Antidepressant-like effects induced by NMDA receptor blockade and NO synthesis inhibition in the ventral medial prefrontal cortex of rats exposed to the forced swim test

Rationale Systemic treatment with NMDA receptor (NMDAR) antagonists, inhibitors of neuronal nitric oxide synthase (nNOS) or of soluble guanylyl cyclase (sGC), induce antidepressant-like effects in rats. Increased levels of glutamate and nitric oxide (NO) in the medial prefrontal cortex (MPFC) of stressed animals have been described in the literature. However, the role of the NMDAR-nNOS-sGC pathway of the MPFC in the mediation of forced swim-induced behaviors remains unclear. Objective The aim of this work was to test the hypothesis that the inhibition of the NMDAR-nNOS-sGC pathway in the ventral MPFC (infralimbic (IL) or prelimbic (PL)) would elicit antidepressant-like effects in the forced swim test (FST). Methods Rats implanted with cannulae aimed at the PL or the IL were exposed to the FST and injected with LY235959 (NMDAR antagonist), NPA (nNOS inhibitor), ODQ (sGC inhibitor), or carboxy-PTIO (NO scavenger). Additional groups received the AMPA antagonist, NBQX, before the effective doses of LY235959 or NPA. Results LY235959 administration into PL or IL before the FS pretest produced no effects. Administration of LY235959 (3 and 10 nmol/0.2 mu L) after pretest was effective only when administered into the PL. However, the administration of NPA (0.01 nmol/0.2 mu L), c-PTIO (1.0 nmol/0.2 mu L), and ODQ (1.0 nmol/0.2 mu L) into the PL or IL before the FST produced antidepressant-like effects. NBQX blocked the antidepressant-like effect of LY235959 but not of NPA. Conclusion Blocking NMDAR or NO signaling in the vMPFC, either in the IL or the PL, induces antidepressant-like effects in the rat FST. These effects seemingly occur through independent mechanisms, since NBQX blocked the former effect but not the latter.