COGNITIVE SCIENCE 107A

Neurotransmitters

Jaime A. Pineda, Ph.D.

Exocytosis ~20 Amino Acids Used for Protein Synthesis

• Non-essential (Our bodies • Essential (body cannot make can make them) them – must get from diet) – Alanine (A) – Histidine (H)* – Arginine (R) – Isoleucine (I) – Asparagine (N) – Leucine (L) – Aspartate (D) – Lysine (K) – Cysteine (C)* – Methionine (M) – Glutamate (E) – Glycine (G)* – Phenylalanine (F) – Glutamine (Z)* – Threonine (T) – Proline (P)* – Tryptophan (W) – Serine (S)* – Valine (V) – Tyrosine (Y)* * Essential only in certain cases Making Proteins

DNA sequences Transcription/Translation RECEPTORS

Ionotropic Metabotropic Ionotropic Form a channel

Metabotropic Ionotropic Receptor

(agonist)

Ionotropic Receptors

1. Work very fast; important role in fast neurotransmission 2. Each is made of several subunits (together form the complete receptor) 3. At center of receptors is channel or pore to allow flow of neurotransmitter 4. At rest - receptor channels is closed 5. When neurotransmitter bind -- channel immediately opens 6. When ligand leaves binding site -- channel quickly closes Metabotropic Receptors

1. Work more slowly than ionotropic receptors 2. Though it takes longer for postsynapic cell to respond, response is somewhat longer-lasting 3. Comprise a single protein subunit, winding back-and-forth through cell membrane seven times (transmembrane domains) 4. They do not possess a channel or pore

Metabotropic Receptor (leads to opening of channel) Changes to Postsynaptic Receptor Density as a Function of the Amount of Neurotransmitter Released

Upregulation

Downregulation Reasons for a chemical signaling system

• Greater degree of amplification and control – Increased computational capability • Lengthens the time of cellular integration from ms to minutes and even hours • Allows neurons to respond differently as a function of preceding activity • Allows the system to be sensitive to behavioral states • Allows for brain circuits to be multifunctional

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Endocrine Cell

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Neurohormone

Neurohormone Slide 6 of 46

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Neuron

Neuron Via synaptic connection Slide 5 of 46 GAP JUNCTIONS: ELECTRICAL SYNAPSES 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 Classes of Neurotransmitters

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

• Principal excitatory NT • Biosynthesized as byproduct of glucose metabolism (Krebs cycle) • Removed by reuptake (neuronal/glia) • Can be neurotoxic • 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/antagonist)

• 2 inside cell – Magnesium (inverse agonist) – PCP (inverse agonist) NMDA Receptor

• “Detects” simultaneous events (“AND” gate; molecular coincidence detector)

• 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 GABA (Gamma Aminobutyric Acid)

• Principal Inhibitory NT • Biosynthesis:

Glu Glutamic Acid GABA Decarboxylase (GAD) and B6

• Removed by reuptake and enzymatically by GABA-oxoglutarate transaminase (GABA-T) • 2 receptor types

• GABAA (ionotropic) – controls Cl- channel

• GABAB (metabotropic; autoreceptor)- controls K+ channel 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 GABAergic Drugs

 Agonists

 Benzodiazepines Ro15-4513, a GABAa antagonist (indirect for GABA, direct for  Barbiturates alcohol) reverses alcohol intoxication  Ethyl alcohol (ETOH)

 Antagonists Picrotoxin

 Inverse agonist

 Ro 15-4513 Acetylcholine (most abundant NT in PNS)

• Mostly excitatory effects

Synthesis: Removal:

Acetyl CoA CoA Acetate + + + Ach Acetylcholine Choline Acetyltransferase Choline Choline (ChAT) ACh Esterase (AChE)

• 2 receptor types • Nicotinic (ionotropic) • Muscarinic (metabotropic)

