Topic 4 - The Chemistry of Behavior PDF

Topic 4 The Chemistry of Behavior • Receptor Features • Neurotransmitters • Basic Pharmacology Types of receptors Ionotropic receptor – ligand-gated ion channel • Fast-acting changes in Vm Metabotropic receptors – (AKA G-protein coupled receptors (GPCRs)) activate intracellular signaling cascade...

Topic 4 The Chemistry of Behavior • Receptor Features • Neurotransmitters • Basic Pharmacology Types of receptors Ionotropic receptor – ligand-gated ion channel • Fast-acting changes in Vm Metabotropic receptors – (AKA G-protein coupled receptors (GPCRs)) activate intracellular signaling cascades • Slow but powerful and diverse effects • Multiple effects possible • Indirectly open ion channels • Change ion channel conductivity • Add/remove receptors • Alter gene expression • Signal amplification Types of receptors Opioid receptor mRNA distribution in human brain Receptor diversity A given neurotransmitter system can act on many receptor subtypes Raynor, Kong, Law, & Heerding, 1996 Major GABAA receptor subtypes Sinkkonen, 2004 Receptor subtypes can: • differ in anatomical distribution • work with different ions • respond to multiple NTs • interact within/across neuron populations to alter signaling in complex ways • have sub-subtypes (and sub-sub-subtypes) Neurotransmitters Neurotransmitter (NT) – endogenous chemical specialized for transmitting information between neurons • Endogenous – naturallyoccurring, originating from organism itself Neurotransmitter criteria Neurotransmitters: • are stored in axon terminals • are synthesized in neurons • are released when APs reach axon terminals • are recognized by receptors on the postsynaptic membrane. • evoke changes in a postsynaptic cell. Three (four?) major NT families Amino acids — GABA, glutamate, glycine, aspartate, histamine Amines — acetylcholine, dopamine, serotonin, norepinephrine, epinephrine, melatonin Neuropeptides — endorphins (class), dynorphins (class), enkephalins (class), oxytocin, vasopressin, neuropeptide Y, substance P, releasing hormones (class) Gases – nitric oxide, carbon monoxide  weird, break NT rules Amino acid – Glutamate Glutamate (Glu) - most common excitatory NT! Involved in every function • Key role in memory formation! Most Glu receptors are ionotropic and permeable to Na+ Important Glu receptors: • • • • AMPA NMDA kainate Metabotropic Glu receptors (mGluRs) – more on these in 301! Amino acid - GABA Gamma-aminobutyric acid (GABA) — most widely distributed inhibitory NT Controls excitability Classes of GABA receptors: -70 • GABAA receptors - ionotropic Clchannels • GABAB receptors – metabotropic, slow inhibition via K+ and other channels Amines Typically alter glutamateGABA signaling balance (neuromodulation) Amine transmitters are synthesized in one area, project throughout brain: • Acetylcholine • Monoamines • Catecholamines • Dopamine • Norepinephrine • Epinephrine • Indolamines • Serotonin • Melatonin Amines - Acetylcholine Acetylcholine (ACh) • Origin: basal forebrain • Learning/memory processes • NT used at neuromuscular junction (NMJ) • Released by parasympathetic nervous system • Major receptor families: • Nicotinic ACh receptor (nAChR) – mostly ionotropic (excitatory) • Muscarinic ACh receptor (mAChR) – metabotropic (excitatory or inhibitory) Amines – Catecholamines - Dopamine Dopamine (DA) is found in two major pathways: • Mesostriatal pathway — origin in substantia nigra • motor control • loss associated with Parkinson’s disease. • Mesolimbocortical pathway — origin in VTA • reward, reinforcement, and associative learning; • abnormalities associated with schizophrenia. Amines – Catecholamines - Dopamine Major receptor families (all metabotropic): • D1-like receptors: D1, D5 - excitatory • D2-like receptors: D2D4 – inhibitory Raza & Su, 2020 DA receptors often heteromerize with other GPCRs Amines – Catecholamines Norepinephrine Norepinephrine (NE) or noradrenaline (NA) Origins: • locus coeruleus (LC) • alertness, emotion, stress/anxiety, attention • lateral tegmental area (LTA) • sympathetic nervous system Amines – Catecholamines Norepinephrine Adrenergic receptors (or adenoceptors) – shared receptors for NE/NA and epinephrine/adrenaline (and other catecholamines Major receptor families (all metabotropic): • Alpha (α) receptors – α1, α2 • Beta (β) receptors – β1,β2,β3 Different receptors have differing affinities for NE versus epinephrine Amines – Indoleamines Serotonin Serotonin (5-HT) – 5hydroxytryptamine • Origins: raphe nuclei • Many functions: mood, anxiety, sexual behavior • Tons of receptors (all but one metabotropic) • 5-HT1, 5-HT2 … 5-HT14 Neuropeptides Chains of typically 10 amino acids or more • large molecules  expensive to synthesize • Typically synthesized on demand where/when needed • Dedicated, specific behavioral functions Opioid peptides - mimicked by opiate drugs • Endorphins, enkephalins – reward/pleasure, control of pain Pituitary hormones • oxytocin and vasopressin – reproductive behavior, socialization Peptides in gut, spinal cord, or brain • Neuropeptide Y - feeding Gases Classified as NTs despite usually breaking the rules: • Produced outside axon terminals (dendrites) • Do not require receptors • Often retrograde transmitters – travel from postsynaptic back to presynaptic neuron Pharmacology Pharmacology - study of how drug affect the body as a whole Neuropharmacology – study of drug effects specifically on the brain. Neuropharmacology terminology Ligand - a substance that binds to a receptor. Agonist - initiates normal effects of the transmitter on that receptor. Antagonist - binds to a receptor and does not activate it, prevents binding by other ligands. Inverse agonist - initiates the reverse of the normal effect. Neuropharmacology terminology Competitive – drug directly competes with endogenous ligand at binding site Noncompetitive – drug does not directly compete, binds to modulatory site instead Pharmacology Binding affinity - degree of chemical attraction between ligand and receptor. • High affinity drugs effective at very low doses. • NTs are low-affinity ligands - can rapidly dissociate from receptors. Pharmacology Efficacy - ability of a bound ligand to activate the receptor. • Agonists have high efficacy; antagonists have low efficacy. Partial agonists produce a medium response regardless of dose. Combination of affinity and efficacy determines the overall action of a drug. Measuring efficacy and affinity Dose-response curve (DRC) - graph of the relationship between drug doses and effects. Pharmacodynamics - the functional relationship between drugs and their targets. Comparing DRCs A) Effective Dose 50% (ED50) – dose that shows half of its maximal effect B) A is more potent than B (lower ED50) C) A has higher maximal response than B. B is a partial agonist D) Nonmonotonic DRC – as dose increases, drug starts to have effect elsewhere in system Bioavailability Amount of drug in body that is free to act Bioavailability varies with route of administration • • • • PO – peroral SC – subcutaneous IM – intramuscular IV - intravenous National Pain Centers More pharmacology! Pharmacokinetics - factors that affect movement of a drug through the body. Blood-brain barrier (BBB)—tight junctions around blood vessels in the CNS protects the brain from toxins/pathogens in blood Prevents many potentially therapeutic drugs from getting to the brain. Bypassing the BBB Nanoparticles - special molecules designed to get drugs past the BBB. • Often coated with molecules that trick the BBB into transporting it into brain • Nickname: Trojan horses Tolerance Reduced effectiveness of a drug after repeated treatments Two key forms: • Metabolic tolerance • Functional tolerance Metabolic tolerance Organ systems become more effective at eliminating drug • Less drug reaches site of action Example: alcohol Parker, Kim, & Gao, 2017 Functional tolerance The tissue targeted by drug alters its sensitivity by changing number of receptors present in the postsynaptic membrane • Down-regulate - fewer receptors available • Agonist drugs • Example – opioid drugs! • Up-regulate – more receptors available • Antagonist drugs Milligan et al., 2001 Cross-tolerance Tolerance to one drug is generalized to other drugs in its class • Drugs that work on same receptors will show cross-tolerance Example: Alcohol, benzodiazepines, barbiturates all act at GABAA receptors Your action items (9/12) Neuroanatomy test is this week in lab (9/12 and 9/14) Listen to Radiolab: The Fix and be ready to discuss • PRA2 due in lab next week Coming Up: • Thursday: Drugs and Addiction (Breedlove 4.4-4.7) Our next GBP talk!