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The present study assessed the efficacy of the cannabinoid CB1 receptor antagonist, SR-141716, in reducing voluntary ethanol intake in selectively bred Sardinian alcohol-preferring (sP) rats. Ethanol (10%, v/v) and food were available in daily 4 h scheduled access periods; water was present 24 h/day. The acute administration of a 2.5 and a 5 mg/kg dose of SR-141716 selectively reduced ethanol intake, whereas a 10 mg/kg dose of SR-141716 reduced to a similar extent both ethanol and food intake. These results suggest that the cannabinoid CB1 receptor is involved in the mediation of the ethanol-reinforcing effects in sP rats.

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The aim of the present study was to compare the effects of the typical antipsychotic haloperidol and the atypical antipsychotics clozapine and olanzapine on both extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) as well as electrical activity of mesoprefrontal DA (mPFC-DA) neurons. Extracellular single unit recordings and microdialysis experiments were carried out in different groups of chloral hydrate anesthetised rats under identical experimental conditions. Intravenous administration of haloperidol, clozapine, and olanzapine increased the firing rate and burst activity of antidromically-identified mPFC-DA neurons; maximal increase in firing rate of approximately 140, 155, and 70 %, was produced by haloperidol, clozapine, and olanzapine at doses of 0.2, 2.5, and 1 mg/kg, i.v., respectivelyThe atypical antipsychotics clozapine and olanzapine have been reported to produce a greater increase in extracellular dopamine (DA) concentration in the medial prefrontal cortex (mPFC) than in the striatum and nucleus accumbens, whereas the prototype typical antipsychotic haloperidol is considered to be much less effective in increasing extracellular DA levels in the mPFC than in the nucleus accumbens and striatum (Moghaddam and Bunney 1990;Nomikos et al. 1994; Pehek and Yamamoto 1994;Volontè et al. 1997;Kuroki et al. 1999).From the "B.B. Brodie" Department of Neuroscience, University of Cagliari, Italy (GLG, PD, GF, MM); Department of Drug Sciences, University of Sassari, Italy (MD); and Neuroscience S.C.AR.L., Cagliari, Italy (MP).Address correspondence to: Prof. G.L. Gessa, Dept. of Neuroscience "B.B. Brodie", University of Cagliari, Via Porcell, 4, 09124 Cagliari, Italy.Received May 24, 1999; revised December 8, 1999; accepted December 28, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 6 Antipsychotic Effects on Mesocortical Dopamine Activity 643 Involvement of dopaminergic hypofunction in the mPFC has been suggested in the pathogenesis of both negative symptomatology and cognitive deficits observed in schizophrenia (Meltzer and Stahl 1976;Snyder 1976;Weinberger 1987;Daniel et al. 1991;Deutch 1992;Lidow et al. 1998). Accordingly, the ability of clozapine and olanzapine to increase DA release in this area has been suggested to mediate their efficacy in improving such disturbances in schizophrenia. However, the mechanism by which the two atypical antipsychotics selectively increase DA release in the mPFC is not clear.To our knowledge, no studies have been performed to examine whether the stimulating effect of clozapine and olanzapine on DA release in the mPFC is due to an increased activity of mPFC-DA neurons or whether it depends on a direct action on the mPFC. Indeed, while various studies have investigated the effect of atypical antipsychotics on the electrical activity of DA neurons in the ventral tegmental area (VTA) (Hand et al. 1987;Stockton and Rasmussen 1996), to date, none of them has analysed the effect of these compounds on the electrical activity of antidromically identi...

Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.

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