Olanzapine and clozapine but not the typical agent chlorpromazine, are effective in ameliorating a sub-chronic PCP induced cognitive deficit in the rat Abdul-Monim Z, Reynolds GP, 1 Neill JC, Bradford School of Pharmacy, University of Bradford, BD7 1DP, and 1The Department of Biomedical Science, The University of Sheffield, S10 2TN, UK.	Print Abstract Search PubMed for: Abdul-Monim Z Reynolds GP Neill JC

Acute PCP treatment, although able to mimic some features of schizophrenia, is limited in its applicability to a chronic disorder (Jentsch and Roth, 1999). A chronic treatment regimen of PCP may provide a more effective way to model the enduring cognitive dysfunction observed (Jentsch et al, 1997). The aim of this study was to examine the pharmacology of the cognitive deficit induced by sub-chronic PCP treatment using a previously established operant reversal-learning paradigm (Abdul-Monim et al, 2003a). The efficacy of the atypical antipsychotics, clozapine and olanzapine, to reverse the sub-chronic PCP deficit was compared with that of the classical antipsychotic, chlorpromazine. Our previous sub-chronic PCP studies have shown degenerative loss of parvalbumin-containing GABAergic neurones in the prefrontal cortex and hippocampal areas (Abdul-Monim et al, 2003b). Female hooded-Lister rats (Harlan, UK, 220±25g), food deprived and maintained under standard laboratory conditions were trained to respond for food using an operant reversal-learning paradigm previously described in detail (Abdul-Monim et al, 2003a). When animals achieved a criterion of 90% correct responding, they were treated with PCP (2mg.kg^-1 ip, n=32) or vehicle (ip, n=8) twice daily for 7 days and, after a further 7 days, tested for their cognitive ability using an operant reversal-learning paradigm. Antipsychotics or vehicle were administered ip 30min prior to testing. Data are expressed as mean ± SEM (n=8-10 per group) of percent correct responding in the initial and reversal phases of the task (5 min per phase) and analysed using 1 and 2-way ANOVA (Factors are drug and task) followed by Bonferroni corrected t-test.

Throughout the experimental period (6 weeks) rats treated with sub-chronic PCP demonstrated significant impairment in the reversal task relative to the initial task. Percent correct responding was reduced from an initial value of 92.5±1.5% to a mean reversal value of 50.2±2.4% (p<0.001). No significant difference between initial and reversal task performance was observed with vehicle controls. Acute treatment with olanzapine (1.5mg.kg^-1 ip) and clozapine (5mg.kg^-1 ip) produced a significant reversal of the impairment induced by sub-chronic PCP in the reversal task. Correct responding increased from 53.4±4.2% (sub-chronic PCP + vehicle) to 78.2±3.8% (sub-chronic PCP + olanzapine) (P<0.001), and clozapine treatment improved the impairment induced by PCP from a mean value of 53.6±4.1% to a value of 69.9±6.1% (P<0.01). In marked contrast to these effects, acute administration of the typical agent chlorpromazine (2mg.kg^-1 ip) failed to significantly reverse the PCP-induced cognitive impairment, Percent correct responding values being 47.8±4.3% (sub-chronic PCP + vehicle) and 53.0±4.1% (sub-chronic PCP + chlorpromazine) respectively. The present results clearly demonstrate that sub-chronic PCP produces an enduring cognitive deficit, an effect that was significantly improved by acute treatment with atypical but not classical antipsychotics. Such effects may be a consequence of dysfunction or loss of parvalbumin immunoreactive GABAergic interneurones induced by sub-chronic PCP (Abdul-Monim et al, 2003b).

Abdul-Monim, Z. et al (2003a) J. Psychopharmacology 17: 57-66.
Abdul-Monim, Z. et al (2003b) Br. Neurosci. Assoc. Abstr. 17: 37.01.
Jentsch, J.D., Roth R.H. (1999) Neuropsychopharmacology 20: 201-225.
Jentsch, J.D. et al (1997) Science 277: 953-955.

Acknowledgement: We thank Pfizer Inc for financial support.