PSYC304 Lecture 05 - Neural Communication II PDF

PSYC304: Neural communication II (between cells) Jay Hosking, PhD 1  Overview A. Receptors B. Types of neurotransmitters 2  Learning objectives 1. Name and describe the two basic types of receptors. Why have both? 2. Describe re...

PSYC304: Neural communication II (between cells) Jay Hosking, PhD 1  Overview A. Receptors B. Types of neurotransmitters 2  Learning objectives 1. Name and describe the two basic types of receptors. Why have both? 2. Describe receptors by their locations. Describe the relationship between receptor location and its function. 3. Name three types of neurotransmitter clean-up. 4. Name the major groups of neurotransmitters, and some examples within each group. 5. Describe the two primary types of drug action. 6. Describe the roles of glutamate, GABA, dopamine, norepinephrine, serotonin, acetylcholine, endocannabinoids, adenosine, and the endogenous opioids. 7. Describe some drugs that affect these systems, including their drug action. 8. Is dopamine the pleasure molecule? Is serotonin the mood molecule? Is norepinephrine the memory molecule? Support your answers with evidence. 3  Next question: How does one neuron transmit its message to another? 4 Introduction  End of the line Axon ends in terminal boutons (“buttons”) Bouton has vesicles (“bubbles”?) filled with neurotransmitters Action potential depolarizes bouton à Vesicles fuse with membrane à Neurotransmitters released into synapse 5 Introduction  Welcome to the synapse Dendrite membrane has special receptors that fit, like lock and key, with the neurotransmitters Receptors are often just (closed) channels that open when they bind with neurotransmitter! i.e. ligand-gated ion channels 6 Glu: glutamate, most common excitatory neurotransmitter Introduction  Receptor types Ionotropic (channels) Metabotropic (signalling proteins) 7 Receptors  Receptor types Ionotropic AKA ligand-gated ion channels Excitatory (depolarize), aka EPSPs Inhibitory (hyperpolarize), aka IPSPs Fast, transient effect 8 Receptors  Receptor types Metabotropic AKA G-protein- coupled receptors Modulate cell Modulate signals Slow, longer lasting effect Cause signal cascades 9 Receptors  Receptor locations Postsynaptic Presynaptic Autoreceptors Heteroreceptors 10 Receptors  Neurotransmitter clean-up Diffusion Enzymatic degradation Re-uptake Pre-synaptic Astrocytes End of neurotransmission 11  Drug types Agonist Antagonist In reality, it’s more complicated e.g. transporter blocker, reuptake inhibitor, enzyme inhibitor 12 Receptors  Onto our specific neurotransmitter systems! 13  >100 identified neurotransmitters Neurons named for NTs “Co-occurrence” is the norm Psychoactive drugs act here Types of neurotransmitters 14  Glutamate Primary excitatory neurotransmitter Used throughout the brain Ionotropic receptors AMPAR NMDAR Kainate receptor Metabotropic receptors mGluR 1-8 Often not a great target for drugs—why? Amino acid neurotransmitters 15  Drugs: Glutamate (all antagonists) Barbiturates Nitrous oxide Ketamine Ethanol Pattern? Agonists? 16 Amino acid neurotransmitters  GABA aka gamma-Aminobutyric acid Primary inhibitory neurotransmitter Used throughout brain Ionotropic and metabotropic receptors Again, often not a great target for drugs Amino acid neurotransmitters 17  Drugs: GABA (all agonists) Benzodiazepines Ethanol Chloroform Ether Pattern? Antagonists? Amino acid neurotransmitters 18  The amines Dopamine (DA) Epinephrine (aka Adrenaline) Norepinephrine (NE, aka Noradrenaline) Histamine Serotonin (5-HT) Almost all metabotropic— play a modulatory role Monoamine neurotransmitters 19 Dopamine (DA) Originates from two nuclei in the tegmentum Substantia nigra pars compacta Ventral tegmental area Projects to some (but not all) brain areas DA also made in hypothalamus Note: I could not find a single Here, it’s a hormone perfectly accurate/complete schematic! This one is missing Precursor from diet: tyrosine VTA à NAcc (and phenylalanine) Converted into DA via enzymes Overlaps with norepinephrine They are both catecholamines Five DA receptors: D1R-D5R / D1-D5 All metabotropic Some positive modulatory, some negative The pleasure/reward molecule? (NO) Monoamine neurotransmitters 20  Motivation for… Brain Stimulation? Olds and Milner (1954) Dopamine axons project from Ventral Tegmental Area (VTA) to Nucleus Accumbens (NAcc) Their conclusion: dopamine related to pleasure Monoamine neurotransmitters 21  Drugs of addiction and dopamine All addictive drugs directly or indirectly increase dopamine transmission Implication? Amphetamine*, cocaine*, heroin, nicotine, oxycodone, ethanol, cannabinoids, and on and on *directly increase DA transmission Monoamine neurotransmitters 22  Dopamine and Parkinson’s Disease (PD) PD caused by the loss of the substantia nigra pars compacta (SNc) PD is a motor disorder L-DOPA