Reversal of Clozapine Effects on Working Memory in Rats with Fimbria–Fornix Lesions

Abstract

Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit, which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, 13 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In shamoperated rats, clozapine caused a significant (Po0.005) working memory impairment. Fimbria-fornix lesions also caused a significant (Po0.05) memory impairment. Interestingly, clozapine had the opposite effect on working memory in the lesioned vs sham-operated rats. In contrast to its effects in controls, clozapine (1.25 mg/kg) significantly (Po0.05) attenuated the working memory deficit caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did not quite significantly improve memory in lesioned rats. The effects of clozapine and nicotine were not additive in the lesioned rats. This study demonstrates the efficacy of clozapine in improving working memory in fimbria-fornix-lesioned rats, whereas it causes impairments in intact rats. Therapeutic treatment with clozapine in people with malfunctions of the hippocampus such as seen in schizophrenia may improve cognitive performance, whereas the same doses of clozapine may impair memory in individuals without hippocampal malfunction.

Ventral hippocampal α7 and α4β2 nicotinic receptor blockade and clozapine effects on memory in female rats

“…Clozapine induced memory improvement in conditions of hippocampal dysfunction such as decreased α4β2 receptor activity in the current study or fimbriafornix lesions in our earlier study (Addy et al 2005) suggests that clozapine may have better efficacy for cognitive improvement in patients with high affinity nicotinic receptor dysfunction in the hippocampus such as patients with Alzheimer's disease. The potentiated clozapine-induced memory impairment with hippocampal α7 receptor blockade suggests that clozapine may be less beneficial with regard to cognitive function in syndromes with hippocampal α7 deficits such as schizophrenia.…”

“…Knife-cut lesions of the fimbria-fornix, which carries cholinergic innervation to the hippocampus among other fibers, caused a significant working memory impairment in the radial-arm maze, an effect which was significantly attenuated by clozapine (Addy et al 2005). The current study provided a more specific challenge to the hippocampal cholinergic system, chronic blockade of α4β2 nicotinic receptors.…”

“…Replicating our previous work Addy et al 2005) clozapine caused a dose-dependent radial-arm maze working memory impairment in intact rats. In the current study, clozapine treatment had differential effects on working memory function in rats given chronic local hippocampal infusions of DHβE and MLA relative to control aCSF infusions.…”

“…A critical component in the nature of clozapine effects on cognitive function appears to be the functionality of the hippocampus. Clozapine doses, which cause significant memory impairment in intact rats, significantly attenuate the memory impairment caused in rats by lesions to the fimbriafornix a principal connection of the hippocampus with the septum, which provides cholinergic innervation to the hippocampus (Addy et al 2005).…”

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

“…However, in this study, few participants were treated with classic D2 blocking antipsychotics, while many were treated with psychiatric medications such as clozapine, bupropion, or fluoxetine that may attenuate the effects of nicotine. Nine subjects were treated with the atypical antipsychotic, clozapine, which has been shown to attenuate the effects of nicotine on both working memory and attentional performance in animal models of schizophrenia (Addy et al, 2005;Rezvani et al, 2007). Seven participants were treated with either bupropion or fluoxetine, which have been shown to have nicotinic antagonist properties in vitro (Hennings et al, 1997;Slemmer et al, 2000).…”