Location(s) and mechanism of action on GABA­A receptor

• Appear to act at the limbic, thalamic, and hypothalamic levels of the CNS

• Neuroanatomically, the amygdala, orbitofrontal cortex, and insula are associated with the production of behavioral responses to fearful stimuli and the central mediation of anxiety and panic

  • PET scans demonstrate increased blood flow to the amygdala concomitant with anxiety responses

• Patients with panic disorders have shown a global decrease in benzodiazepine binding, largely in the orbitofrontal cortex and insula

• Blockade of GABAergic function can elicit anxiogenic-like effects

  • Increased activity of amygdala function along with concurrent lowered GABAergic inhibition of function produces anxiogenic responses

    • The conclusion is that hypofunctional GABA_A-receptor activity may sensitize the amygdala to anxiogenic responses

    • It is thought that the benzodiazepines may reset the threshold of the amygdala to a more normal level of responsiveness

• VTA has been shown as a possible sit for anxiolytic actions of benzodiazepines

  • We know that dopamine neurons synapse with and are regulated by GABA_A Cl^- channels in the VTA

  • Flurazepam injections into the VTA have been shown to block anxious responses¹

Location of Action	Therapeutic Effect
Amygdala	Alleviate anxiety, agitation, and fear
Orbitofrontal Cortex
Insula
Cerebral Cortex	Mental confusion, amnesia, antiepileptic actions
Hippocampus
Spinal Cord	Mild muscle-relaxing effects
Cerebellum
Brain Stem
Ventral Tegmental Area	Abuse potential, and psychological dependence
Nucleus Accumbens

Category: Pharmacology Notes