COGNITIVE SCIENCE 17 The Chemical Brain Part 2 Matt Schalles, Rev. Classes of Neurotransmitters ● Amino Acids fast +/- (sensory/motor) ● Glutamate and GABA cortex → cortex ● Biogenic Amines slow +/-/modulatory ● Acetylcholine, Dopamine, midbrain → cortex ● Norepinephrine, Serotonin ● Neuropeptides ● Endorphins ● Others ● Lipids, gases Glutamate ● Principal excitatory NT ● Biosynthesized as byproduct of cell metabolism (Krebs cycle) ● Removed by reuptake ● 4 receptor types ● NMDA ● AMPAa Ionotropic ● Kainate ● AMPAb Metabotropic NMDA Binding Sites ● 4 outside cell ● Glutamate ● Glycine – Obligatory co-agonist – Inhibitory NT at its “own” receptor ● Zinc (inverse agonist) ● Polyamine (indirect agonist) ● 2 inside cell ● Magnesium (inverse agonist) ● PCP (inverse agonist) NMDA 'AND' Gate ● Detects correlation depolarization Glu Glycine between inputs from different cells Removes Open ● Mg++ channel Mediates long term pore potentiation (LTP) Opens Ca++ channel GABA (Gamma Aminobutyric Acid) • Principal Inhibitory NT • Biosynthesis: Glu GABA Glutamic Acid Decarboxylase (GAD) and B6 • Removed by reuptake • 2 receptor types • GABAA (ionotropic) • GABAB (metabotropic) GABAa Binding Sites ● GABA ● Muscimol (direct agonist); bicuculine (direct antagonist) ● Benzodiazepine (indirect agonist) ● Natural inverse agonist binds here (fear, tension, anxiety) ● Tranquilizing drugs (anxiolytics): valium, librium ● Likely site for alcohol ● Barbiturate (indirect agonist) ● Phenobarbital; pentobarbital ● Steroid (indirect agonist) ● Picrotoxin (inverse agonist): causes convulsions Acetylcholine ● First NT discovered ● Mostly excitatory effects ● Neuromuscular Junction Synthesis: Removal: Acetyl CoA CoA Acetate + + + Ach Acetylcholine Choline Choline Acetyltransferase ACh Choline (ChAT) Esterase (AChE) • 2 receptor types • Nicotinic (ionotropic) • Muscarinic (metabotropic) ACh Receptors ● Muscarinic – Smooth Muscles (heart & eye) ● Agonized by muscarine – Amanita muscaria ● Antagonized by atropine – Alkaloid from Atropa belladona ACh Receptors ● Nicotinic ● Skeletal muscles (neuro-muscular junction) ● Agnoized by nicotine ● Antagonized by curare Ayahuasca ● Psychedelic brew used by Shamans in Amazon Basin ● DMT (indolamine) + MAOI ● Extremely potent 5HT2a agonist Painting by Pablo Amaringo, Peruvian shaman w/ photographic memory Serotonin ● Mood, social cognition ● Biosynthesis: Tryptophan 5-HTP 5-HT Tryptophan 5-HT Hydroxylase Decarboxylase • At least 9 receptor types, all metabotropic and postsynaptic except: • 5-HT1A,B,D (autoreceptors) • 5-HT (inhibitory, ionotropic) 3 Major 5-HT Pathways ● Dorsal Raphe Nuclei cortex, striatum ● Roles in: Medial Raphe Nuclei cortex, hippocampus Mood Eating Sleep and dreaming Arousal Pain Aggression Dopamine ● Rewarding effects ● Biosynthesis: Tyrosine L-DOPA DA Tyrosine DOPA Hydroxylase Decarboxylase • 5 receptor types (D1–D5, all metabotropic) • D1 (postsynaptic) • D2 (pre and postsynaptic) Major DA Pathways ● Nigrostriatral (Substantia Nigra Striatum) [Motor movement] ● Mesolimbic (VTA limbic system) [Reinforcement and Addiction] ● Mesocortical (VTA prefrontal cortex) [Working memory and planning] Norepinephrine ● Arousal, attention ● Biosynthesis: DA NE Dopamine Beta-hydroxylase • Many receptor types (metabotropic) ∀ α β 1, 1-2 (postsynaptic, excitatory) ∀ α 2 (autoreceptor, inhibitory) Major NE Pathway ● Locus Coeruleus throughout brain [vigilance and attentiveness] Opioids: General ● Genetically coded, synthesized from mRNA ● Colocalized with and modulate effects of other neurotransmitters ● Act as neurotransmitters and neuromodulators ● Broken down by enzymes (no reuptake) ● Usually modulatory/inhibitory Opioids: Specific ∀ β-endorphin ● made from proopiomelanocortin (POMC) ● produced in pituitary gland, hypothalamus, brain stem ● Enkephalin ● made from proenkephalin (PENK) ● produced throughout brain and spinal cord ● Dynorphin ● made from prodynorphin (PDYN) ● produced throughout brain and spinal cord Opioids Receptors Receptor High affinity ligands mu β-endorphin, enkephalins delta enkephalins kappa dynorphins • Opioids act at all opioid receptors, but with different affinities • Distributed throughout brain and spinal cord, especially in limbic areas • Some overlap but quite distinct localizations Opioid Receptors continued ● Metabotropic, with either ● moderately fast indirect action on ion channels ● long-term action via changes in gene expression ● Most analgesic effects from mu receptor action ● Some analgesic effects from delta ● Many negative side effects from kappa .