Cotinine, a major metabolite of nicotine, has produced improved learning and memory in rodents and non-human primates and corrects apomorphine-induced loss of pre-pulse startle inhibition in rats. The present study assessed cotinine, both acute and chronic (7-day), in the sensory inhibition paradigm in DBA/2 mice. These mice spontaneously show a deficit in hippocampal sensory inhibition, as assessed by the P20-N40 EEG paradigm, which models the deficit observed in schizophrenia patients. Anesthetized DBA/2 mice were recorded in the CA3 region of hippocampus for inhibition of paired, identical auditory stimuli, then administered cotinine (0.33, 0.1, 0.33, 1.0 or 3.3 mg/kg SQ) and recorded for 90 minutes. At doses of 0.1, 0.33 and 1.0 mg/kg, there were significant increases in conditioning amplitude, with no changes in test amplitude or TC ratio. Blockade of α4β2 nicotinic receptors with central administration of DHβE blocked the increase in conditioning amplitude induced by the 1.0 mg/kg dose of cotinine, as did blockade of α7 nicotinic receptors with α-bungarotoxin. Daily injections of 0.33, 1.0 or 3.3 mg/kg for 7 days produced similar increases in conditioning amplitude on the 7th day, but only at the 0.33 and 3.3 mg/kg doses. Determination of the “carry over” effect of the previous 6 daily doses of cotinine, prior to the 7th dose, showed that there was a significant increase in conditioning amplitude as compared to the baseline data for mice receiving the equivalent acute dose. There were no significant effects on test amplitude or TC ratio for any of the chronic doses. These data suggest that cotinine modulates the conditioning amplitude in the sensory inhibition paradigm through the α4β2 nicotinic receptor and possibly also through the α7 nicotinic receptor, as well. However the data do not suggest that cotinine is a potential therapeutic for the treatment of sensory inhibition deficits in schizophrenia.

Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6 mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also examined α4β2* and α7* nAChR selective antagonist pre-administration prior to varenicline administration in order to determine the impact of these two nAChR subtypes in the effects produced by varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6 mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3 mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline’s effects on auditory evoked responses in DBA/2 mice.