Chapter 4 Lecture PDF

Chapter 4: The Chemical Basis of Behavior: Neurotransmitters and Neuropharmacology Principles of Psychopharmacology Pharmacokinetics Pharmacodynamics Neurotransmitters and Neuromodulators Classical Neurotransmitters Acetylcholine Monoamines Amino Acids...

Chapter 4: The Chemical Basis of Behavior: Neurotransmitters and Neuropharmacology Principles of Psychopharmacology Pharmacokinetics Pharmacodynamics Neurotransmitters and Neuromodulators Classical Neurotransmitters Acetylcholine Monoamines Amino Acids Peptide Neurotransmitters Opioid peptides Non-Opioid Peptides Unconventional Neurotransmitters Soluble Gases Endocannabinoids 1 1 Principles of Psychopharmacology Definition of a Drug - exogenous chemical, that is not an essential nutrient, that significantly alters function of cells when taken in low doses Effects of a Drug - changes in physiological processes and behavior - e.g. opiates induce analgesia, sedation, respiratory and cardiac depression, diminished digestion, hypotonia, pupillary constriction, euphoria, after acute administration Definition of a Psychoactive Drug - drugs that alter mood, thought, or behavior - most used to manage psychopathology - some used recreationally Sites of Drug Action - molecules on or within cells 2 2 Principles of Psychopharmacology Pharmacokinetics - study of the processes by which drugs are absorbed, distributed, metabolized, and excreted (ADME) Pharmacodynamics - study of the effectiveness of drugs Pharmacokinetics is what the body does to a drug Pharmacodynamics is what the drug does to a body 3 3  Principles of Psychopharmacology Pharmacokinetics - Routes of Drug Administration - ingested/absorbed oral sublingual suppository topical skin patch - injected (peripheral) subcutaneous intra-muscular intraperitoneal intravenous - inhaled - injected (spinal/intracranial) intrathecal intracerebroventricular intraparenchymal 4 4 Principles of Psychopharmacology Pharmacokinetics - Routes of Drug Administration - ingested/absorbed oral sublingual suppository topical skin patch - injected (peripheral) subcutaneous intra-muscular intraperitoneal intravenous - inhaled - injected (spinal/intracranial) intrathecal intracerebroventricular intraparenchymal 5 5 Principles of Psychopharmacology Pharmacokinetics - Distribution of Psychoactive Drugs - lipid solubility is the most important factor determining entry of drug through BBB 6 6  Principles of Psychopharmacology Pharmacokinetics - Metabolism of Psychoactive Drugs - rate of enzymatic breakdown and excretion determines half-life - however, some drugs broken down into biologically active molecules, extending effective lifespan - individual differences in metabolism 7 7 Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - study of biochemical and physiological actions of a drug - study of the relationship between drug dose and effect 8 8 Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - dose-response function: plot of effectiveness across doses dose-response function 9 9  Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - dose-response function: comparison of potencies between drugs drug A drug B dose-response function 10 10 Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - therapeutic index: drugs usually have more than one effect - comparison of doses that exert beneficial effects vs. doses that exert toxic effects (margin of safety) - LD50/ED50 margin of safety 11 11 Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - sensitization: increase in effectiveness of a drug with repeated/chronic exposure - tolerance: decrease in effectiveness of a drug with repeated/chronic exposure - cross sensitization/cross tolerance: increase/decrease in effectiveness of a novel drug after repeated or chronic exposure to a different drug - sensitization and tolerance are action-specific, and may be dissociable - (e.g. barbiturate sedation shows tolerance, respiratory depression does not) sensitized tolerant baseline sensitization/tolerance 12 12  Principles of Psychopharmacology Pharmacodynamics - Two Major Classes of Psychoactive Drugs - agonists: mimic or increase neurotransmitter actions - antagonists: block or decrease neurotransmitter actions - competitive (direct) agonists and antagonists: engage in agonist or antagonist actions by attaching to same binding site as endogenous neurotransmitter - non-competitive (indirect) agonists and antagonists: engage in agonist/antagonist actions through binding to a noncompetitive site competitive agonist non-competitive agonist or antagonist or antagonist 13 13 Principles of