Effect of lithium on the deficit in performance of a reversal learning task induced by phencyclidine in the rat

Behavioural Pharmacology

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induced in dopamine D3 KO mice by pretreatment with BAP(1-42). Different groups of mice were injected intracerebroventricularly (i.c.v.) with 400pMol BAP(1-42) and 14 days later tested in a step-through passive avoidance paradigm. The cannabinoid CB1 receptor antagonists, rinmnabant or AM251 were injected intraperitoneally (i.p.) 30rain prior to 1st or the 2nd retention test made 1 and 7 days after the learning trial, respectively. Control wild type (WT) animals were injected with saline. Dopamine D3 KO mice showed a reduced retention of passive avoidance response as compared to WT control mice. Treatment with rimonabant or AM251 was tbllowed by an increased latency of passive avoidance response. Pretreatment with BAP(1-42) induced a worsening of passive avoidance reaction both in WT and dopamine D3 KO mice, but this deficit was reverted by CB1 receptor blockade. Interestingly, cannabinoid CB 1 receptor blockade counteracted memory deficit ofdopamine D3 KO mice which were not pretreated with BAP(1-42). These data suggest that dopamine D3 KO mice might exhibit, under basal condition, an activation of endocannabinoid system that may account for their poor performance in passive avoidance paradigm.

References [1] Mazzola C, Micale V,, Drago F, 2003. Anmesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur J Pharmacol 477(3), 219-25.

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Effect of lithium on the deficit in performance of a reversal learning task induced by phencyclidine in the rat

N. Idris 1, B. Grayson 1, J.C. Neill 1. 1 Universityof Bradford,

Pharmacology, Bradford Westyorkshire, UnitedKingdom Introduction: N-methyl-D-aspartate ('NMDA) receptor

antagonists such as phencyclidine (PCP) produce schizophrenia-like symptoms in humans including cognitive impairment. In our laboratory, both acute and sub-chronic PCP treatment induces a cognitive deficit in a preclinical model with potential relevance for the pathology of schizophrenia (Abdul-Monin~ et al., 2003). This deficit is reversed by the anticonvulsant and mood stabilizer, lamotrigine and atypical, but not classical, antipsychotics (Abdul-Monin~ et al., 2003, Idris et al., 2005). We have recently shown that PCP significantly alters steady state glutamate and GABA tissue levels in cortical areas at doses and injection regimes that produce a reversal learning deficit. These data are in part consistent with the hypothesis that PCP-induced disruption

of cognition is mediated via disruption of the cortical glutamatergic system. Aim" The present study aimed to explore further the mechanism by which PCP produces its effects in this paradigm by testing the ability of lithium, a mood stabilizer without anticonvulsant properties, to prevent the PCPinduced cognitive deficit in this paradigm. Methods: Subjects were 45 adult female hoodedLister rats (Harlan, UK) housed under standard laboratory conditions on a 12 h light-dark cycle (lights on 0700 h). Rats were maintained at 85% free-feeding weight (approx 225 g) and trained to perform an operant reversal learning task to 90% criterion by a method previously described in detail (Abdul-Monim et al., 2003). PCP and lithium were injected ip 30rain prior to testing. Data are expressed as mean -4- SEM (n = 9 per group) of percent correct responding in the initial and reversal phase of the task (5 min per phase). Statistical comparisons were made using a two-way ANOVA with post-hoc Dunnett' s t-test. Results: PCP at 1.5 mg/kg produced a selective and significant reduction in performance of the reversal phase of the task with no effect on initial phase performance (p < 0.01, n = 9). Percent correct responding was reduced from 79.4-4-4.2 to 54.3• in the reversal phase of the task following 1.5 mg/kg PCP; the initial phase was unaffected by PCR Lithium (25-75 mg/kg, n = 9) had no effect on cognitive performance when administered alone and was unable to prevent the cognitive deficit induced by PCR Percent correct responding in the reversal phase was reduced from 78.2-4-4.7 to 54.7-4-6.8 (PCP + 25mg/kg lithium), 79.3-4-5.2 to 56.4.3-4-6.4 (PCP + 50mg/kg lithium) 79.2-4-54.4 to 57.7.3-4-5.7 (PCP + 75mg/kg lithium). Conclusions: These results show that not all mood stabilizers are active in this paradigm, strengthening the hypothesis that sodium channel blockade is a mechanism by which certain mood stabilising drugs can ameliorate the PCP-induced deficit in this paradigm. These findings are consistent with the hypothesis that PCP-induced disruption of cognition in this paradigm is mediated via an interaction with the glutamatergic system and is in agreement with the NMDA receptor hypoiimction hypothesis of schizophrenia (Olney and Farber 1999).

