Search

Drugs of abuse including cannabis and inhalants impair risk/reward decision making. Cannabis use is often concurrent with inhalant intoxication; yet, preclinical studies investigating the role of endocannabinoids in inhalant misuse are limited. To address this gap in the literature, we used the well-validated probabilistic discounting task to assess risk/reward decision making in rodents following combinations of toluene vapor (a common inhalant) and manipulations of cannabinoid receptor type 1 (CB1R) signaling. As reported previously, acute exposure to toluene vapor disrupted behavioral flexibility during probabilistic discounting. Systemic administration of the CB1R inverse agonist AM281 did not prevent toluene-induced alterations in risky choices, but did independently reduce win-stay behavior, increase choice latency, and increase omissions. Toluene-induced deficits in probabilistic discounting are thought to involve impaired medial prefrontal cortex (mPFC) activity. As we previously reported that some of toluene's inhibitory effects on glutamatergic signaling in the mPFC are endocannabinoid-dependent, we tested the hypothesis that mPFC CB1R activity mediates toluene-induced deficits in discounting. However, bilateral injection of the CB1R inverse agonist AM251 prior to toluene vapor exposure had no effect on toluene-induced changes in risk behavior. In a final set of experiments, we injected the CB1R inverse agonist AM251 (5 and 50 ng), the CB1R agonist WIN55,212–2 (50 ng and 500 ng), or vehicle into the mPFC prior to testing. While mPFC CB1R stimulation did not affect any of the measures tested, the CB1R inverse agonist caused a dose-dependent reduction in win-stay behavior without altering any other measures. Together, these studies indicate that toluene-induced deficits in probabilistic discounting are largely distinct from CB1R-dependent effects that include decreased effectiveness of positive reinforcement (mPFC CB1Rs), decision making speed, and task engagement (non-mPFC CB1Rs). [ABSTRACT FROM AUTHOR]

Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1–10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30–70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1–3 mg/kg) also significantly and dose-dependently inhibited (by 25–90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.Neuropsychopharmacology (2008) 33, 1735–1745; doi:10.1038/sj.npp.1301552; published online 29 August 2007 [ABSTRACT FROM AUTHOR]

Discusses a research on CB1 cannabinoid receptor agonists that increase intracranial self-stimulation thresholds in a rat. Commonalities of addictive drugs in animal behavioral models; Types of abused substances that produce euphoric states in humans; Effects of systemically administered HU-210 on brain stimulation rewars in drug-naive rats.