Psychopharmacology Pharmacodynamics - Two Major Classes of Psychoactive Drugs - affinity: the attraction of the drug for its target - efficacy: the ability of the drug to exert its physiological action agonist antagonist 14 14 Principles of Psychopharmacology Pharmacodynamics - Two Major Classes of Psychoactive Drugs - irreversible antagonists: modify receptor rendering it permanently inactive - partial agonists: exert agonist actions that are not as effective as a full agonist - inverse agonists: bind to same receptor as a known agonist, but produces action opposite to that agonist 15 15  Principles of Psychopharmacology Pharmacodynamics - Effectiveness of Psychoactive Drugs - withdrawal symptoms: rebound actions after repeated/chronic drug administration, observed upon cessation of drug taking - generally opposite to acute drug actions - occur because of drug-induced tolerance - alterations in receptor number or affinity - alterations in receptor-coupling to effectors (ion channels and/or second messengers) heroin acute actions: analgesia, constipation, relaxation, euphoria heroin withdrawal: hyperalgesia, diarrhea, agitation, dysphoria sensitized tolerant baseline sensitization/tolerance 16 16 Principles of Psychopharmacology Mechanisms Whereby Psychoactive Drugs Interact with Neurotransmitters - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks postsynaptic receptors reuptake drug inactivates drug blocks metabolizing enzyme postsynaptic receptors 17 17 Neurotransmitters and Neuromodulators Criteria for a Classical Neurotransmitter/Neuromodulator: 1. synthesized by presynaptic neuron (contains appropriate biosynthetic enzymes) 2. released by presynaptic neuron when stimulated 3. can be chemically or pharmacologically identified 4. binds to specific receptors on postsynaptic membrane 5. should reproduce at postsynaptic cell effects that are observed upon stimulation of presynaptic neuron 6. blocking release, or blocking binding to postsynaptic receptors prevents presynaptic activity (action potentials) from affecting postsynaptic neuron 7. active mechanisms to terminate actions of chemical (neuronal or glial uptake, enzymatic degradation) - we now know some substances that don’t match classical criteria (e.g. nitric oxide, endocannabinoids) 18 18  Neurotransmitters and Neuromodulators Definitions of Neurotransmitter and Neuromodulator - we refer to broad array of substances released by neurons as neurotransmitters - recent challenges: - recognition that glutamate/GABA/glycine are principle effectors, whereas neuromodulators perform broader actions on functional circuits - e.g. ACh arouses cortex and facilitates learning, but specific cellular coding of neuroplasticity involves glutamatergic and GABAergic/glycinergic mechanisms - e.g. NE increases overall arousal and vigilance - e.g. DA is implicated in behavioral reinforcement, but glutamate is involved in sensitization to drugs of abuse - it is proposed that glutamate, GABA, and glycine are pure neurotransmitters, whereas others may technically be considered neuromodulators 19 19 Neurotransmitters and Neuromodulators Neuromodulatory Actions - synaptic actions: actions on synaptic receptors to modulate actions of glutamate, GABA, and glycine - metabotropic receptors - extrasynaptic actions: actions on receptors outside of synapse to modulate actions of glutamate, GABA, and glycine - spillover, varicosities that do not form synapses 20 20 Neurotransmitters and Neuromodulators Neuromodulatory Actions - axoaxonic synapses: modulate neurotransmitter release per action potential - presynaptic facilitation / presynaptic inhibition - cytosolic and nuclear receptors: lipid soluble hormones - retrograde signaling: lipid soluble substances signal back to the presynaptic terminal to regulate NT release - soluble gases, lipid derived transmitters 21 21  Neurotransmitters and Neuromodulators Classical Neurotransmitters - quaternary amine (acetylcholine) - monoamines (catecholamines and indoleamines) - amino acids: - small storage vesicles - active reuptake - mostly synthesized in nerve terminal by enzymatic modification of precursors - presence of specific enzymes determines type of biogenic amine synthesized by cells Quaternary Amine acetylcholine Monoamines catecholamines indoleamines dopamine melatonin norepinephrine Amino Acids GABA glutamate serotonin epinephrine glycine 22 22 Neurotransmitters and Neuromodulators Classical Neurotransmitters - OUTLINE - Biochemistry (mechanisms of synthesis, packaging, inactivation/reuptake…) - Neuroanatomy - Receptors - Functional Implications - Drugs 