Monoamines

• Catecholamines • Indolamines Dopamine - DA Serotonin - 5-HT – Dopaminergic – Serotonergic Norepinephrine - NE – Noradrenergic Tryptophan 5-HTmelatonin TH Epinephrine - E – Adrenergic ~ TH-tyrosine/tryptophan hydroxylase AADC-aromatic acid decarboxylase or Tyrosine  L-DOPA DA  NE  E DOPA decarboxylase DBH-dopamine beta TH AADC DBH PNMT hydroxylase PNMT-phenylethanolamine N-methyltransferase

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 (MAOA/B) – catechol-O-methyltranferase - COMT • Axonal varicosities (bead-like swellings) with both targeted and diffuse release Indirect Monoamine Agonists

• MAOIs Iproniazid • Reuptake blockers – Tricyclic antidepressants • Imipramine • Desipramine - SSRIs – Cocaine & Amphetamine ~ Dopamine • Reward, motivation, cognition, memory, learning, and fine motor control, and modulation of neuroendocrine signaling Biosynthesis: Tyrosine L-DOPA DA Tyrosine DOPA Hydroxylase Decarboxylase

• Dopamine reuptake transporter (DAT) • 5 receptor types (D1–D5, all metabotropic) • D1 (postsynaptic)… activate cAMP • D2 (pre autoreceptors and postsynaptic) • Autoreceptors are release-regulating homeostatic mechanisms… inhibit cAMP 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, stress • Biosynthesis:

DA NE Dopamine Beta-hydroxylase

• DBH found in vesicles (released with neurotransmission) • Norepinephrine reuptake transporter (NET) • Many receptor types (metabotropic)

• α1, β1-2 (postsynaptic, excitatory)

• α2 (autoreceptor, inhibitory) Major NE Pathway

• Locus Coeruleus  throughout brain [vigilance and attentiveness] Serotonin

• Mood, eating, sleep/dreaming arousal, pain, aggression (social cognition) • Biosynthesis:

Tryptophan 5-HTP 5-HT Tryptophan 5-HT Hydroxylase Decarboxylase

• Similar structure as LSD; serotonin reuptake transporter (SERT) • At least 9 receptor types, all metabotropic and postsynaptic except:

• 5-HT1A,B,D (autoreceptors)…subordinates; • 5-HT2…dominant

• 5-HT3 (inhibitory, ionotropic) Major 5-HT Pathways

• Dorsal Raphe Nuclei  cortex, striatum • Medial Raphe Nuclei  cortex, hippocampus Serotonergic Drugs

• Agonists • Antagonists – SSRIs – Psilocybin • Selective Serotonin – LSD Reuptake Inhibitors – MDMA • Ecstacy ~ Opioids: General

• Genetically coded, synthesized from mRNA as prohormones (slow response to increased demand) • Biosynthesis in cell body; large vesicles (100 nm) • Colocalized with and modulate effects of other neurotransmitters • Act as neurotransmitters and neuromodulators • Released by repetitive stimulation or burst firing • Broken down by enzymes (no reuptake); metabolites can be biologically active • Usually modulatory/inhibitory Why so many neuropeptides?

• Afferent convergence on a common neuron – To distinguish multiple inputs (chemical coding) • Colocalization

• No reuptake mechanisms may mean more non- synaptic release Opioids: Specific

• β-endorphin – made from proopiomelanocortin (POMC) – produced in pituitary gland, hypothalamus, brain stem

• Enkephalin (met- and leu-) – 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 (1,2) β-endorphin, enkephalins Delta enkephalins Kappa dynorphins Omega

• 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 Other (Unconventional) NTs

• Do not meet the criteria for a neurotransmitter yet seem to be important for communication – Growth factors • Brain derived neurotrophic gactor (BDNF) – Nitric Oxide (NO) - It’s a gas • Carbon Monoxide (CO) and hydrogen sulfide • Not stored in vesicles – Anandamide ligand for THC-R ~