Involvement of cholinergic system in state-dependent learning induced by lithium in mice

Objective: The influence of cholinergic drugs on lithium-induced statedependent learning has been investigated in adult male mice. Method: A single-trial step-down inhibitory avoidance task was selected. The drugs used in the study were lithium chloride physostigmine , nicotine hydrogen tartrate and scopolamine hydrobromide, atropine sulphate. The drugs were administrated through the peritoneal route. Control animals received saline or respective vehicle for nicotine. Ten animals were used in each experimental group. on day 1 or training session, the animals being trained in the step-down inhibitory avoidance task, and then immediately received post-training treatment of lithium or atropine or scopolamine. On day 2 or testing session, the animals firstly received pre-test administration of drugs (for nicotine 30 min, for lithium 45 min and for cholinergic antagonists 60 min before the test), and then were tested for step-down latency. Results: The results showed that post-training and pre-test intraperitoneal (i.p.) administration of lithium (10 mg/kg) induced state-dependent learning. In addition, pre-test administration of an anticholinesterase, physostigmine (0.3 and 0.6 mg/kg, i.p.) and nicotinic acetylcholine receptor agonist, nicotine (0.1 and 0.5 mg/kg) could substitute for pre-test lithium. Pre-test coadministration of an ineffective dose of physostigmine (0.1 mg/kg) but not nicotine (0.01 mg/kg), with lower doses of lithium (2.5 and 5 mg/kg) potentiated the effect of the latter drug on step-down latency. Post-training administration of a nonselective antagonist of muscarinic acetylcholine receptors, atropine, decreased the step-down latency, but pre-test administration of the same dose of the drug and also lithium, could not reverse the decrease of step-down latency. On the other hand, pre-test atropine at higher doses (0.3 and 0.6 mg/kg) disrupted lithium-induced statedependent learning. On the contrary, the decrease of step-down latency due to post-training administration of another nonselective muscarinic antagonist, scopolamine (1 mg/kg, i.p.) reversed by pre-test administration of not only the same dose of the drug, but also lithium (10 mg/kg). Interestingly, pre-test administration of scopolamine (1 mg/kg) also reversed the decrease of stepdown latency induced by post-training lithium (10 mg/kg). Conclusion: cholinergic system(s) may be involved in the lithium-induced state- dependent learning and the involvement of muscarinic receptors is more possible than nicotinic ones.