23 23 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Acetycholine (ACh), Biochemistry - synthesized by choline acetyltransferase (ChAT) from choline and acetyl-CoA - packaged into vesicles by VAChT - inactivated by hydrolysis of ACh to choline by acetylcholinesterase (AChE) and butyrylcholinesterase - choline is reuptaken by high affinity choline transporter (ChT), and then converted back to ACh 24 24  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Acetycholine (ACh), Neuroanatomy - found in preganglionic fibers of sympathetic ns and all fibers of parasympathetic ns - found in all motor neurons, released at all neuromuscular junctions - brainstem: pedunculopontine nucleus and dorsolateral tegmental nuclei, - projections to brainstem, deep cerebellar nuclei, LC, raphe, inferior olive - basal forebrain: basal nucleus of Meynert and medial septal nucleus - projections to neocortex and hippocampus - internal transmission in striatum 25 25 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Acetycholine (ACh), Receptors - binds to ionotropic nicotinic receptors (2 molecules) - Na+ channel - neuromuscular junctions and CNS axoaxonic synapses (facilitation) - binds to metabotropic muscarinic receptors - predominant form of ACh receptor in CNS 26 26 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Acetycholine (ACh), Functional Implications - implicated in motor function (NMJs), REM sleep (pons), learning and memory (basal forebrain activating cortical arousal), addictive effects of nicotine - deficits in Alzheimer’s disease - deficits in Myasthenia Gravis 27 27  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Acetycholine (ACh), Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks postsynaptic receptors reuptake nicotine, muscarine drug inactivates drug blocks metabolizing enzyme postsynaptic receptors Aricept (donepezil) curare neostigmine 28 28 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Monoamines - Catecholamines, Biochemistry - dopamine, norepinephrine, epinephrine - synthesized by enzymatic modification of tyrosine (tyr or Y) - at least 3 release mechanisms - Ca2+-dependent exocytosis - spontaneous or drug-induced reversal of DAT and NET - Ca2+-independent dendritic release - inactivated primarily by reuptake through DAT or NET - also inactivated by MAO-A, MAO-B, COMT 29 29 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Dopamine, Neuroanatomy - synthesized mostly in nigrostriatal and mesocorticolimbic neurons (A9 and A10) and tubero-infundibular neurons arcuate nucleus 30 30  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Dopamine, Receptors - binds to metabotropic receptors - D1 class = D1, D5, positive association with 1 adenylate cyclase - exclusively postsynaptic - mediate EPSPs S 2 i - D2 class = D2, D3, D4, negative association with adenylate cyclase - pre- and postsynaptic - D2 autoreceptors on dendrites and soma hyperpolarize membrane - D2, D3, D4 on postsynaptic membrane - mediate IPSPs 31 31 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Dopamine, Functional Implications - implicated in movement, attention, learning, motivation - implicated in inhibition of lactation - deficits/abnormalities in Parkinson’s disease, schizophrenia, drug addiction 32 32 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Dopamine, Drugs - agonists and antagonists drug is a precursor drug inactivates l-DOPA biosynthetic enzyme drug prevents storage reserpine drug activates autoreceptors drug stimulates apomorphine NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks/reverses postsynaptic receptors reuptake bromocriptine, cocaine, Ritalin apomorphine MAO-B amphetamine drug blocks drug inactivates postsynaptic receptors metabolizing enzyme neuroleptics deprenyl 33 33  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Dopamine, Drugs - agonists and antagonists 34 34 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Norepinephrine, Neuroanatomy - synthesized in postganglionic fibers of sympathetic nervous system and released at targets of sympathetic innervation - synthesized in cells that project from locus coeruleus and lateral tegmental field, and released through varicosities - these do not from traditional synapses 35 35 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Norepinephrine, Receptors - binds to metabotropic receptors - α1, α2, β1, β2 adrenoceptors found in CNS and PNS - β3 adrenoceptors found in PNS (especially adipose - enhances lipolysis) - all 5 types sensitive to EPI as well as norEPI - α1 produce EPSP; α2 are autoreceptors produce IPSP - β1, β2 adrenoceptors