Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys, and the ability of pharmacological or behavioral manipulations to modify such behavior. One pharmacokinetic approach to the treatment of cocaine abuse and toxicity involves the development of compounds that can be safely administered to humans and that accelerate the metabolism of cocaine to inactive components. Catalytic antibodies have been developed and shown to accelerate cocaine metabolism, but their catalytic efficiency for cocaine is relatively low. Mutations of human butyrylcholinesterase and a bacterial cocaine esterase found in the soil of coca plants have also been developed. These compounds accelerate cocaine metabolism and antagonize the behavioral and toxic effects of cocaine in animal models. We have studied the effects of one such enzyme (Albu-CocH) on the behavioral effects of cocaine in squirrel monkeys (Schindler et al., 2013). Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. In behavioral experiments in monkeys, pre-treatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 g/kg/injection) for over 24 hours. Pre-treatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative-stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related behavioral effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted. Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine methamphetamine addiction. We examined the influence of methamphetamine self-administration on gene and protein expression that may form substrates for methamphetamine-induced neuronal plasticity in the dorsal striatum (Krasnova et al., 2013). Male Sprague-Dawley rats self-administered methamphetamine or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of methamphetamine exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of methamphetamine-induced transcription. Methamphetamine self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. Methamphetamine also caused changes in FosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1 month of drug abstinence. Importantly, ChIP-PCR showed that methamphetamine self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that methamphetamine-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, methamphetamine self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity. Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors. Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, we previously found that AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of AM404 on intravenous nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues (Gamaleddin et al., 2013). The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming. Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers. Our results also suggest that anandamide uptake inhibitors can prevent relapse to nicotine-seeking behavior independent of effects on other non-cannabinoid receptor sites. Although it is more common for drug abuse to progress from tobacco to cannabis, in many cases cannabis use develops before tobacco use. Epidemiological evidence indicates that prior cannabis use increases the likelihood of becoming dependent on tobacco. To determine whether this effect might be due to cannabis exposure per se, in addition to any genetic, social, or environmental factors that might be involved, we extended our series of studies on 'gateway drug'effects in animal models of drug abuse. Rats were exposed to THC, the main psychoactive constituent of cannabis, for 3 days (two injections per day). Then, starting 1 week later, they were allowed to self-administer nicotine intravenously. THC exposure increased the likelihood of acquiring the nicotine self-administration response from 65% in vehicle-exposed rats to 94% in THC-exposed rats. When the price of nicotine was manipulated by increasing the response requirement, THC-exposed rats maintained higher levels of intake than vehicle-exposed rats, indicating that THC exposure increased the value of nicotine reward. These results contrast sharply with our earlier findings that prior THC exposure did not increase the likelihood of rats acquiring either heroin or cocaine self-administration, nor did it increase the reward value of these drugs. The findings obtained here suggest that a history of cannabis exposure might have lasting effects that increase the risk of becoming addicted to nicotine.

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Panlilio, Leigh V; Hogarth, Lee; Shoaib, Mohammed (2015) Concurrent access to nicotine and sucrose in rats. Psychopharmacology (Berl) 232:1451-60
Justinova, Zuzana; Redhi, Godfrey H; Goldberg, Steven R et al. (2014) Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on ýý9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys. J Neurosci 34:6480-4
Schindler, Charles W; Justinova, Zuzana; Lafleur, David et al. (2013) Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. Addict Biol 18:30-9
Le Foll, Bernard; Di Ciano, Patricia; Panlilio, Leigh V et al. (2013) Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: preclinical evidence. Curr Drug Targets 14:768-76
Panlilio, Leigh V; Justinova, Zuzana; Goldberg, Steven R (2013) Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacol Ther 138:84-102
Krasnova, Irina N; Chiflikyan, Margarit; Justinova, Zuzana et al. (2013) CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis 58:132-43
Panlilio, Leigh V; Zanettini, Claudio; Barnes, Chanel et al. (2013) Prior exposure to THC increases the addictive effects of nicotine in rats. Neuropsychopharmacology 38:1198-208
Schindler, Charles W; Panlilio, Leigh V; Thorndike, Eric B (2009) Effect of rate of delivery of intravenous cocaine on self-administration in rats. Pharmacol Biochem Behav 93:375-81
Scherma, Maria; Fadda, Paola; Le Foll, Bernard et al. (2008) The endocannabinoid system: a new molecular target for the treatment of tobacco addiction. CNS Neurol Disord Drug Targets 7:468-81
Solinas, M; Goldberg, S R; Piomelli, D (2008) The endocannabinoid system in brain reward processes. Br J Pharmacol 154:369-83

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