Rationale: Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer's disease.
Methods: We modeled in rats the cognitive effects of chronic decrease in hippocampal alpha7 or alpha4beta2 receptors with 4-week continuous bilateral local infusions of the alpha7 nicotinic antagonist methyllycaconitine (MLA) or the alpha4beta2 antagonist dihydro-beta-erythroidine (DHbetaE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine.
Results: Chronic ventral hippocampal DHbetaE infusion caused a significant (p < 0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p < 0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p < 0.025) attenuated the memory deficit caused by chronic hippocampal DHbetaE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p < 0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects.
Conclusions: The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.