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Abstract: The CB1 cannabinoid receptor antagonist SR-141716A (Rimonabant) markedly diminishes the behavioral effects of opiates and nicotine and has been an important tool to ascertain the role of cannabinoid receptors in drug addiction. The present goal was to determine the less-explored interaction of SR-141716A and d-amphetamine in neurochemical and behavioral assays. Additionally, the effect of the substituents and substitution patterns on the phenyl ring located at the 5 position of SR-141716A (4-chlorophenyl), and of the CB1/CB2 cannabinoid receptor agonist WIN-55,212-2, was determined. SR-141716A, AM-251 (4-iodophenyl) and NIDA-41020 (4-methoxyphenyl) did not alter amphetamine-evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine. MRI-8273-30-1 (4-fluorophenyl; 0.1–10 μM) attenuated amphetamine (3 μM)-evoked [3H]overflow, and MRI-8273-59 (3,4-dichlorphenyl; 0.01–10 μM) augmented amphetamine (0.3–3 μM)-evoked [3H]overflow. WIN-55,212-2 was without effect. In a locomotor activity experiment, SR-141716A and MRI-8273-30-1 did not alter amphetamine-induced hyperactivity. However, MRI-8273-59 (1–3 mg/kg) dose-dependently attenuated amphetamine (1 mg/kg)-induced hyperactivity. The present results suggest that SR-141716A is less efficacious to alter amphetamine effects than its reported efficacy to diminish the effects of opiates and nicotine. Modification of the 5-phenyl position of SR-141716A affords compounds that do interact with amphetamine in vitro and in vivo. [Copyright &y& Elsevier]

Abstract: Nicotine, the main psychoactive ingredient in tobacco, plays a key role in the development of cigarette smoking addiction. The endocannabinoid system has been demonstrated to have an important role in the motivational and reinforcing effects of drugs. The present study used behavioral and neurochemical techniques to study the interaction of cannabinoid receptors and nicotine pharmacology. In a locomotor activity experiment in rats, the CB1/CB2 cannabinoid receptor agonist WIN-55,212-2 (0.28–2.8 mg/kg) attenuated nicotine (0.4 mg/kg)-induced hyperactivity, but did not alter nicotine (1.0 mg/kg)-induced hypoactivity. In contrast, the selective CB1 cannabinoid receptor antagonist SR-141716A (1.0 mg/kg) diminished nicotine-induced hypoactivity, but did not alter nicotine-induced hyperactivity. In a neurochemical experiment, rat striatal slices preloaded with [3H]dopamine were superfused with WIN-55,212-2 or SR-141716A. A high concentration (100 μM) of WIN-55,212-2 evoked [3H]overflow, but this effect was not blocked by the cannabinoid receptor antagonist AM-251. SR-141716A did not evoke [3H]overflow, and neither WIN-55,212-2 nor SR-141716A altered nicotine-evoked [3H]overflow. Overall, these results indicate a behavioral interaction between cannabinoid receptors and nicotine pharmacology. Likely, WIN-55,212-2 and SR-141716A block nicotine-induced changes in behavior through an indirect mechanism, such as alteration in endocannabinoid regulation of motor circuits, rather than directly through blockade of nicotinic acetylcholine receptors. [Copyright &y& Elsevier]

Purpose: Lobeline perturbs intra- and extracellular neurotransmitter levels and diminishes the in vitro and in vivo effects of psychostimulants. More recently, lobeline was shown to bind to μ opiate receptors, block the effects of opiate receptor agonists, and decrease heroin self-administration in rats. The present study determined the effect of lobeline on morphine-induced changes in locomotor behavior in rats. Methods: For 12 consecutive days (Days 1 - 12), male rats were administered lobeline (0.3 or 1 mg/kg) followed by morphine (5 or 10 mg/kg) and locomotor activity was measured. On Day 13, the effect of lobeline on the expression of morphine-induced increases in activity was determined. Results: With repeated morphine treatment, an increase in locomotor activity was observed. In a dosedependent manner, lobeline decreased the morphine-induced increase in activity. Acute lobeline challenge on Day 13 also attenuated the expression of this morphine-induced increase in activity. Conclusion: These results are consistent with previous work where lobeline blocks the locomotoractivtating properties of psychostimulants, and these findings support an emerging literature suggesting that lobeline produces its behavioral effects through an interaction with μ opiate receptors. [ABSTRACT FROM AUTHOR]

Abstract: Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil''s mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64–128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100–300 μM) evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 μM) blocked modafinil-evoked [3H]overflow, and concentrations of modafinil (<100 μM) that did not have intrinsic activity attenuated amphetamine (1 and 3 μM)-evoked [3H]overflow. Modafinil-evoked [3H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [3H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil''s mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine. [Copyright &y& Elsevier]