increase excitability of postsynaptic membranes 36 36  Neurotransmitters and Neuromodulators Classical Neurotransmitters - NE, Functional Implications - regulation of mood, arousal, sexual behavior, autonomic nervous system tone, “fight-or-flight” responses, energy metabolism, vigilance, vasoconstriction - deficiency/disregulation in ADHD, depression, schizophrenia, hypotension - deficiency suspected in Alzheimer’s disease because release from varicosities has anti-inflammatory role in CNS 37 37 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Norepinephrine, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks postsynaptic receptors reuptake bromocriptine trycyclics, NSRIs apomorphine MAO-A Ritalin ephedrine drug inactivates drug blocks metabolizing enzyme postsynaptic receptors clorgyline β-blockers 38 38 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Epinephrine - synthesized by chromaffin cells in adrenal medulla and released in response to sympathetic innervation - minor neurotransmitter in brain - implicated in energy metabolism, “fight-or-flight” responses 39 39  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Monoamines - Indoleamines - serotonin, melatonin - synthesized by enzymatic modification of tryptophan (trp or W) pineal gland 40 40 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Serotonin, Biochemistry - at least 3 release mechanisms - Ca2+-dependent exocytosis - spontaneous or drug-induced reversal of SERT - Ca2+-independent dendritic release - inactivated primarily by reuptake through SERT - deaminated preferentially by MAO-B 41 41 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Serotonin, Neuroanatomy - synthesized in 9 raphe nuclei and released from varicosities, not axon terminals - some varicosities (D system from dorsal raphe) do not appear to form synapses, and release is diffuse (neuromodulation) - some varicosities (M system from median raphe) form conventional synapses 42 42  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Serotonin, Receptors - binds to at least 14 different kinds of receptors - 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F all metabotropic - 5HT2A, 5HT2B, 5HT2C all metabotropic - 5HT3 is ionotropic, Cl- channel - 5HT1B, 5HT1D are presynaptic autoreceptors 43 43 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Serotonin, Functional Implications - implicated in regulation of mood, feeding, sleep, arousal, pain, sensory processing - disregulation implicated in major depression, bipolar disorder, OCD 44 44 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Serotonin, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug blocks drug activates reuptake postsynaptic receptors SSRIs, NSRIs LSD, buspirone drug inactivates drug blocks metabolizing enzyme postsynaptic receptors clozapine 45 45  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Melatonin - released from pineal gland - elevated in evening, induces sleepiness 46 46 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Amino Acids - Glutamate, Biochemistry - glutamic acid, most abundant excitatory neurotransmitter in CNS - synthesized from glucose metabolism (α-ketoglutarate) and amino acid precursors (glutamine) in axon terminals - recycled through glial uptake and metabolism to glutamine 47 47 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Neuroanatomy - ubiquitous, predominant excitatory neurotransmitter in CNS and PNS 48 48  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Receptors - 4 major subtypes of glutamate receptors, w/ at least 8 types of mGluRs - AMPA receptor; ionotropic (most abundant; Na+ channel) - NMDA receptor; ionotropic (Ca2+ channel) - kainate receptor; ionotropic (Na+ channel) - mGluR1- mGluR8; metabotropic 49 49 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Receptors - multiple binding sites on NMDA receptor - glutamate - glycine, co-binding required - Zn2+, binding decreases activity - polyamine (promote growth and development), binding increases activity - Mg2+- blocks Ca2+ conductance - PCP - blocks Ca2+ conductance - alcohol 50 50 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Functional Implications - activation of NMDA receptor-associated ion channels is dependent upon contiguous presynaptic and postsynaptic activity - at resting potential, NMDA ion channels are blocked by Mg2+ - if the postsynaptic membrane is sufficiently depolarized, Mg2+ is expelled 2+ Ca Therefore, NMDA receptors function as “coincidence detectors” for presynaptic Mg2+ neurotransmitter release, and postsynaptic depolarization. depolarized -70 mV Na+ Ca2+-dependent