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

Farnaz Karimani,L. Delphi,A. Rezayof

Published 2019 in Neurobiology of Learning and Memory

ABSTRACT

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.

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