Effect of nitrergic signals on serotonin release in the rat medial prefrontal cortex

Nitric oxide (NO) is involved in modulating the activity of several neurotransmitter systems in the brain. However, the effects of NO on serotonergic activity of the medial prefrontal cortex (mPFC) remain poorly understood. We have previously shown that exogenous nitrergic stimulation of the mPFC by local administration of the NO donor diethylamine nonoate (DEA, 0.1–1 mM) dose-dependently increases extracellular serotonin levels in this area. The purpose of the work was to study the effects of endogenous nitrergic stimulation of the mPFC on serotonin release in this cortical region, and to determine the effect of more intense exogenous nitrergic stimulation of the mPFC on serotonin release by introducing 3 mM DEA. In Sprague-Dawley rats by means of in vivo microdialysis and high-performance liquid chromatography, we showed that intra-mPFC infusion of L-arginine (0.1 mM, 1 mM), the NO synthase substrate, produces a dose-dependent increase in extracellular serotonin level in this aria. The intra-mPFC infusion of 5 mM L-arginine increases extracellular serotonin to the same extent as the infusion of 1 mM L-arginine. The intra-mPFC administration of 3 mM DEA causes an initial increase of the mPFC extracellular serotonin followed by a decrease of serotonin level below the baseline. The present data indicate that endogenous nitrergic stimulation of the mPFC activates serotonin neurotransmission in this area, as evidenced by the L-arginine-induced increase in mPFC serotonin levels. Strong exogenous nitrergic stimulation of mPFC by administration of 3 mM DEA has a biphasic effect on the activity of the mPFC serotonin system, initially increasing and then rapidly decreasing the level of extracellular serotonin.