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Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.

Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.

Evidence indicates that the antipsychotic drug clozapine has a low propensity for the induction of extrapyramidal motor symptoms, and also that clozapine has therapeutic effects in patients with idiopathic Parkinson's disease. Because tacrine-induced tremulous jaw movements in rats have been suggested as a possible model of extrapyramidal motor dysfunctions, including parkinsonian tremor, the present work was undertaken to investigate the effects of clozapine on tremulous jaw movements. Clozapine decreased tacrine-induced tremulous jaw movements in a dose-related manner, with an ED50 of approximately 3.3 mg/kg. In order to determine the relative potency of this effect compared to other behavioral effects of clozapine, suppression of lever pressing was also studied. Clozapine reduced lever pressing in a dose-related manner, with an ED50 of approximately 5.4 mg/kg. This indicates that clozapine suppressed jaw movements at or below the doses required for suppression of lever pressing. In contrast, the typical antipsychotic drug haloperidol failed to suppress tacrine-induced tremulous jaw movements in doses up to 1.0 mg/kg, which is about 11-fold higher than the ED50 for suppression of lever pressing with that drug. Thioridazine and risperidone also suppressed tremulous jaw movements in roughly the same dose range at which lever pressing was reduced. It is possible that the suppression of tacrine-induced tremulous jaw movements by clozapine in rats is related to the unique behavioral and motor effects of clozapine. The ratio of potencies of these effects (i.e., suppression of tremulous jaw movements versus suppression of lever pressing) could be used as a behavioral procedure for assessing clozapine-like activity in novel compounds.