca2+ Ca2+ EPSP Ca2+ Ca2+ Therefore. Mg2+ is expelled.mGluR7.blocks Ca2+ conductance PCP . NMDA receptors function as “coincidence detectors” for presynaptic neurotransmitter release.Neurotransmitters and Neuromodulators AMPA NMDA kainate mGluR1 mGluR2 mGluR3 mGluR4 mGluR5 Gl R5 mGluR6 mGluR7 glutamate .kainate receptor.If the postsynaptic membrane is sufficiently depolarized.4 major subtypes of glutamate receptors. GABAA receptor. ionotropic (Cl.2 subtypes of GABA receptors .inhibitory effects through receptor actions on postsynaptic receptors . metabotropic (K+ channel.synthesized from glutamic acid by GAD . postsynaptic receptor) .problems with GABA neurotransmission implicated in epilepsy Neurotransmitters and Neuromodulators GABA . postsynaptic receptor and presynaptic autoreceptor) .GABAB receptor. G protein-coupled. the predominant inhibitory neurotransmitter in CNS Neurotransmitters and Neuromodulators GABA GABAA GABAB .channel.Neurotransmitters and Neuromodulators amino acids glutamate GABA glycine aspartate others .directly elevates threshold for excitatory effects on axons .multiple binding sites on GABAA receptor GABA barbiturate benzodiazepine steroid picrotoxin .ubiquitous distribution. opium.biosynthetic pathway not well characterized . enkephalins. etc.Neurotransmitters and Neuromodulators glutamate GABA glycine aspartate others amino acids .channel) . no reuptake Neurotransmitters and Neuromodulators endorphins enkephalins dynorphins substance P neuropeptide Y others opioids neuropeptides non-opioids > neuropeptides. opioids .short chains of amino acids.manufactured in soma.extracellular peptides degraded by enzymes.also binds to NMDA receptor (excitatory) glycine R NMDAR glycine Neurotransmitters and Neuromodulators endorphins enkephalins dynorphins substance P neuropeptide Y others opioids neuropeptides non-opioids > neuropeptides id . and delivered to terminal by axonal transport .inhibitory effects throughout lower brain and spinal cord .ionotropic glycine receptor (inhibitory. including extrasynaptic sites . morphine. dynorphins. act as counterfeit opioids . all cleavage products of larger proteins . Cl. heroin.released from all parts of terminals.endogenous opioids = endorphins. proDYN . N/OFQ . proENK.ubiquitous distribution β-MSH proopiomelanocortin N-terminal GP γ-MSH β-LPH ACTH α-MSH CLIP γ-LPH β-endorphin .from POMC. socialization. δ.Neurotransmitters and Neuromodulators opioid . feeding.endogenous opioid receptors = μ. inhibition of defense responses and anxiety responses.neuropeptide Y .cholecystokinin h l ki i (CCK) ( ) .often co-released with other neurotransmitters and other peptides. NOP mu mu delta kappa mu mu d lt delta kappa mu mu delta kappa mu mu delta kappa β-endorphin enkephalin l enkephalin leu-enkephalin k k h hlili met-enkephalin enkephalin dynorphin enkephalin N/OFQ NOP Neurotransmitters and Neuromodulators opioid > neuropeptides. gastric motility .substance P . exerting ti regulatory l t functions f ti Neurotransmitters and Neuromodulators opioids neuropeptides non-opioids . behavioural reinforcement.corticotropin releasing hormone .implicated in analgesia. κ.oxytocin endorphins enkephalins dynorphins substance P neuropeptide Y others . opioids . NO manufactured by at least 3 forms of nitric oxide synthase (NOS) . A3 adenosine A1 A2a A2b A3 Neurotransmitters and Neuromodulators soluble gases nitric oxide others . A2a. another endogenous THC ligand Neurotransmitters and Neuromodulators nucleosides adenosine guanosine ATP others .neurons that release adenosine have not been well characterized .NO more extensively studied than CO .sugar + purine or pyrimidine base.g. and activates second messenger mechanisms .g.Neurotransmitters and Neuromodulators lipids anandamide .2-arachidonyl glycerol. endogenous ligand for THC receptor . A2b.receptors: A1.NO is manufactured at many sites in cells.anadamide. and diffuses immediately . modulation of dopamine neurotransmission . adenosine – a purine nucleoside = ribose + adenine . carbon monoxide (CO) .nitric oxide (NO).NO enters neighbouring cells.functions f ti as a neuromodulator d l t e. e. g. and excreted > How Do Psychoactive Drugs Get into the Nervous System? . thought. sedation. opiates = analgesia. hypotonia.most used to manage/treat psychopathology .changes in physiological processes .Principles of Psychopharmacology > Definition of a Drug .an exogenous chemical not necessary for normal cellular function that significantly alters the