enzymes (e.g. CAM kinase II) 51 51  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Functional Implications - activation of NMDA receptor-associated ion channels is dependent upon contiguous presynaptic and postsynaptic activity - at resting potential, NMDA ion channels are blocked by Mg2+ - if the postsynaptic membrane is sufficiently depolarized, Mg2+ is expelled 2+ Ca Therefore, NMDA receptors function as “coincidence detectors” for presynaptic Mg2+ neurotransmitter release, and postsynaptic depolarization. depolarized -70 mV Na+ Ca2+-dependent enzymes (e.g. CAM kinase II) 52 52 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Functional Implications - activation of NMDA receptor-associated ion channels is dependent upon contiguous presynaptic and postsynaptic activity - at resting potential, NMDA ion channels are blocked by Mg2+ - if the postsynaptic membrane is sufficiently depolarized, Mg2+ is expelled 2+ Ca Therefore, NMDA receptors function as “coincidence detectors” for presynaptic Mg2+ neurotransmitter release, and postsynaptic depolarization. depolarized -70 mV Na+ Ca2+-dependent enzymes (e.g. CAM kinase II) 53 53 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Functional Implications - implicated in sensory processing, plasticity, and virtually every brain function - disregulation implicated in schizophrenia, epilepsy 54 54  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glutamate, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates postsynaptic receptors drug blocks NMDA, AMPA reuptake drug blocks drug inactivates postsynaptic receptors metabolizing enzyme CNQX, DNQX MK-801, APV, PCP, memantine 55 55 Neurotransmitters and Neuromodulators Classical Neurotransmitters - GABA, Biochemistry - gamma aminobutyric acid, most abundant inhibitory neurotransmitter in CNS - synthesized from glucose metabolism (α-ketoglutarate) through a glutamic acid intermediate by glutamic acid decarboxylase (GAD) - recycled through glial uptake and metabolism to glutamine 56 56 Neurotransmitters and Neuromodulators Classical Neurotransmitters - GABA, Neuroanatomy - ubiquitous, predominant inhibitory neurotransmitter in CNS and PNS 57 57  Neurotransmitters and Neuromodulators Classical Neurotransmitters - GABA, Receptors - 2 subtypes of GABA receptors - GABAA receptor; ionotropic (Cl- channel), postsynaptic - GABAB receptor; metabotropic (G-protein-coupled to K+ channel), presynaptic autoreceptor and postsynaptic receptor - multiple binding sites on GABAA receptor - GABA - barbiturate and alcohol - benzodiazepine - steroid - picrotoxin 58 58 Neurotransmitters and Neuromodulators Classical Neurotransmitters - GABA, Functional Implications - implicated in virtually every brain function - disregulation implicated in epilepsy 59 59 Neurotransmitters and Neuromodulators Classical Neurotransmitters - GABA, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks postsynaptic receptors reuptake diazepam, EtOH SSRIs, NSRIs pentobarbital drug inactivates drug blocks metabolizing enzyme postsynaptic receptors bicuculine 60 60  Neurotransmitters and Neuromodulators Classical Neurotransmitters - Amino Acids - Glycine, Biochemistry and Neuroanatomy - derived from glucose metabolism through serine intermediate - recycled through glial uptake and metabolism to glutamine - predominant inhibitory neurotransmitter in brainstem, spinal cord, and retina - binds to ionotropic glycine receptor; ionotropic (Cl- channel), postsynaptic - co-factor in NMDA receptor activation serine glycine → serine hydroxy- methyltransferase 61 61 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Amino Acids - Glycine, Receptors and Functional Implications - derived from glucose metabolism through serine intermediate - recycled through glial uptake and metabolism to glutamine - predominant inhibitory neurotransmitter in brainstem, spinal cord, and retina - binds to ionotropic glycine receptor; ionotropic (Cl- channel), postsynaptic - co-factor in NMDA receptor activation 62 62 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Glycine, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates postsynaptic receptors drug blocks reuptake drug inactivates drug blocks metabolizing enzyme postsynaptic receptors strychnine, tetanus toxin 63 63  Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Biochemistry - Opioid Peptides (endorphin, enkephalin, dynorphin, N/OFQ) - Non-Opioid Peptides (peptide YY, substance P, CCK, and many others) - short chains of amino acids cleaved from macroproteins by peptidases - manufactured in soma, transported slowly to axon