COGNITIVE SCIENCE 107A

Neurotransmitters

Jaime A. Pineda, Ph.D.

Exocytosis

~20 Amino Acids Used for Protein Synthesis

•  Non-essential (Our bodies can make them) –  Alanine (A) –  Arginine (R) –  Asparagine (N) –  Aspartate (D) –  Cysteine (C)* –  Glutamate (E) –  Glycine (G)* –  Glutamine (Z)* –  Proline (P)* –  Serine (S)* –  Tyrosine (Y)*

•  Essential (body cannot make them – must get from diet) –  Histidine (H)* –  Isoleucine (I) –  Leucine (L) –  Lysine (K) –  Methionine (M) –  Phenylalanine (F) –  Threonine (T) –  Tryptophan (W) –  Valine (V)

* Essential only in certain cases

Making Proteins DNA sequences Transcription/Translation

RECEPTORS

Ionotropic Metabotropic

Ionotropic

Metabotropic

Form a channel

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)

Upregulation

Downregulation

Changes to Postsynaptic Receptor Density as a Function of the Amount of Neurotransmitter Released

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

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Neuron

Neuron Via synaptic connection

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

–  Kainate

–  AMPAb Metabotropic

Ionotropic

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:

•  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

Glu GABA Glutamic Acid Decarboxylase (GAD) and

B6

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

Ro15-4513, a GABAa antagonist (indirect for GABA, direct for alcohol) reverses alcohol intoxication

  Agonists

  Benzodiazepines

  Barbiturates

  Ethyl alcohol (ETOH)

  Antagonists

Picrotoxin

  Inverse agonist

  Ro 15-4513

Acetylcholine (most abundant NT in PNS)

•  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:

Monoamines

•  Catecholamines Dopamine - DA

–  Dopaminergic Norepinephrine - NE

–  Noradrenergic Epinephrine - E

–  Adrenergic ~

•  Indolamines Serotonin - 5-HT

–  Serotonergic

Tyrosine L-DOPA DA NE E TH AADC DBH PNMT

TH-tyrosine/tryptophan hydroxylase AADC-aromatic acid decarboxylase or DOPA decarboxylase DBH-dopamine beta hydroxylase PNMT-phenylethanolamine N-methyltransferase

Tryptophan 5-HTmelatonin TH

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

•  MAOIs Iproniazid •  Reuptake blockers

–  Tricyclic antidepressants •  Imipramine •  Desipramine

- SSRIs – Cocaine & Amphetamine ~

Indirect Monoamine Agonists

Dopamine •  Reward, motivation, cognition, memory,

learning, and fine motor control, and modulation of neuroendocrine

signaling Biosynthesis:

Tyrosine L-DOPA DA Tyrosine

Hydroxylase DOPA

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

Hydroxylase 5-HT

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 –  SSRIs

•  Selective Serotonin Reuptake Inhibitors

–  MDMA •  Ecstacy ~

•  Antagonists –  Psilocybin –  LSD

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 ~