Nicotinic antagonist effects in the mediodorsal thalamic nucleus: Regional heterogeneity of nicotinic receptor involvement in cognitive function

Nicotine has been found in many studies to improve cognitive function. However, some studies have not found this effect and others have seen nicotine-induced impairments. Systemic administration bathes the brain with drugs. However, the brain is quite intricately organized with various regions playing very different roles in the bases of cognitive function. We have examined the role of nicotinic receptors in a variety of brain areas for memory. In the hippocampus and amygdala, local infusions of both α7 and α4β2 antagonists methyllyaconitine (MLA) and dihydro-β-erythroidine (DHβE) significantly impair memory. In the current studies we locally infused acute and chronic doses of MLA and DHβE into the mediodorsal thalamic nucleus and tested memory function on a 16-arm radial maze. The rats also received systemic nicotine to determine the impact of more generalized nicotine effects. Since nicotinic treatments are being developed for cognitive impairment of schizophrenia, interactions were studied with the antipsychotic drug clozapine. In the acute study, the 6.75 μg/side of DHβE improved working memory. Co-administration of MLA reversed the DHβE-induced improvement. Chronic DHβE infusions into the mediodorsal thalamic nucleus also improved working memory. Systemic nicotine reversed this effect. Clozapine had no significant interaction. Nicotinic α4β2 receptors in the mediodorsal thalamic nucleus appear to play an opposite role with regard to working memory than those in the hippocampus and amygdala. Heterogeneity in response to nicotinic drugs given systemically may be due to anatomically distinct nicotinic systems in the brain and their unique roles in the neural bases of cognitive function.