THE GABA RECEPTOR COMPLEX: The foremost inhibitory neurotransmitter in the brain. There are three known families: GABA-A, GABA-B and GABA-C: + All are ligand-gated ion channels + All have 4 columns surrounding a central ion channel + All have multiple receptors! + GABA-A: Inhibits by opening a chloride channel, allowing Cl- to enter and hyperpolarize the cell + Hence generating fast inhibitory potentials + GABA-B: Opens potassium channels, leading to slow inhibitory potentials + GABA-C: New discovery, very low amounts of GABA open chloride channels for a very long time! THE GABA-A RECEPTOR: + Currently the most important for psychopharm + Has as many as 4 receptor sites: i. GABA: opens the chlorine channel ii. Benzodiazepine - in positive allosteric relationship to the GABA receptor - Benzodiazepines are powerful anxiolytics - There are also inverse agonists, the -carbolines, which bind to the BZ receptor, causing FEAR iii. Picrotoxin: Closes the channel: inverse agonists such as picrotoxin cause convulsions iv. Barbiturate/ethanol site: Agonists here open the chloride channel EXCITATORY AMINO ACID RECEPTORS: Recall that glutamate is the primary excitatory neurotransmitter in brain + There are 4 known glutamate receptor types, each with sub-types + Three of these are excitatory via ion channels; all open sodium and potassium channels, leading to depolarization. These are: 1. NMDA: the most investigated of the 3: important for memory, excitotoxicity a. Involves slow EPSPs 2. AMPA, & 3. Kainate - Fast EPSPS - also important for neurotoxicity 4. Metabotropic receptors: Second messenger systems, 7 families now known! CATECHOLAMINE SYNTHESIS TYROSINE HYDROXYLASE DOPA DECARBOXYLASE DOPAMINE -HYDROXYLASE PHENYLETHANOLAMINE N-METHYLTRANSFERASE SUBSTRATE IN BOXES ENZYMES TO LEFT; COFACTORS NOT SHOWN TYROSINE HYDROXYLASE IS RATE-LIMITING CATECHOLAMINE METABOLISM A. DOPAMINE: MONOAMINE OXIDASE (MAO) CATECHOL-O- METHLYTRANSFERASE (COMT) B. NOREPINEPHRINE: MAO COMT SEROTONIN SYNTHESIS AND METABOLISM A. SYNTHESIS: TRYPTOPHAN HYDROXYLASE L AROMATIC ACID DECARBOXYLASE THE AVAILABILITY OF TRYPTOPHAN IS RATE-LIMITING B. SEROTONIN METABOLISM: MAO NOTES ON MONOAMINE SYNTHESIS: 1. COFACTORS: All of the synthetic enzymes require cofactors. These are not shown, in the interests of student sanity and because they have as yet little therapeutic relevance 2. SUPPLY OF AMINO ACIDS TO THE BRAIN: A. UPTAKE. All amino acids, including tyrosine and tryptophan, cross the blood-brain barrier by a process of active uptake. B. COMPETITION. Since the carrier is not specific, amino acids COMPETE for carrier occupancy C. IMPLICATIONS FOR SEROTONIN: The supply of tryptophan is rate- limiting in the synthesis of serotonin. Hence: i. Diets low in tryptophan but high in other amino acids can reduce CNS serotonin, possibly triggering depression ii. Some compounds, including steroids, can cause the liver to metabolize tryptophan, thus reducing CNS serotonin, and possibly triggering depression 3. CONTROL OF SYNTHESIS RATES: Several factors are important here: A. AUTORECEPTORS: Autoreceptor stimulation generally reduces synthesis rates. B. END-PRODUCT INHIBITION: Tyrosine hydroxylase, and hence dopamine synthesis, is subject to end-product inhibition.