1. COGNITIVE SCIENCE 17 The Chemical Brain Part 2 Jaime A. Pineda, Ph.D.

2. 20 Amino Acids Used for Protein Synthesis Non-essential (Our bodies can make them) –Alanine –Arginine –Asparagine –Aspartate –Cysteine –Glutamate –Glycine –Glutamine –Proline –Serine –Tyrosine Essential (body cannot make them – must get from diet) –Histidine –Isoleucine –Leucine –Lysine –Methionine –Phenylalanine –Threonine –Tryptophan –Valine

3. Criteria for a Neurotransmitter Must be synthesized and released from neurons. Appropriate biochemical machinery must exist in the presynaptic neuron. Must be released in response to an electrical signal. Should produce a physiological response in the postsynaptic target. Postsynaptic effects should be blocked by known antagonists of the transmitter in a dose-dependent manner Appropriate mechanisms must exist to terminate the action of the neurotransmitter –Chemical deactivation –Recapture (endocytosis) –Glial uptake –diffusion

4. Classes of Neurotransmitters Amino Acids fast +/- –Glutamate and GABA Biogenic Amines slow +/-/modulatory –Acetylcholine, Dopamine, –Norepinephrine, Serotonin Neuropeptides –Endorphins Others –Lipids, gases

5. Glutamate Principal excitatory NT Biosynthesized as byproduct of cell metabolism (Krebs cycle) Removed by reuptake 4 receptor types –NMDA –AMPAa –Kainate –AMPAb Metabotropic Ionotropic

6. 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)

7. NMDA Receptor “Detects” simultaneous events (“AND” gate) Gated by combination of voltage and ligand –Glu + Gly opens channel to Ca ++, –Magnesium (Mg ++ ) block removed by membrane depolarization Mediates learning and memory via LTP (long term potentiation) –Involved in process of addiction; behavioral sensitization, and drug craving

8. GABA (Gamma Aminobutyric Acid) Principal Inhibitory NT Biosynthesis: Removed by reuptake 2 receptor types GABA A (ionotropic) GABA B (metabotropic) GluGABA Glutamic Acid Decarboxylase (GAD) and B6

9. 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

10. Acetylcholine Mostly excitatory effects Removal: Acetyl CoA + Choline CoA + ACh Choline Acetyltransferase (ChAT) Ach Acetate + Choline Acetylcholine Esterase (AChE) 2 receptor types Nicotinic (ionotropic) Muscarinic (metabotropic) Synthesis:

13. Monoamines (DA, NE, 5-HT) Modulatory (can have both excitatory and inhibitory effects- varies by receptor) Recycled by reuptake transporter Excess NT in terminal broken down by monoamine oxidase (MAO) Axonal varicosities (bead-like swellings) with both targeted and diffuse release

14. Dopamine Rewarding effects Biosynthesis: TyrosineL-DOPADA Tyrosine Hydroxylase DOPA Decarboxylase 5 receptor types (D1–D5, all metabotropic) D1 (postsynaptic) D2 (pre and postsynaptic)

15. Major DA Pathways Nigrostriatral (Substantia Nigra  Striatum) [Motor movement] Mesolimbic (VTA  limbic system) [Reinforcement and Addiction] Mesocortical (VTA  prefrontal cortex) [Working memory and planning]

16. Norepinephrine Arousal, attention Biosynthesis: DANE Dopamine Beta-hydroxylase Many receptor types (metabotropic)  1,  1-2 (postsynaptic, excitatory)  2 (autoreceptor, inhibitory)

17. Major NE Pathway Locus Coeruleus  throughout brain [vigilance and attentiveness]

18. Serotonin Mood, social cognition Biosynthesis: Tryptophan5-HTP5-HT Tryptophan Hydroxylase 5-HT Decarboxylase At least 9 receptor types, all metabotropic and postsynaptic except: 5-HT 1A,B,D (autoreceptors) 5-HT 3 (inhibitory, ionotropic)

19. Major 5-HT Pathways Dorsal Raphe Nuclei  cortex, striatum Medial Raphe Nuclei  cortex, hippocampus Roles in: Mood Eating Sleep and dreaming Arousal Pain Aggression

20. 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

21. Opioids: Specific  -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

22. Opioids Receptors ReceptorHigh affinity ligands mu  -endorphin, enkephalins deltaenkephalins kappadynorphins 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

23. 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