Nitric oxide blockade in mediodorsal thalamus impaired nicotine/ethanol-induced memory retrieval in rats via inhibition of prefrontal cortical pCREB/CREB signaling pathway.

Reciprocal connections between the mediodorsal thalamic nucleus (MD) and the prefrontal cortex (PFC) are important for memory processes. Since the co-abuse of nicotine and ethanol affects memory formation, this study investigated the effect of nitric oxide inhibition in the MD on memory retrieval induced by co-administration of nicotine and ethanol. Subsequently, western blot analysis was used to evaluate how this change would alter the PFC pCREB/CREB signaling pathway. Male Wistar rats were bilaterally cannulated into the MD and the memory retrieval was measured by passive avoidance task. Intraperitoneal (i.p.) administration of ethanol (1 g/kg, i.p) 30 min before the test impaired memory retrieval and caused ethanol-induced amnesia. Subcutaneous (s.c.) administration of nicotine (0.05-0.2 mg/kg, s.c.) prevented ethanol-induced amnesia and improved memory retrieval. Intra-MD microinjection of a nitric oxide synthase (NOS) inhibitor, L-NAME (0.5-1 μg/rat) inhibited the improving effect of nicotine (0.2 mg/kg, s.c.) on ethanol-induced amnesia, while intra-MD microinjection of a precursor of nitric oxide, l-arginine (0.25-1 μg/rat), potentiated such effect. Noteworthy, intra-MD microinjection of the same doses of L-NAME or l-arginine by itself had no effect on memory retrieval. Furthermore, intra-MD microinjection of L-NAME (0.05, 0.1 and 0.3 μg/rat) reversed the l-arginine improving effect on nicotine response. Successful memory retrieval significantly increased the p-CREB/CREB ratio in the PFC tissue. Ethanol-induced amnesia, however, decreased this ratio in the PFC while the co-administration of nicotine and ethanol increased the PFC CREB signaling. Interestingly, the inhibitory effect of L-NAME and the potentiating effect of l-arginine on nicotine response were associated with the decrease and increase of the PFC p-CREB/CREB ratio respectively. It can be concluded that MD-PFC connections are involved in the combined effects of nicotine and ethanol on memory retrieval. The mediodorsal thalamic NO system possibly mediated this interaction via the pCREB/CREB signaling pathways in the PFC.