Aim To review briefly the methods, assumptions, models, accomplishments, drawbacks and future directions of research using drug self-administration in animals and humans. Background The use of drug self-administration to study addiction is based on the assumption that drugs reinforce the behavior that results in their delivery. A wide range of drug self-administration techniques have been developed to model specific aspects of addiction. These techniques are highly amenable to being combined with a wide variety of neuroscience techniques. Conclusions The identification of drug use as behavior that is reinforced by drugs has contributed greatly to the understanding and treatment of addiction. As part of a program of pre-clinical research that also involves screening with a variety of simpler behavioral techniques, drug self-administration procedures can provide an important last step in testing potential treatments for addiction. There is currently a concerted effort to develop self-administration procedures that model the extreme nature of the behavior engendered by addiction. As advances continue to be made in neuroscience techniques, selfadministration should continue to provide a means of applying these techniques within a sophisticated and valid model of human drug addiction.

Activation or blockade of cannabinoid CB1 receptors markedly alters many effects of opioids. In the present study, we investigated whether the cannabinoid antagonist (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) could alter the reinforcing effects of heroin in rats. A ⌬ 9 -tetrahydrocannabinol (THC) drugdiscrimination procedure was first used to determine effective CB1 antagonist doses of SR-141716A and optimal pretreatment times for self-administration studies. Subsequently, Sprague-Dawley rats learned to self-administer heroin under three different schedules of intravenous drug injection: a continuous reinforcement schedule [fixed ratio (FR)1], a fiveresponse, fixed ratio schedule (FR5), and a progressive ratio schedule. Then, SR-141716A (1 mg/kg i.p.) was administered 60 min before the start of the session for three consecutive daily sessions. SR-141716A markedly decreased heroin selfadministration under the progressive ratio schedule at heroin doses ranging from 12.5 to 100 g/kg/injection. In contrast, SR-141716A had no effect on heroin self-administration under the FR1 schedule at heroin doses of 50 or 100 g/kg/injection, but produced small decreases in self-administration at lower doses (25 and 12.5 g/kg/injection). Consistent with a behavioral economics evaluation, SR-141716A produced a small but significant decrease in self-administration of the higher 50 g/ kg/injection dose of heroin when the fixed ratio requirement was raised to five (FR5). Thus, blockade of CB1 receptors differentially decreased the reinforcing efficacy of heroin depending on the number of responses required for each injection (price). These findings indicate a facilitatory modulation of opioid reward by endogenous cannabinoid activity and provide support for the use of cannabinoid CB1 antagonists as medications for heroin addiction.A wide range of functional interactions between opioid and cannabinoid systems have been found in the areas of nociception, physical dependence development, direct measures of reward, such as intravenous drug self-administration behavior, and indirect measures of reward, such as drug-induced alterations in thresholds for electrical brain self-stimulation and conditioned place preference (Manzanares et al., 1999;Maldonado, 2002). Interactions reported have largely involved opioid modulation of cannabinoid effects. For example, self-administration of cannabinoid CB1 receptor agonists is reduced by pretreatment with an opioid antagonist in mice and squirrel monkeys (Goldberg et al., 2001;Navarro et al., 2001). Also, development of a preference for a distinctive compartment associated with THC administration is lost in -receptor knockout mice (Ghozland et al., 2002), and reduction by THC of the threshold for electrical brain self-stimulation is prevented by naloxone administration (Gardner and Lowinson, 1991). Studies of cannabinoid effects on opioid reinforcement indicate that opioid-cannabinoid interactions can also be bidirectional. For example...

Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB 1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of ⌬ 9 -tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB 1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB 1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3Ј-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.Nicotine, the main psychoactive component of tobacco, plays a major role in tobacco dependence by acting directly as a reinforcer of drug-seeking and drug-taking behavior (Le Foll and Goldberg, 2006). In rats, nicotine can reinforce drug self-administration behavior (Corrigall and Coen, 1989) and induce conditioned place preference (CPP) (Le Foll and Goldberg, 2005), and it can trigger relapse to previously acquired drug-seeking behavior (Shaham et al., 1997). Nicotine's rewarding effects are believed to stem from its ability to activate the mesolimbic dopaminergic system by enhancing firing rate and burst firing of dopaminergic neurons in the ventral tegmental area (VTA) (Mereu et al., 1987) and increasing dopamine release in terminal areas, especially in the nucleus accumbens shell (Pontieri et al., 1996).Recent findings suggest that behavioral and motivational

In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine-and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition.

Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.

Rationale-Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g. URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic.Objectives-We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies.Results-We found that URB597 (0.1-0.3mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 July 1. Conclusions-Our findings show that FAAH inhibition does not affect anxiety under mildlystressful circumstances but protects against the anxiogenic effects of aversive stimuli.

Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.

Background-Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. FAAH inhibition increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty-acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly-acting PPAR-α agonists can modulate rewardrelated effects of nicotine.