References [1] Abdul-Monim, Z., Reynolds, G.P., and Neill, J.C., 2003. The atypical antipsychotic ziprasidone, but not haloperidol, improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat. J Psychopharmacol 17, 57-65. [2] Idris, N.E, Repeto, P., Neill, J.C., and Large, C.H., 2005. Investigation of the effect of lamotrigine and

Behavioural Pharmacology clozapine to improve reversal learning impairments induced by acute PCP and d-amphetamine in the rat. Psychopharmacology 179, 336-48. [3] Olney, J.W., Newcomer, J.W., and Farber, N.B., 1999. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33, 523-33.

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the role of these drugs in cue-induced nicotine-seeking behavior in rats after a period of extinction. It has been proposed that this procedure has relevance to relapse behavior in human drug abusers. The results indicated that administration of the novel nicotinic receptor antagonist MRZ 2/621 (1-10mg/kg, i.p., salt) prior to the reinstatement sessions had no effect on nicotine-seeking behavior at the tested dose range. Pretreatment with mecamylamine (0.1-1mg/kg, Effects of nicotinic receptor blockade on s.c.) significantly decreased cue-induced responding. nicotine conditioned behaviors in rats In the second series of experiments, rats were trained to associate nicotine (0.4mg/kg, i.p.) injections with E.S. Zakharova1, O.A. Dravolina1, W. Danysz2, placement into one compartment of the two-compartment E.E. Zvartau 1, A.Y. Bespalov 1. 1Parlor Medical shuttle box while injections of its vehicle were paired University, Institute of Pharmacology, St. Petersburg, with placements into another compartment. Following five Russia," 2Merz Pharmaceuticals, Department of drug place pairings, rats given a free choice between Pharmacology, Frankfurt am Main, Germany the compartments spent significantly more time on the Abuse potential of nicotine is strongly linked to central nicotine-associated side. nicotinic receptors. Unlike the prototypic nicotine channel Pretreatment with both MRZ 2/621 (2.5-10mg/kg) blocker mecamylamine, a novel non-competitive nicotinic and mecamylamine (0.1-3 mg/kg) significantly attenuated receptor antagonist MRZ 2/621 (1-amino- 1,3,3-trinlethylexpression of nicotine-conditioned place preference. cyclohexane) has no activity at Gt3134 receptors and is Thus, nicotinic receptor blockade produced by either expected to be devoid of ganglionic activity (W. Danysz, mecamylamine or MRZ 2/621 reduces reactivity to NIDA Contract N01DA- 8- 8089). Yet, some o f the previous nicotine-associated contextual cues (place conditioning research attributed potential anti-addictive properties of studies). Nicotine-seeking triggered by exposure to nicotine receptor antagonists to the ability to block Gt3134- nicotine-associated discrete cues is affected by mecamycontaining receptors (Glick et al., 2002). Thus, the aim lamine but not MRZ 2/621, suggesting Gt3134-dependent of the present study was to evaluate MRZ 2/621 and mechanisms of this phenomenon. mecamylamine using two experimental paradigms that Acknowledgments: Supported by the Fogarty Internaare commonly thought to model the role of classical tional Research Collaboration Award #1R03TW00714. conditioning mechanisms of nicotine addiction. These methods used in the studies presented here involved References the assessment of nicotine-seeking behavior triggered by [1] Bespalov, A.Y., Dravolina, O.A., Sukhanov, I., exposing the rats to contextual and discrete stimuli that Zakharova, E., Blokhina, E., Zvartau, E., Danysz, W., were previously associated with the drug delivery. Such Van Heeke, G., and Markou, A., 2005. Metabotropic a conditioned reinstatement procedure focuses on the glutamate receptor (mGluR5) antagonist MPEP role that conditioning processes play in maintaining the attenuated cue- and schedule-induced reinstatement drug addiction in the absence of nicotine administration of nicotine self-administration behavior in rats. or availability. Such conditioned behavior in non-human Neuropharmacology 49, 167-78. experimental subjects is consistent with the clinical [2] Glick, S.D., Maisonneuve, I.M., and Kitchen, B.A., evidence on cue-induced relapse to drug use. 2002. Modulation of nicotine self-administration in The first experiment involved three phases: (i) acquisirats by combination therapy with agents blocking tion phase where the rats with intravenous catheter were alpha3beta4 nicotinic receptors. Eur J Pharnlacol 448, trained to nose-poke to receive intravenous response185-91. contingent nicotine infusions (0.01 mg/kg per infusion, free base; final schedule of reinforcement FR5 TO 60 s); (ii) extinction phase when nose-poke responding was no longer reinforced by nicotine or nicotine-conditioned cues and, thus, was extinguished to near-baseline levels; and (iii) reinstatement phase during which responses in the active hole resulted in response-contingent presentations of the nicotine-associated discrete light cues but no nicotine was delivered (Bespalov et al., 2005). Here we addressed

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