Activation of the ventral tegmental area nitric oxide system potentiates nicotine reversal effects on ethanol amnesia

Abstract

The possible involvement of nitric oxide (NO) systems in the ventral tegmental area (VTA) in nicotine's reversal effect on ethanol-induced amnesia and ethanol state-dependent memory in adult male Wistar rats was investigated. The animals were bilaterally implanted with chronic cannulae in the VTA. Animals were trained in a step-through type inhibitory avoidance task, and tested 24 h after training to measure step-through latency as memory retrieval. We found that pre-training or pre-test intraperitoneal (i.p.) injection of ethanol (0.8 g/kg) induced amnesia. The pre-test administration of ethanol (0.4 and 0.8 g/kg) reversed the amnesia induced by pre-training ethanol (0.8 g/kg), indicating a state-dependent effect. Similar to ethanol, pre-test intra-VTA injection of nicotine (0.3 and 0.6 µg/rat) alone or nicotine (0.1, 0.3 and 0.6 µg/rat, intra-VTA) plus an ineffective dose of ethanol (0.2 g/kg) also significantly reversed the ethanol amnesia. Ethanol induced amnesia was also reversed by pre-test intra-VTA microinjection of L-arginine (0.4 µg/rat), a nitric oxide precursor. Interestingly, co-administration of L-arginine (0.2 and 0.4 µg/rat, intra-VTA) with an ineffective dose of nicotine (0.1µg/rat, intra-VTA) significantly potentiated the memory-improving effect of nicotine on ethanol amnesia. In contrast, pre-test intra-VTA administration of L-NAME, a nitric oxide synthase inhibitor blocked the reversal effect of nicotine or nicotine plus L-arginine on ethanol amnesia. These results suggest that the VTA NO system(s) may potentially play an important role in reversal effect of nicotine on ethanol amnesia via dopamine release in the target areas of mesolimbic dopamine pathway originating from the VTA.