COGNITIVE SCIENCE 17

The Chemical Brain

Part 2

Matt Schalles, Rev.

Classes of Neurotransmitters

● Amino Acids fast +/- (sensory/motor)● Glutamate and GABA cortex → cortex

● Biogenic Amines slow +/-/modulatory● Acetylcholine, Dopamine, midbrain → cortex● 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 'AND' Gate● Detects correlation

between inputs from different cells

● Mediates long term potentiation (LTP)

depolarization Glu Glycine

Opens Ca++ channel

Open channel pore

Removes Mg++

GABA (Gamma Aminobutyric Acid)

• Principal Inhibitory NT• Biosynthesis:

• Removed by reuptake• 2 receptor types

• GABAA (ionotropic)

• GABAB (metabotropic)

Glu GABAGlutamic 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

Acetylcholine● First NT discovered● Mostly excitatory effects● Neuromuscular Junction

Removal:

Acetyl CoA+

Choline

CoA+

AChCholine Acetyltransferase (ChAT)

AchAcetate

+CholineAcetylcholine

Esterase (AChE)

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

Synthesis:

ACh Receptors● Muscarinic

– Smooth Muscles (heart & eye)

● Agonized by muscarine– Amanita muscaria

● Antagonized by atropine– Alkaloid from Atropa

belladona

ACh Receptors● Nicotinic

● Skeletal muscles (neuro-muscular junction)

● Agnoized by nicotine● Antagonized by curare

Ayahuasca● Psychedelic brew

used by Shamans in Amazon Basin

● DMT (indolamine)+ MAOI

● Extremely potent 5HT2a agonist

Painting by Pablo Amaringo, Peruvian shaman w/ photographic memory

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

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)∀ α1, β1-2 (postsynaptic, excitatory)

∀ α2 (autoreceptor, inhibitory)

Major NE Pathway

● Locus Coeruleus throughout brain [vigilance and attentiveness]

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

∀ β-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 β-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