Lamotrigine and clozapine reverse an established cognitive deficit induced by sub-chronic PCP (phencyclidine) in the rat N.F. Idris1, C.H. Large2, G.P. Reynolds3, J.C. Neill1, 1Bradford School of Pharmacy, University of Bradford, BD7 1DP, 2Dept. of Biology, Psychiatry CEDD, GSK S.p.A., Verona, Italy 3Department of Biomedical Science, The University of Sheffield, S10 2TN, UK.	Print Abstract Search PubMed for: Idris NF Large CH Reynolds GP Neill JC

We have recently shown that acute treatment with PCP (phencyclidine) produces a selective cognitive deficit in the rat that is improved by the anticonvulsant, lamotrigine, and atypical, but not classical, antipsychotics (Abdul-Monim et al, 2003a; Idris et al, 2003). Also, sub-chronic PCP treatment produces an enduring cognitive deficit and neuropathological changes of particular relevance to schizophrenia (Abdul-Monim et al, 2003b). The aim of this study was to compare the efficacy of acute and sub-chronic treatment with lamotrigine and clozapine to reverse a cognitive deficit produced by sub-chronic PCP. Subjects were food-deprived adult female hooded-Lister rats (Harlan, UK, 225±20g) housed under standard laboratory conditions. Rats were trained to perform an operant reversal-learning task to 90% criterion by a previously described method (Abdul-Monim et al, 2003a). Rats were subsequently treated with PCP (2mg.kg^-1 ip) or vehicle i.p. twice daily for 6 days followed by 6 drug-free days. Rats were then treated acutely with lamotrigine isethionate (25mg.kg^-1 ip) clozapine (5mg.kg^-1 ip) or vehicle i.p. Lamotrigine was given 90 min and clozapine was given 60 min prior to testing. Treatment with lamotrigine, clozapine or vehicle was continued for a further 5 days (once daily for 5 days) and rats were again tested in the reversal-learning paradigm following drug treatment on day 5. Data are expressed as mean ± SEM (n=10 per group) of percent correct responding in the initial and reversal phases of the task (5 min per phase). Statistical comparisons were made using 2 way and 1 way ANOVA with post-hoc Bonferroni corrected t-test.

Sub-chronic PCP significantly reduced performance of the reversal task compared with the initial task. Percent correct responding was reduced from 86.9±1.8 in the initial task to 47.3±3.2 in the reversal task (p<0.001), this cognitive deficit was stable throughout the 3 week test period. The cognitive deficit was significantly improved by acute treatment with clozapine and the improvement in reversal task performance in the sub-chronic PCP + acute lamotrigine group approached significance when compared with the sub-chronic PCP + vehicle group. Percent correct responding in the reversal task increased from 49.7±4.8 (sub-chronic PCP + vehicle) to 66.7±4.5 (sub-chronic PCP + 5mg.kg^-1 clozapine; p<0.05) and 65.0±5.8 (sub-chronic PCP + 25mg.kg^-1 lamotrigine; p=0.051). Further sub-chronic treatment with clozapine (5mg.kg^-1 ip) or lamotrigine (25mg.kg^-1 ip) produced a robust and significant improvement in the cognitive deficit observed in the sub-chronic PCP + vehicle group. Percent correct responding in the reversal task increased from 52.0±4.7 (sub-chronic PCP + sub-chronic vehicle) to 70.8±3.5 (sub-chronic PCP plus sub-chronic clozapine; p<0.01) and 70.4±5.4 (sub-chronic PCP plus sub-chronic lamotrigine; p<0.05). Sub-chronic PCP in the rat may model both the cognitive deficits and neuropathology occurring in schizophrenia. This indicates that lamotrigine may have potential to improve symptoms that respond poorly to classical antipsychotic therapy.

Abdul-Monim, Z. et al (2003a) J. Psychopharmacology 17: 57-66.
Abdul-Monim, Z. et al (2003b) Br. Neurosci. Assoc. Abstr. 17: 37.01P.
Idris, N.F. et al (2003) Br. J. Pharmacol. 138: 106P.

NF Idris is supported by a GlaxoSmithKline studentship.