Role of Ventral Hippocampal GABA_A and NMDA Receptors in the Anxiolytic Effect of Carbamazepine in Rats Using the Elevated Plus Maze Test

Abstract

Background: The successful use of antiepileptic drugs to treat a wide range of nonepileptic disorders led us to evaluate the potential efficacy of carbamazepine (CBZ) in anxiety disorders. Anxiety may be related to the imbalance between γ-aminobutyric acid (GABA) and glutamate neurotransmitters, systems that are also involved in the CBZ effects. We investigated the role of these systems in the ventral hippocampus (VH) and their interactions with the CBZ effect on anxiety-like behavior in rats using the elevated plus maze. Methods: Animals received GABAergic and NMDA agents in a volume of 1 μl/rat, which was injected into the VH (0.5 μl for each side) 60 min after receiving systemic administration of CBZ. The test sessions took place 10 min later. Results: The systemic administration of CBZ increased the percentage of open arm time (%OAT) at the dose of 40 mg/kg, which is representative of an anxiolytic response. Intra-VH injection of the GABA_A receptor agonist muscimol (0.25–1 μg/rat) in the absence or presence of an ineffective dose of CBZ (30 mg/kg) did not show any significant changes in the parameters of anxiety-like behavior. The administration of GABA_A receptor antagonist bicuculline by itself decreased %OAT at a dose of 1 μg/rat, indicating possible anxiogenic effect. The antagonist (0.75 and 1 μg/rat) also decreased CBZ response. A microinjection of NMDA (0.125 and 0.25 μg/rat) decreased %OAT, which was reversed by the administration of CBZ (40 mg/kg). This indicates interaction between the two drugs. However, the NMDA receptor antagonist DAP-5 (1 μg/rat) significantly increased %OAT, but combined with the lower dose of CBZ (30 mg/kg), it did not trigger any response on anxiety-like parameters. Conclusion: Both GABAergic and NMDA systems in the VH play a role in modulation of anxiety-like behavior of rats. The anxiolytic-like effects of CBZ seem to be mediated, at least in part, through an interaction with GABA_A and NMDA systems in the VH.

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

“…Our findings also contribute to a number of functional studies that demonstrate the involvement of hippocampal GABA in anxiety (Engin & Treit, 2007;Guilloux et al, 2012;Kalueff, 2007;Kalueff & Nutt, 1996;Nuss, 2015), and studies alluding to the role of SST in ADs (Lin & Sibille, 2013. In line with this, acute injections of bicuculline, a GABA A receptor antagonist, directly into the vHip increased anxiety-like behavior in rats, and reversed anxiolytic effects of GABA A receptor agonists (Rezvanfard, Zarrindast, & Bina, 2009). Furthermore, genetic deletion of the γ-GABA A receptor subunit (essential for GABAergic synaptic inhibition) from SST-positive neurons was anxiolytic, via a process of disinhibition of SST neurons, resulting in enhanced inhibition of pyramidal CA1 neurons (Fuchs et al, 2017).…”

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects

“…The selected drug doses and the time interval between drug infusions and behavioral testing were based either on previous studies (Rezayat et al, 2005;Rezvanfard et al, 2009;Zarrindast et al, 2011Zarrindast et al, , 2012 or on preliminary studies. (+)-MK-801 (Sigma, Poole, Dorset, UK), (+)-bicuculline, and muscimol hydrobromide (Sigma Chemical Co, St Loui, Missouri, USA) were used for intra-CA1 injections.…”

Effect of d-cycloserine and valproic acid on the extinction of reinstated fear-conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial

“…4). Some neuroactive effects, such as an anxiolytic effect (Rezvanfard et al 2009) of DCS and VPA, could eliminate the interindividual variability in reactivity to reinstated fear-conditioned stimuli, which would decrease the SEM of the suppression rate for the DCS, VPA, and COMB groups. However, from a pharmacokinetic perspective, since VPA blocks voltage-gated sodium channels and T-type calcium channels and inhibits gamma-aminobutyric acid transaminase, it may compete with DCS by inhibiting excitatory post-synaptic action potentials that NMDA receptors regulate (Kempf et al 1982;Larsson et al 1986;Wilder and Rangel 1988).…”