terminal opioid proopiomelanocortin (POMC) β-MSH N-terminal GP ACTH β-LPH non-opioid γ-MSH α-MSH CLIP γ-LPH β-endorphin β-endorphin substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser- Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn- Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu 64 64 Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Biochemistry - Opioid Peptides (endorphin, enkephalin, dynorphin, N/OFQ) - Non-Opioid Peptides (peptide YY, substance P, CCK, and many others) - short chains of amino acids cleaved from macroproteins by peptidases - manufactured in soma, transported slowly to axon terminal - stored in large (~100nm) dense core vesicles, release from HFS or burst-firing APs - cannot respond quickly to increased demand - inactivated by diffusion or enzymatic metabolism; some products retain biological activity (e.g. angiotensin I converted to more and more active angiotensin II and III) 65 65 Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Opioid Peptides, Neuroanatomy - endorphins, enkephalins, dynorphins, N/OFQ - derived from POMC, proENK, proDYN, proN/OFQ - fairly ubiquitous distribution, descending projections from periaqueductal grey, opioid actions in forebrain (social), midbrain (motivation), brainstem (life functions) 66 66  Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Opioid Peptides, Receptors - binding to metabotropic receptors - enkephalins = µ, δ, κ - endorphins = µ, δ, κ - dynorphins = µ, δ, κ - N/OFQ = NOP - all 4 receptors, negative association with adenylate cyclase and open K+ channels 67 67 Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Opioid Peptides, Functional Implications - implicated in analgesia, socialization, feeding, behavioural reinforcement, defense responses, anxiety responses, gastric motility 68 68 Neurotransmitters and Neuromodulators Classical Neurotransmitters - Opioid Peptides, Drugs - agonists and antagonists drug is a precursor drug inactivates biosynthetic enzyme drug prevents storage drug activates autoreceptors drug stimulates NT release drug blocks drug inhibits autoreceptors NT release drug activates drug blocks postsynaptic receptors reuptake heroin, morphine, SSRIs, NSRIs oxycodone drug inactivates drug blocks metabolizing enzyme postsynaptic receptors naloxone, naltrexone 69 69  Neurotransmitters and Neuromodulators Peptide Neurotransmitters - Non-Opioid Peptides - NPY, PYY, CCK - regulation of feeding, gastric motility, circadian rhythms, anxiety/stress responses - binds to Y1-Y5 GPCRs - substance P - principal mechanism of pain signaling - mood disorders, stress, nausea - binds to neurokinin 1 (NK1) receptor - others - neurotensin, galanin, somatostatin, VIP, TRH, CRH, AGRP, bombesin, ghrelin, orexin, oxytocin, vasopressin, various neurokinins, relaxin, etc. 70 70 Neurotransmitters and Neuromodulators Unconventional Neurotransmitters - Soluble Gases - NO identified on basis that it causes rapid blood vessel dilation - cannot be stored - NMDAR activation strongly activates NO synthase in Ca2+-dependent manner - NO synthase oxidizes arg to synthesize NO - NO stimulates cGMP formation - no known mechanism for inactivation of NO - CO and H2S also function as soluble gaseous neurotransmitters 71 71 Neurotransmitters and Neuromodulators Unconventional Neurotransmitters - Lipids - Endocannabinoids (eCB) - 2 forms of eCBs: anandamide (AEA) and 2-arachidonylglycerol (2-AG) - synthesized from lipid precursors in response to Ca2+ influx or Ca2+ release from intracellular stores - eCBs diffuse across synaptic cleft to bind to presynaptic CB1Rs, which are negatively coupled to membrane Ca2+ channels - decreases presynaptic Ca2+ influx and NT release 72 72  Neurotransmitters and Neuromodulators Unconventional Neurotransmitters - Nucleosides - sugar + nucleotide, adenosine - released by astrocytes causing vasodilation - accumulates from neuronal metabolism of ATP - binds to A1, A2A, A2B, A3 metabotropic receptors - caffeine is antagonist 73 73 Neurotransmitters and Neuromodulators Why Multiple Types of Neurotransmitters? - segregation of multiple inputs that carry different information to dendrites, soma, axon on receptive neuron - changes in firing rates or patterns of firing (e.g. burst firing) recruits release of different types of neurotransmitters for a single neuron - differing distances to travel for synaptic and extrasynaptic communication, where long distance favours neurotransmission that lacks high affinity reuptake - simultaneous stimulation of ionotropic (fast) and metabotropic (enduring and metabolically active) receptors 74 74