as gold standard PD treatment PD, L-DOPA, and pleasure? Other PD drugs (e.g. D1 agonist) PD drug side effects? (Not pleasure) Monoamine neurotransmitters 23 What about L-DOPA for healthy participants? Monoamine neurotransmitters 24  Dopamine and schizophrenia Schizophrenia medications are dopamine D2R antagonists Dopamine theory of schizophrenia Do individuals with schizophrenia have higher baseline pleasure? (NO) https://www.boredpanda.com/18-year-old-schizophrenic-artist-drawing-hallucinations/ Monoamine neurotransmitters 25  Psychostimulants and dopamine Psychostimulants act on the monoamine systems, esp. DA, NE, 5-HT You can think of them like monoamine agonists e.g. Cocaine, crack cocaine, methamphetamine, amphetamine, cathinones These drugs cause a wide variety of effects (including euphoria) But high doses, they can also cause temporary psychosis Not easily distinguished from positive symptoms of schizophrenia Monoamine neurotransmitters 26  Separating Pleasure from Motivation Salamone (1990s) – T-maze task Low effort, low reward vs. high effort, high reward Dopamine antagonists Decrease motivation but not pleasure Can be systemic or directly injected into VTA or NAcc 1. Training 2. Free choice baseline 3. Choice + DA antagonist 4. Choice + DA antagonist + no barrier Monoamine neurotransmitters 27  Dopamine and reward prediction error Schultz et al. (1990s) Pavlovian learning VTA (DA) neurons Fire at first for unexpected reward Shift their firing to stimuli that predict reward Go silent when predicted reward Raster plot not delivered Can be chained forward in time 28 Monoamine neurotransmitters So what does dopamine do? Important for movement Important for motivation Important for learning as related to movement and motivation Important for levels of arousal, attention, executive function More on all of these later It is NOT the pleasure molecule! 29 Monoamine neurotransmitters Norepinephrine (aka noradrenaline) Both a hormone and neurotransmitter! As NT, it originates in brain stem region called the locus coeruleus NE projects all over the brain Two main receptor types (⍺1-2, β1-3) with subtypes & sub-subtypes all metabotropic (GPCRs) NE and epinephrine act similarly, on same receptors Causes heterosynaptic facilitation (via heteroreceptors) Baseline levels in wakefulness/arousal Enhancement of memory by stress/emotion Evolutionarily useful Monoamine neurotransmitters 30 Post-traumatic stress disorder (PTSD) and propranolol Propranolol (norepinephrine receptor antagonist, aka noradrenergic receptor antagonist, aka “beta blockers”) Potential PTSD treatment via reconsolidation Eternal Sunshine of the Spotless Mind? Not really, but not entirely unalike Monoamine neurotransmitters 31 Serotonin Originates from the raphe nuclei (brain stem) Projects all over brain, esp. cortex, thalamus, cerebellum 15 receptor types, almost all metabotropic Precursor: tryptophan Serotonin depletion effects (e.g. Young, 2013) Stroop task Monoamine neurotransmitters 32 Selective Serotonin Reuptake Inhibitors aka SSRIs, e.g. Prozac (fluoxetine) For depression “Chemical imbalance” History of monoamines implicated in mood disorders Block serotonin from being removed from the synapse Effects of SSRIs quick, improvements slow Monoamine neurotransmitters 33 SSRI efficacy Original meta-analyses: SSRIs no better than placebo for mild to moderate depression May help with major depression Effect size is relatively small Fournier et al. 2013 Kirsch et al. 2008 Monoamine neurotransmitters 34 Hallucinogens Psychedelic drugs like LSD, DMT, psilocybin etc. are serotonin receptor agonists! Radical changes to our conscious perception and thoughts, minimal effects on mood (implication?) Recent reexamination of psychedelics’ therapeutic value: end of life care, PTSD, addiction, and more Serotonin: not simply a “mood molecule”! Monoamine neurotransmitters 35  Acetylcholine The first discovered neurotransmitter The neuromuscular junction Also basal forebrain Wakefulness, attention, etc. Nicotine: acetylcholine receptor agonist Other small neurotransmitters 36 Endocannabinoids Two NTs, two receptors (both GPCRs) Travel from dendrite to axon, i.e. retrograde transmission Weaken connection between two cells at a synapse THC (in cannabis) is a cannabinoid receptor agonist CBD (also in cannabis) is a less clear story Other small neurotransmitters 37  Adenosine Remember: ATP is cellular energy Adenosine is ATP byproduct Adenosine receptors Caffeine/theophylline Other small neurotransmitters 38  Endogenous opioids aka Endorphins Giant peptide neurotransmitters Receptors are all GPCRs Many NT and receptor types/subtypes The neurotransmitter system that exogenous opioids (e.g. heroin) mimic Fentanyl and naloxone Receptors found in spinal cord, periacqueductal grey (PAG), nucleus accumbens, more Large molecule neurotransmitters 39