psychopharmacology final study guide
Module 5a:
Anxiolytics I GABA
● 2 inhibitory NTs: GABA & glycine
● GABA only manufactured by GABAergic neurons
● Synthesis: glutamate → GABA via glutamic acid decarboxylase (GAD)
● Drugs allylglycine, thiosemicarbazide & 3-mecaptoproprionic acid block GABA synthesis
○ → leads to convulsions
● GABA important in regulating brain excitability
Vesicularization & Reuptake
● Vesicular GABA transporter (VGAT) = vesicular inhibitory AA transporter (VIAAT)
○ Also in neurons that use glycine as NT
● VMAT- DA, NE & 5-HT
● 3 reuptake transporters on membranes of neurons & glia: GAT-1,GAT-2, GAT-3
○ GAT-1 & 2 expressed in neurons & astrocytes
○ GAT-3 only in astrocytes
○ GAT-1 @ nere terminals of GABAergic neurons- important for GABA reuptake
■ Tiagabine: selective GAT-1 inhibitor, elevates extracellular GABA &
enhances GABA transmission (especially in cortex & hippocampus)
● Gabitril (tiagabine): used for treatment-resistant partial seizures
● Enzymatic breakdown of GABA: GABA→ succinate semialdehyde
via GABA aminotransferase (GABA-T)
○ Glutamate is a by product (can be used to resynthesize GABA)
○ Some glutamate taken up by astrocyes → glutaminase (via
glutamine synthetase)--> GABAergic neuron → glutamate (via
glutaminase)
● Vigabatrin (sabril): irreversible inhibitor of GABA-T used to treat epilepsy
○ Prevents degradation of synaptic GABA
○ May lead to constriction of visual field b/c GABAergic neurons in retina
Corelease
● GABA synthesized & coreleased in neurons that also use glycine, ACh & DA
● Co-expression accomplished by co-expression of multiple vesicular transporters in same neuron
○ Ex. VIAAT & VAChT
● Glycine has NT role in brainstem & spinal cord
○ Inhibitory interneurons in this area release GABA only, glycine only, or both
● Some neurons express VIAAT & VGlu1 or 2
● 2 possibilities for GABA-glu co-release:
1. Separate vesicles w/ distinct release sites
2. Mix of vesicles w/ just GABA, just glu, or both
,psychopharmacology final study guide
● Allows for fine tuning
GABAergic System
Interneurons & Projections Neurons
● 10-40% GABA nerve terminals in cerebral cortex, hippo, substantia nigra
● Other areas rich in GABA: cerebellum, striatum, global pallidus & olfactory bulbs
● Cortex & hippocampus have large # local GABA interneuons
,psychopharmacology final study guide
● GABAergic projection neurons carry inhibitory info longer distances w/in brain
○ Striatum → global pallidus & substantia nigra
● DA input to striatum damaged by Parkinson’s → abnormal firing
of striatal GABAergic neurons
○ Causes motor abnormalities
● GABA is also NT in Purkinje cells of cerebellar cortex
○ Project to deep cerebellar nuclei & brain stem: fine motor control & coordination
○ Holmes cerebellar degeneration (of Purkinje cells)- ataxia when walking,
impaired fine hand movement, defective speech & tremors
GABA receptors
● GABAa receptor: ionotropic, prominent role in GABA transmission
○ Target of many psychoactive drugs
○ Axosomal, axodendritic; postsynaptic inhibition
○ Cl- influx
○ IPSP (hyperpolarization) → decrease APs
○ Target of many depressants
● GABAb receptor: metabotropic
○ Axoaxonal; presynaptic inhibition
○ Presynaptic: decrease Ca2+ influx → decrease transmitter
release
○ Postsynaptic: K+ efflux → decreased APs
○ Target of few drugs: qagonist baclofen, GHB
Structure & Function of GABAa Receptor
● GABAa receptors= ion channels that allow Cl- influx →
hyperpolarization → inhibition of postsynaptic cell
● More Cl- influx thru GABAa if membrane previously depolarized by excitatory synaptic inputs
● GABAa can blunt depolarization & prevent firing of APs
● Each GABAa receptor has 5 subunits
○ 3 or 4 different kinds of subunits in single GABAa complex
○ Alpha, beta, gamma, & delta subunits
● Most GABAa receptors subunits= 2 alpha, 2 beta, & 1 gamam
● Multiple isoforms of all subunits: alpha1-6, beta1-3, gamma1-3
● 60% GABAa receptors in brain: (alpha1)2(beta2)2(gamma2)
● 15-20%: (alpha2)2(beta3)2(gamma2)
● 10-15%: (alpha3)2(betaX)2(gamma2)
● Small # of GABAa have a delta subunit instead of gamma
○ If have delta subunit, usually w/ 2 alpha4 or alpha6 & 2 normal beta subunits
○ Outside synapse area- respond to low levels of GABA that avoided reuptake &
escaped cleft
, psychopharmacology final study guide
○ Role: exert mild tonic hyperpolarizing/inhibitory effect on cells w/ extrasynaptic
GABAa receptors
● Muscimol: GABAa receptor agonist from mushroom (same as original source of ACH
muscarine)
○ Easier to catch flies after musicmol ingestion
