Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and provoke relapse to previously extinguished drug-seeking behavior in abstinent animals. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration and relapse behavior rats and monkeys, and the ability of pharmacological manipulations to modify such behavior. Based on work in rodents, Group II metabotropic glutamate receptors (mGluRs) have been considered as targets for nicotine addition treatment. The prototype drug used to assess the function of Group II mGluRs is LY379268, an orthosteric agonist that binds to both mGluR2s and mGluR3s. In rats, pretreatment with LY379268 decreases nicotine self-administration and discrete cue-induced reinstatement of nicotine seeking. We have recently shown that injections of LY379628 will block nicotine, but not cocaine, self-administration in squirrel monkeys. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement. LY379268 blocked cue-induced reinstatement in both nicotine- and cocaine-experienced squirrel monkeys. These results provide support for the potential utility of mGluR2/3 receptor agonists in the treatment of nicotine dependence. While our work, and that of others, with LY379268 suggests the utility of mGluR2 receptor agonists in the treatment of nicotine dependence, LY379268 does not distinguish between the mainly presynaptic inhibitory mGluR2 and mGluR3 receptors. In addition, tolerance develops to these mGluR2/3 agonist, making them less than ideal targets for medication development. To further address the utility of mGluR2 receptor agonists in nicotine dependence, we have recently determined the effects of AZD8529, a selective positive allosteric modulator (PAM) of mGluR2, on the abuse-related effects of nicotine in squirrel monkeys and rats. AZD8529 potentiated agonist-induced activation of mGluR2 in both a functional in vitro assay in membrances prepared from a cell line expressing human mGluR2 and in brain slices of primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (0.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. These results provide strong evidence for efficacy of PAMs of mGluR2 in non-human primate models of nicotine reinforcement and relapse and the potential utility of these drugs in the treatment of nicotine dependence. Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 and URB694, in squirrel monkeys. Both FAAH inhibitors blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors. Both inhibitors also shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward, blocked reinstatement of nicotine seeking induced by re-exposure to either nicotine priming or nicotine-associated cues and had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist MK886. Unlike URB597, which is not self-administered by monkeys, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell-consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. 3,4-Methylenedioxypyrovalerone (MDPV) and methylone are synthetic drugs found in so-called bath salts products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine and serotonin (5-HT). We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. To test this hypothesis, we compared behavioral effects of MDPV and methylone using i.v. self-administration in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly, and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. By contrast, methylone self-administration (0.3 & 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats suggesting these drugs possess significant abuse liability in humans.
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