COGNITIVE SCIENCE 17 The Chemical Brain Part 2

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

2. 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 20 Amino Acids Used for Protein Synthesis

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

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. Glu GABA Glutamic Acid Decarboxylase (GAD) and B6 GABA (Gamma Aminobutyric Acid) • Principal Inhibitory NT • Biosynthesis: • Removed by reuptake • 2 receptor types • GABAA(ionotropic) • GABAB(metabotropic)

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

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. Tyrosine L-DOPA DA Tyrosine Hydroxylase DOPA Decarboxylase Dopamine • Rewarding effects • Biosynthesis: • 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. DA NE Dopamine Beta-hydroxylase Norepinephrine • Arousal, attention • Biosynthesis: • Many receptor types (metabotropic) • 1, 1-2 (postsynaptic, excitatory) • 2 (autoreceptor, inhibitory)

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

18. Tryptophan 5-HTP 5-HT Tryptophan Hydroxylase 5-HT Decarboxylase Serotonin • Mood, social cognition • Biosynthesis: • At least 9 receptor types, all metabotropic and postsynaptic except: • 5-HT1A,B,D (autoreceptors) • 5-HT3(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 Receptor High affinity ligands mu-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

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