function of certain cells when taken in fairly low doses > Psychoactive Drugs . euphoria > Site of Action of a Drug .locations at which molecules of drug interact with molecules located on or in cells > Pharmacokinetics . metabolized.routes of administration Principles of Psychopharmacology Principles of Psychopharmacology absorbed oral sublingual suppository topical skin patch injected subcutaneous intra-muscular intraperitoneal intravenous inhaled spinal/intracranial intrathecal intracerebroventricular intraparenchymal . or behavior .some used recreationally > Effects of a Drug .process by which drugs are absorbed. pupillary constriction. depressed cardiac respiratory and digestive function.drugs that alter mood.e. distributed. respiratory depression 20 10 low 0 low Dose of Drug high shift in dose-response function .Differences in effectiveness: differing drugs = differing sites of action differing drugs = differing affinities differing drugs = differing efficacies .Affinity: the attraction of a drug for its target .differential distribution into body and brain. the Blood-Brain Barrier > Drug Effectiveness Principles of Psychopharmacology high 30 Effect of Drug .Therapeutic Index: most drugs = more than one effect margin of safety measured as therapeutic index therapeutic index = LD50/ED50 high 30 Effect of Drug > .analgesia .Principles of Psychopharmacology > How Do Psychoactive Drugs Get into the Nervous System? .Efficacy: the ability of a drug to exert its biological action 20 10 low 0 low Dose of Drug high dose-response function Principles of Psychopharmacology Drug Effectiveness . constipation. dysphoria Drug Actions > Two Major Classes of Psychoactive Drugs . euphoria Withdrawal: hyperalgesia. agitation.Tolerance: A decrease in the apparent effect of a drug with repeated or chronic exposure high 30 . 2. Competitive antagonists attach to the same binding site as the endogenous neurotransmitter and block the receptor. These are known as direct antagonists. 3. Noncompetitive. Irreversible antagonists actually modify the receptor so that the endogenous neurotransmitter cannot exert further effects. occurs upon cessation of drug administration generally opposite to the actions of the drug occur because of drug-induced tolerance alterations in receptor number or affinity alterations in receptor-coupling to effectors (ion channels. . Noncompetitive antagonists attach to a different binding site than does the endogenous neurotransmitter for that receptor.Sensitization: An increase in the apparent effect of a drug with repeated or chronic exposure Effect of Drug .Withdrawal Symptoms: rebound actions after repeated drug administration.tolerant 20 10 low 0 low Dose of Drug high shift in dose-response function . relaxation.Agonists: mimic or increase the effects of a particular neurotransmitter or class of neurotransmitters .Antagonists: block or decrease the effects of a particular neurotransmitter or class of neurotransmitters .Principles of Psychopharmacology > Effects of Repeated Administration .Competitive. These antagonists are known as indirect antagonists. second messengers) Heroin: analgesia. and Irreversible Antagonists: 1.Cross Sensitization / Cross Tolerance: An increase / decrease in the apparent effect of a novel drug after repeated or chronic exposure to another drug Principles of Psychopharmacology > Effects of Repeated Administration . diarrhea.baseline .sensitized . . 7. . . . prevents storage in synaptic vesicles. . . . decreases release fusaric acid. 7.antagonists: AMPT. 33. blocks α2 adrenoceptors . . Drug Actions > 1. Two Major Classes of Psychoactive Drugs . Drug increases catabolism Drug decreases neurotransmitter release Drug activates autoreceptors to increase autoreceptor-mediated inhibition of synthesis and release Drug binds to postsynaptic receptors and antagonizes them Drug increases degradation or reuptake of released neurotransmitters . 6. . . 2. 5. . . 2. . . Drug destroys catabolizing enzymes Drug increases neurotransmitter release Drug antagonizes autoreceptors to prevent autoreceptor-mediated inhibition of synthesis and release Drug binds to postsynaptic receptors and activates them Drug blocks degradation or reuptake of released neurotransmitters . precursor) Drug enhances packaging/transport of synthesized neurotransmitter into vesicles and granules . Agonists and Antagonists norepinephrine . . monoamine oxidase-A inhibitor (MAOI) clonidine.AGONISTS Drug increases neurotransmitter synthesis (e. . activates α2 adrenoceptors NSRIs . . 