Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine, and cocaine in rats.

RATIONALE: Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats. OBJECTIVES: Here we investigated the relative involvement of adenosine A(1) and A(2A) receptors in nicotine, cocaine, and methamphetamine discrimination, before and/or during chronic caffeine exposure. MATERIALS AND METHODS: The nonselective adenosine receptor antagonist caffeine, the A(1)-receptor antagonist cyclopentyltheophylline (CPT), and the A(2A)-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of adenosine receptor antagonists were then compared in rats discriminating nicotine, methamphetamine, or cocaine from saline during chronic caffeine exposure in their drinking water. RESULTS: Caffeine, CPT, and MSX-3 partially generalized to nicotine and shifted nicotine dose-response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose-response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose-response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose-response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose-response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose-response curves leftwards. CONCLUSIONS: Both adenosine A(1) and A(2A) receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A(1)- and A(2A)-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A(1)-mediated, but not A(2A)-mediated, effects in methamphetamine- and cocaine-trained rats.

Effects of baclofen on conditioned rewarding and discriminative stimulus effects of nicotine in rats.

Neurochemical studies suggest that baclofen, an agonist at GABA(B) receptors, may be useful for treatment of nicotine dependence. However, its ability to selectively reduce nicotine's abuse-related behavioral effects remains in question. We assessed effects of baclofen doses ranging from 0.1 to 3mg/kg on nicotine-induced conditioned place preferences (CPPs), nicotine discrimination, locomotor activity and food-reinforced behavior in male Sprague-Dawley rats. The high dose of baclofen (3mg/kg) totally eliminated food-reinforced responding and significantly decreased locomotor activity. Lower doses of baclofen did not have nicotine-like discriminative effects in rats trained to discriminate 0.4mg/kg nicotine from saline under a fixed-ratio 10 schedule of food delivery. Lower doses of baclofen also did not reduce discriminative stimulus effects of the training dose of nicotine and did not significantly shift the dose-response curve for nicotine discrimination. Rats treated with the high 3mg/kg dose of baclofen did not express nicotine-induced CPP. These experiments, along with previous reports that baclofen can reduce intravenous nicotine self-administration behavior, confirm the potential utility of baclofen as a tool for smoking cessation.

Topiramate does not alter nicotine or cocaine discrimination in rats.

The effects of topiramate, a potential treatment for drug dependence, were evaluated in two groups of rats trained to discriminate the administration of either 0.4 mg/kg nicotine or 10 mg/kg cocaine from that of saline, under a fixed-ratio 10 schedule of food delivery. Topiramate (1-60 mg/kg, intraperitoneal) did not produce any nicotine-like or cocaine-like discriminative effects by itself and did not produce any shift in the dose-response curves for nicotine or cocaine discrimination. Thus, the ability to discriminate the effects of nicotine or cocaine does not appear to be altered by topiramate administration. Furthermore, topiramate, given either alone or in combination with nicotine or cocaine, did not depress rates of responding. These experiments indicate that topiramate does not enhance or reduce the ability of rats to discriminate the effects of nicotine or cocaine.

Nicotinic facilitation of delta9-tetrahydrocannabinol discrimination involves endogenous anandamide.

Systemic administration of the main active ingredient in cannabis, Delta9-tetrahydrocannabinol (THC), alters extracellular levels of acetylcholine in several brain areas, suggesting an involvement of the cholinergic system in the psychotropic effects of cannabis. Here, we investigated whether drugs acting at either nicotinic or muscarinic receptors can modulate the discriminative effects of THC. In rats that had learned to discriminate effects of 3 mg/kg i.p. injections of THC from injections of vehicle, the nicotinic agonist nicotine (0.1-0.56 mg/kg subcutaneous) and the muscarinic agonist pilocarpine (0.3-3 mg/kg i.p.) did not produce THC-like effects, but they both potentiated the discriminative effects of low doses of THC (0.3-1 mg/kg). Neither the nicotinic antagonist mecamylamine (1-5.6 mg/kg i.p.) nor the muscarinic antagonist scopolamine (0.01-0.1 mg/kg i.p.) altered the discriminative effects of THC, but they blocked the potentiation of discriminative effects of THC by nicotine and pilocarpine, respectively. The cannabinoid CB(1) antagonist rimonabant (1 mg/kg i.p.) reversed nicotine- but not pilocarpine-induced potentiation of THC discrimination, suggesting that nicotine potentiation is, at least in part, mediated by release of endogenous cannabinoids in the brain. In addition, when metabolic degradation of the endogenous cannabinoid anandamide was blocked by the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoylbiphenil-3-yl-ester (URB-597; 0.3 mg/kg i.p.) nicotine, but not pilocarpine, produced significant THC-like discriminative effects that were antagonized by rimonabant. Our results suggest that nicotinic and muscarinic cholinergic receptors modulate the discriminative effects of THC by fundamentally different mechanisms. Nicotinic, but not muscarinic, modulation of THC discrimination involves elevations in endogenous levels of anandamide.