Differential effects of GABA A receptor activation in the prelimbic and orbitofrontal cortices on anxiety

Rationale The development of effective anxiety treatments has been hindered by limited understanding of the neurobiological mechanisms involved in anxiety regulation. Whilst gamma-aminobutyric acid (GABA) neurotransmission in the prefrontal cortex (PFC) is one mechanism consistently implicated in anxiety regulation, PFC subregions may contribute uniquely. Objectives The present study examined the effects of inactivating the PFC subregions of the prelimbic cortex (PrL) or orbitofrontal cortex (OFC) through GABA A receptor (GABA A R) activation, on anxiety behaviours in male Wistar rats. Methods Sixty-six male Wistar rats were surgically implanted with bilateral cannulae into the PrL ( n = 33) or the OFC ( n = 33). Rats then received a microinjection of either the GABA A receptor agonist muscimol or vehicle prior to each experiment, conducted 1 week apart. Measures of anxiety were examined using the elevated plus maze (EPM) and the emergence test (ET). The effect on locomotor activity (baseline or methamphetamine-induced) was also tested. Results Differential effects of brain region inactivation on anxiety-like behaviour were shown by measures in the EPM and ET; muscimol infused into the PrL-reduced anxiety-like behaviour, yet had no significant effect when infused into the OFC, compared with control treated rats. No effects on locomotor activity at baseline or following methamphetamine treatment were found. Conclusions This study highlights that activation of GABA A Rs specifically within the PrL, but not OFC, reduces anxiety behaviours in male rats. This suggests that activity of the PrL plays a more important role than the OFC in the neurobiological mechanisms of unconditioned anxiety and should be targeted for future therapies.