33. inhibits dopamine-β-hydroxylase. . 5. decreases biosynthesis yohimbine.ANTAGONISTS Drug decreases neurotransmitter synthesis Drug interrupts packaging/transport of synthesized neurotransmitter into vesicles and granules . decreases biosynthesis reserpine.g. 4. .Drug Actions > 1. . 4. inhibits reuptake moclobemide. . inactivates TH. .agonists: desipramine. Two Major Classes of Psychoactive Drugs . 6. . . agonist. blocks NMDA receptors CNQX.mixed: apomorphine. increases 5-HT release and blocks reuptake. precursor.agonists: l-dopa. agonist at D2 class deprenyl. decreases release SCH 23390 blocks D1 chlorpromazine and haloperidol. increases biosynthesis cocaine. activates NMDA receptors AMPA.antagonist. treatment of depression. and blocks reuptake bromocriptine. monoamine oxidase-B inhibitor (MAOI) .agonists: n-methyl-D-aspartic acid. memantine blocks NMDA receptors AP5. decreases biosynthesis reserpine. activates AMPA receptors kainate. higher affinity for presynaptic D2 autoreceptors than for postsynaptic D2 receptors therefore. anxiety. decreases release ketanserin.antagonists: reserpine. antagonist at low doses. prevents storage in synaptic vesicles. increases release. inhibits reuptake. blocks 5-HT2A receptors Agonists and Antagonists glutamate . inactivates TH.agonists: fluoxetine (Prozac). neuroleptic – blocks D2 clozapine. activates kainate receptors . activates D2 class. treatment of obesity (appetite suppressant) 8-OH-DPAT.antagonists: i AMPT. SSRI. blocks AMPA and kainate receptors glycine . none identified . prevents storage in synaptic vesicles.antagonists: MK-801. OCD fenfluramine. death . activates 5-HT1A receptors . agonist at higher doses Agonists and Antagonists serotonin . atypical neuroleptic – blocks D4 . blocks reuptake amphetamine. strychnine = convulsions.Agonists and Antagonists dopamine . μ antagonist.agonists: opium.antagonists: caffeine. antagonist at GABAA receptors bicuculline. selective μ/δ/κ antagonists adenosine . sedative. sedative barbiturates. theophylline. long-lasting form of naloxone CTOP/ naltrindole/nor-BNI. δ agonist (highly selective) U-50. used for overdose naltrexone. GABAB agonist. highly toxic (low therapeutic index) EtOH. non selective The Classification of Psychoactive Drugs > > > > > Sedative Hypnotics and Anxiolytics Antipsychotics Antidepressants Narcotic Analgesics Psychostimulants . anxiolytic.agonists: muscimol. κ agonist (highly selective) . chlordiazepoxide or librium) . activates GABAA receptors through GABA site benzodiazepines (diazepam or valium. heroin. GABAA agonists. blocks GABA binding site on GABAA receptors Agonists and Antagonists opioids . 488H. morphine. μ agonists (somewhat selective) DAMGO. probably binds to benzo binding site various steroids.antagonists: picrotoxin. μ agonist (highly selective) DPDPE. muscle relaxant .antagonists: naloxone (NARCAN). anxiolytic. GABAA agonists.Agonists and Antagonists GABA . sedatives baclofen. GABAA agonists. amphetamine/cocaine psychosis glutamate hypothesis of schizophrenia The Classification of Psychoactive Drugs > Antidepressants 7.efficacy of neuroleptics at D2. and D4 receptors .alcohol.an SSRI) (Cymbalta – an NSRI) delay between onset of actions at synapses (immediate) and clinical efficacy (weeks) is not understood .tricyclic antidepressants .second generation antidepressants (fluoxetine . barbiturates. risperidone antagonists at dopamine receptors dopamine hypothesis of schizophrenia .monoamine oxidase inhibitors (MAOIs) . D3. chlorpromazine.6-8. benzodiazepines (valium) All drugs in this group produce tolerance Cross-tolerance is also seen Actions on GABA receptor The Classification of Psychoactive Drugs > Antipsychotic Agents neuroleptics – haloperidol.The Classification of Psychoactive Drugs > Sedative Hypnotics and Anxiolytics minor tranquilizers / anxiolytics / sleeping pills - . atypical neuroleptics – clozapine.9% of population = lifetime incidence of depression usually recovery before one year some refractory high incidence of suicide . and κ opioid receptors imitate endogenous enkephalin.Bulletin of the WHO. wherein positive reinforcers elicit approach. codeine. 1987 “A psychomotor stimulant theory of addiction” A common denominator of addictive substances is their ability to induce psychomotor activation. etc. and activate dopaminergic fibers. and dynorphin opioid neurotransmitters The Classification of Psychoactive Drugs > Stimulants . 