COGNITIVE SCIENCE 17

The Chemical Brain

Part 2

Jaime A. Pineda, Ph.D.

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

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 cell metabolism (Krebs cycle)

• Removed by reuptake

• 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)

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

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

GABA (Gamma Aminobutyric Acid)

• Principal Inhibitory NT• Biosynthesis:

• Removed by reuptake• 2 receptor types

• GABAA (ionotropic)

• GABAB (metabotropic)

Glu GABAGlutamic AcidDecarboxylase (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

Acetylcholine

• Mostly excitatory effects

Removal:

Acetyl CoA+

Choline

CoA+

AChCholine Acetyltransferase (ChAT)

AchAcetate

+CholineAcetylcholine

Esterase (AChE)

• 2 receptor types• Nicotinic (ionotropic)

• Muscarinic (metabotropic)

Synthesis:

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

Dopamine

• Rewarding effects

• Biosynthesis:

Tyrosine L-DOPA DATyrosine

HydroxylaseDOPA

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 NEDopamine

Beta-hydroxylase

• Many receptor types (metabotropic) 1, 1-2 (postsynaptic, excitatory)

2 (autoreceptor, inhibitory)

Major NE Pathway

• Locus Coeruleus throughout brain [vigilance and attentiveness]

Serotonin

• Mood, social cognition

• Biosynthesis:

Tryptophan 5-HTP 5-HTTryptophanHydroxylase

5-HTDecarboxylase

• At least 9 receptor types, all metabotropic and postsynaptic except:• 5-HT1A,B,D (autoreceptors)

• 5-HT3 (inhibitory, ionotropic)

Major 5-HT Pathways

• Dorsal Raphe Nuclei cortex, striatum• Medial Raphe Nuclei cortex, hippocampus

Roles in:MoodEatingSleep and dreamingArousalPainAggression

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

-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 ligandsmu -endorphin,

enkephalinsdelta enkephalinskappa 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