Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212-2 and nicotine or ethanol in mice

•Pre-training administration of WIN impaired memory retrieval.•Pre-test systemic administration of nicotine or ethanol reversed WIN-induced amnesia.•Activation of CA1 and MS nAChRs improved WIN-nicotine state-dependent memory (STD).•Blockade of CA1 nAChRs inhibited WIN-nicotine or -ethanol STD.•Blockade of MS nAChRs inhibited WIN-nicotine STD, but not WIN-ethanol.

The present study examined whether nicotinic acetylcholine receptors (nAChRs) of the CA1 regions of the dorsal hippocampus and medial septum (MS) are involved in cross state-dependent memory retrieval between WIN55, 212-2 (WIN, a non-selective CB1/CB2 receptor agonist) and nicotine or ethanol. Memory retrieval was measured in one-trial step-down type passive avoidance apparatus in male adult mice. Pre-training intraperitoneal administration of WIN (0.1–1 mg/kg) dose-dependently impaired memory retrieval when it was tested 24 h later. Pre-test systemic administration of nicotine (0.6 and 0.7 mg/kg, s.c.) or ethanol (0.5 g/kg, i.p.) improved WIN-induced memory impairment, suggesting a cross state-dependent memory retrieval between the drugs. Pre-test intra-CA1 microinjection of nicotine (1 and 2 μg/mouse) before systemic administration of an ineffective dose of nicotine (0.5 mg/kg, s.c.) or ethanol (0.25 g/kg) significantly reversed WIN-induced memory impairment. Pre-test intra-CA1 microinjection of mecamylamine (1 and 3 μg/mouse) inhibited cross state-dependent memory between WIN and nicotine or ethanol. Moreover, pre-test intra-MS microinjection of nicotine (1 and 2 μg/mouse) in combination with systemic administration of a lower dose of nicotine (0.5 mg/kg), but not ethanol (0.25 g/kg), improved memory impairment induced by pre-training administration of WIN. On the other hand, in the animals that received pre-training WIN and pre-test systemic administration of nicotine (0.7 mg/kg), but not ethanol (0.5 g/kg), pre-test intra-MS microinjection of mecamylamine (1–5 μg/mouse) inhibited WIN-nicotine state-dependent memory retrieval. It should be noted that pre-test intra-CA1 or intra-MS microinjection of nicotine or mecamylamine by itself had no effect on memory retrieval and also could not reverse memory impairment induced by pre-training administration of WIN. It can be concluded that WIN and nicotine or WIN and ethanol can induce state-dependent memory retrieval. In addition, our results showed that a cross-state dependency between these drugs may be mediated through a cholinergic nicotinic mechanism.