1965 “Drug dependence: its significance and characteristics” Opiate/drug addiction defined in terms of physical dependence and withdrawal symptoms . psilocybin Drug Abuse > Addiction and Dependence . and Bozarth.psychedelic drugs alter sensory processing and cognition mescaline.opium. morphine.A.. LSD. agonists at endogenous μ. fentanyl. . δ.behavioral stimulants increase motor behavior. M. endorphin. R..A.The Classification of Psychoactive Drugs > Narcotic Analgesics derived from opium poppy or artificially synthesized . heroin. and it varies from drug to drug. elevate mood cocaine and amphetamine . The role of physical dependence is ascribed a secondary role.Wise. drug liking decreases. motivating further drug-taking behaviour.E. and persists after termination of the drug exposure. T. and for the persistence or reinstatement of drug craving long after discontinuation.. Drug Abuse > Addiction and Dependence 1.Drug Abuse > Addiction and Dependence .F.Koob G. pleasurable drug effects 2.not very satisfactory.behavior has been described as “time out” from social rules. and Bloom F. Stinus L. associative conditioning 3. and Berridge. or alcohol myopia . Le Moal M.. (1989) “Opponent process theory of motivation…” Drug exposure initiates an adaptive process that opposes the hedonic effects of the drug.E.suppression of cortical function (judgment and reasoning) while sparing subcortical function (drives) .Robinson.. inhibition/disinhibition seen in different circumstances . As drug craving increases.. 1994 “The neural basis of drug craving: an incentive-sensitization theory of addiction” Drug addiction theories must account for the intense craving exhibited by addicts. K.C. attribution of incentive salience to drug-related stimuli Drug Abuse > Behavior on Drugs Common effect is behavioral disinhibition disinhibition theory: .. . loss of appetite.concordance in twin studies. sleeplessness.Drug Abuse > Individual Differences in Vulnerability to Drug Abuse evidence for genetic predisposition: . dizziness. depression.MPTP contamination in synthetic heroin risk from direct actions of drugs: . blurred vision. garbled speech. seizures. gastrointestinal disturbances.gamma hydroxybutyrate (GHB) = drowsiness. and death long-term effects = memory loss. fatal respiratory problems - rohypnol = decreased blood pressure.stress hyper-responsive rats > The Potential Harmfulness of Recreational Drugs Drug Abuse risk of impurities: . tremors. trembling. weakness. sweating. paranoia. numbness. urinary retention effects are aggravated by alcohol - Drug Abuse > The Potential Harmfulness of Recreational Drugs risk from direct actions of drugs: . nausea is common two long-term disorders = persistent psychosis and “hallucinogen persisting perception disorder” (which used to be called "flashbacks") phencyclidine (PCP) = hallucinations. more likely to be alcoholic . vomiting. decreased DA transporters - - - - lysergic acid diethylamide (LSD) = elevated body temperature. dry mouth. catatonia. impaired motor function.animals generally don’t drink alcohol. loss of reflexes. high blood pressure. death . disordered thinking. impaired breathing. but selectively bred strains of mice do personality traits: . coma.ecstasy particularly known for contaminants . headache. dizziness. nausea.risk taking behavior . potential cardiac damage. loss of balance. drooling. confusion. violence. loss of consciousness. increased heart rate and blood pressure. visual disturbances. amnesia. nystagmus. violent or suicidal outbursts.methamphetamine = memory loss. vomiting. and weight loss . difficulties with speech and thinking. coma. nausea. neurotoxic to dopaminergic neurons. aggression. cardiac and respiratory depression. depression. especially identical .onset of overdose is EXTREMELY rapid - ketamine = delerium.adopted children of biological parents who are alcoholic. psychotic behavior (amphetamine psychosis). vomiting. death - ecstasy = neurotoxic to serotonergic neurons. Rosenzweig. respiratory and cardiac depression.Drug Abuse > The Potential Harmfulness of Recreational Drugs risk from direct actions of drugs: - opiates = nausea. & Watson . hypertension. malignant hyperthermia leading to muscle breakdown and potentially fatal kidney and cardiovascular system failure continued use may also lead to heart attacks. dehydration. strokes. elevated heart rate and blood pressure. and seizures in some users - Reading Assignment Before next class Chapter 5: Hormones and the Brain Breedlove. coma.