Module 5a:
Anxiolytics I GABA
● 2 inhibitory NTs: GABA & glycine
● GABA only manufactured by GABAergic neurons
● Synthesis: glutamate → GABA via glutamic acid decarboxylase (GAD)
● Drugs allylglycine, thiosemicarbazide & 3-mecaptoproprionic acid block GABA synthesis
○ → leads to convulsions
● GABA important in regulating brain excitability
Vesicularization & Reuptake
● Vesicular GABA transporter (VGAT) = vesicular inhibitory AA transporter (VIAAT)
○ Also in neurons that use glycine as NT
● VMAT- DA, NE & 5-HT
● 3 reuptake transporters on membranes of neurons & glia: GAT-1,GAT-2, GAT-3
○ GAT-1 & 2 expressed in neurons & astrocytes
○ GAT-3 only in astrocytes
○ GAT-1 @ nere terminals of GABAergic neurons- important for GABA reuptake
■ Tiagabine: selective GAT-1 inhibitor, elevates extracellular GABA &
enhances GABA transmission (especially in cortex & hippocampus)
● Gabitril (tiagabine): used for treatment-resistant partial seizures
● Enzymatic breakdown of GABA: GABA→ succinate semialdehyde
via GABA aminotransferase (GABA-T)
○ Glutamate is a by product (can be used to resynthesize GABA)
○ Some glutamate taken up by astrocyes → glutaminase (via
glutamine synthetase)--> GABAergic neuron → glutamate (via
glutaminase)
● Vigabatrin (sabril): irreversible inhibitor of GABA-T used to treat epilepsy
○ Prevents degradation of synaptic GABA
○ May lead to constriction of visual field b/c GABAergic neurons in retina
Corelease
● GABA synthesized & coreleased in neurons that also use glycine, ACh & DA
● Co-expression accomplished by co-expression of multiple vesicular transporters in same neuron
○ Ex. VIAAT & VAChT
● Glycine has NT role in brainstem & spinal cord
○ Inhibitory interneurons in this area release GABA only, glycine only, or both
● Some neurons express VIAAT & VGlu1 or 2
● 2 possibilities for GABA-glu co-release:
1. Separate vesicles w/ distinct release sites
2. Mix of vesicles w/ just GABA, just glu, or both
,psychopharmacology final study guide
● Allows for fine tuning
GABAergic System
Interneurons & Projections Neurons
● 10-40% GABA nerve terminals in cerebral cortex, hippo, substantia nigra
● Other areas rich in GABA: cerebellum, striatum, global pallidus & olfactory bulbs
● Cortex & hippocampus have large # local GABA interneuons
,psychopharmacology final study guide
● GABAergic projection neurons carry inhibitory info longer distances w/in brain
○ Striatum → global pallidus & substantia nigra
● DA input to striatum damaged by Parkinson’s → abnormal firing
of striatal GABAergic neurons
○ Causes motor abnormalities
● GABA is also NT in Purkinje cells of cerebellar cortex
○ Project to deep cerebellar nuclei & brain stem: fine motor control & coordination
○ Holmes cerebellar degeneration (of Purkinje cells)- ataxia when walking,
impaired fine hand movement, defective speech & tremors
GABA receptors
● GABAa receptor: ionotropic, prominent role in GABA transmission
○ Target of many psychoactive drugs
○ Axosomal, axodendritic; postsynaptic inhibition
○ Cl- influx
○ IPSP (hyperpolarization) → decrease APs
○ Target of many depressants
● GABAb receptor: metabotropic
○ Axoaxonal; presynaptic inhibition
○ Presynaptic: decrease Ca2+ influx → decrease transmitter
release
○ Postsynaptic: K+ efflux → decreased APs
○ Target of few drugs: qagonist baclofen, GHB
Structure & Function of GABAa Receptor
● GABAa receptors= ion channels that allow Cl- influx →
hyperpolarization → inhibition of postsynaptic cell
● More Cl- influx thru GABAa if membrane previously depolarized by excitatory synaptic inputs
● GABAa can blunt depolarization & prevent firing of APs
● Each GABAa receptor has 5 subunits
○ 3 or 4 different kinds of subunits in single GABAa complex
○ Alpha, beta, gamma, & delta subunits
● Most GABAa receptors subunits= 2 alpha, 2 beta, & 1 gamam
● Multiple isoforms of all subunits: alpha1-6, beta1-3, gamma1-3
● 60% GABAa receptors in brain: (alpha1)2(beta2)2(gamma2)
● 15-20%: (alpha2)2(beta3)2(gamma2)
● 10-15%: (alpha3)2(betaX)2(gamma2)
● Small # of GABAa have a delta subunit instead of gamma
○ If have delta subunit, usually w/ 2 alpha4 or alpha6 & 2 normal beta subunits
○ Outside synapse area- respond to low levels of GABA that avoided reuptake &
escaped cleft
, psychopharmacology final study guide
○ Role: exert mild tonic hyperpolarizing/inhibitory effect on cells w/ extrasynaptic
GABAa receptors
● Muscimol: GABAa receptor agonist from mushroom (same as original source of ACH
muscarine)
○ Easier to catch flies after musicmol ingestion
