Lectures 16-17 – Chemical Mediators: Amino acids and other neurotransmitters (Glutamate, aspartate, GABA, glycine, and dopamine

Glutamate

Main excitatory amino acid neurotransmitter in the brain; involved in fast synaptic transmission; derived from glucose via Krebs cycle or from glutamine supplied by glial cells.

Aspartate

Excitatory amino acid neurotransmitter similar to glutamate; found in certain brain areas.

Ionotropic glutamate receptors

Ligand-gated ion channels for Na+ and Ca2+; mediate fast excitatory transmission; include NMDA, AMPA, and kainate receptors.

Metabotropic glutamate receptors (mGluRs)

G-protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic plasticity; divided into three groups (1–3) based on location and function.

NMDA receptors

Subtype of ionotropic glutamate receptor composed of GluN1, GluN2A-D, GluN3A/B; permeable to Ca2+; require both glutamate and glycine for activation; blocked by Mg2+; involved in long-term potentiation (LTP).

AMPA receptors

Subtype of ionotropic glutamate receptor (GluA1–4) responsible for fast excitatory synaptic transmission; mediate short-lasting depolarizations.

Kainate receptors

Subtype of ionotropic glutamate receptor (GluK1–5); mediate excitatory neurotransmission; less understood compared to NMDA/AMPA.

Ketamine

Non-competitive NMDA receptor antagonist; used as an anesthetic; produces dissociative effects.

Phencyclidine (PCP)

NMDA receptor channel blocker; psychomimetic (causes hallucinations and psychosis-like symptoms).

Memantine

Moderate-affinity NMDA receptor antagonist; used in treatment of Alzheimer’s disease to reduce excitotoxicity.

Perampanel

Non-competitive AMPA receptor antagonist; used to treat epilepsy.

Group 1 mGluRs

mGlu1 and mGlu5; located postsynaptically; excitatory; increase intracellular Ca2+ and neuronal excitability.

Group 2 & 3 mGluRs

mGlu2, 3, 4, 6, 7, 8; located presynaptically; inhibitory; decrease neurotransmitter release and synaptic excitability.

Excitotoxicity

Pathological process caused by excessive glutamate leading to neuronal injury or death; involved in stroke and neurodegenerative diseases.

GABA (γ-aminobutyric acid)

Main inhibitory neurotransmitter in the brain; synthesized from glutamate via glutamic acid decarboxylase; taken up by transporters after release.

GABAA receptor

Ligand-gated Cl– ion channel composed of α, β, and γ subunits; mediates fast inhibitory synaptic transmission; activation causes hyperpolarization.

GABAB receptor

Metabotropic GPCR coupled to Gi/Go proteins made of dimers; inhibits Ca2+ channels and adenylate cyclase; opens K+ channels; mediates slow inhibitory effects.

Extrasynaptic GABAA receptors

High-affinity receptors for GABA located outside synapses; mediate tonic inhibition.

Benzodiazepines

Positive allosteric modulators of GABAA receptors; enhance Cl– channel opening frequency; used as anxiolytics, sedatives, and anticonvulsants.

Barbiturates

Increase duration of Cl– channel opening at GABAA receptors; used as sedatives and anticonvulsants.

Muscimol

GABAA receptor agonist; psychoactive compound found in Amanita muscaria mushrooms.

Picrotoxin

GABAA receptor antagonist; convulsant; used experimentally.

Baclofen

GABAB receptor agonist; reduces spasticity by decreasing neuronal excitability.

Alcohol

Enhances GABAA receptor function; depresses CNS activity.

Glycine

Inhibitory neurotransmitter in spinal cord and brainstem; activates ligand-gated Cl– channels similar to GABAA receptors; regulates motor control and pain transmission.

Strychnine

Competitive antagonist at glycine receptors; causes convulsions.

Tetanus toxin

Prevents glycine release from inhibitory neurons in spinal cord; causes muscle rigidity and spasms.

Dopamine

Monoamine neurotransmitter involved in motor control, motivation, reward, and hormone regulation; synthesized from tyrosine but lacks dopamine β-hydroxylase.

Dopamine degradation

Occurs via monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

D1-like dopamine receptors (D1, D5)

Activate adenylate cyclase (AC) and increase cAMP; generally excitatory and postsynaptic.

D2-like dopamine receptors (D2, D3, D4)

Inhibit adenylate cyclase; act as autoreceptors (presynaptic) or postsynaptic inhibitory receptors; regulate neurotransmitter release.

Nigrostriatal pathway

Dopaminergic pathway between substantia nigra and corpus striatum; involved in motor control; degeneration causes Parkinson’s disease.

Mesolimbic pathway

Dopaminergic pathway from ventral tegmental area (VTA) to limbic system; mediates reward, emotion, and addiction.

Mesocortical pathway

Dopaminergic pathway to prefrontal cortex; involved in cognition and behavior; dysfunction linked to schizophrenia.

Tuberohypophyseal pathway

Dopaminergic pathway from hypothalamus to pituitary; inhibits prolactin release.

Parkinson’s disease

Neurodegenerative disorder caused by loss of dopaminergic neurons in substantia nigra; treated with L-DOPA or dopamine agonists.

Schizophrenia

Mental disorder linked to dopamine imbalance—overactivity in mesolimbic pathway and underactivity in mesocortical pathway.

Amphetamine & cocaine

Increase dopamine levels by inhibiting reuptake transporters; cause euphoria and addiction.

Excitatory neurotransmitters

Neurotransmitters that depolarize the postsynaptic membrane (e.g., glutamate, aspartate).

Inhibitory neurotransmitters

Neurotransmitters that hyperpolarize the postsynaptic membrane (e.g., GABA, glycine).

Long-term potentiation (LTP)

Long-lasting increase in synaptic strength; involves NMDA and AMPA receptors; crucial for learning and memory.