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
– Acetylcholine, Dopamine,
– Norepinephrine, Serotonin
• Neuropeptides
– Endorphins
• Others
– Lipids, gases
slow +/-/modulatory
Glutamate
• Principal excitatory NT
• Biosynthesized as byproduct of cell metabolism (Krebs
cycle)
• Removed by reuptake
• 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)
• 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:
Glu
GABA
Glutamic Acid
Decarboxylase (GAD) and
B6
• Removed by reuptake
• 2 receptor types
• GABAA (ionotropic)
• GABAB (metabotropic)
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:
Synthesis:
Acetyl CoA
+
Choline
Choline Acetyltransferase
(ChAT)
CoA
+
ACh
• 2 receptor types
• Nicotinic (ionotropic)
• Muscarinic (metabotropic)
Ach
Acetylcholine
Esterase (AChE)
Acetate
+
Choline
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
Tyrosine
Hydroxylase
DA
DOPA
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
NE
Dopamine
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
Tryptophan
Hydroxylase
5-HT
5-HT
Decarboxylase
• 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:
Mood
Eating
Sleep and dreaming
Arousal
Pain
Aggression
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 ligands
mu
delta
kappa
-endorphin, enkephalins
enkephalins
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