Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the "anti-relapse" potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

Differential role of hypothalamic orexin/hypocretin neurons in reward seeking motivated by cocaine versus palatable food.

Hypothalamic orexin/hypocretin (Orx/Hcrt) neurons are thought to mediate both food-reinforced behaviors and behavior motivated by drugs of abuse. However, the relative role of the Orx/Hcrt system in behavior motivated by food versus drugs of abuse remains unclear. This investigation addressed this question by contrasting hypothalamic Orx/Hcrt neuronal activation associated with reinstatement of reward seeking induced by stimuli conditioned to cocaine (COC) versus highly palatable food reward, sweetened condensed milk (SCM). Orx/Hcrt neuronal activation in the lateral hypothalamus, dorsomedial hypothalamus and perifornical area, determined by dual c-fos/orx immunocytochemistry, was quantified in rat brains, following reinstatement of reward seeking induced by a discriminative stimulus (S+ ) conditioned to COC or SCM. The COC S+ and SCM S+ initially produced the same magnitude of reward seeking. However, over four subsequent tests, behavior induced by the SCM S+ decreased to extinction levels, whereas reinstatement induced by the COC S+ perseverated at undiminished levels. Following both the first and fourth tests, the percentage of Orx/Hcrt cells expressing Fos was significantly increased in all hypothalamic subregions in rats tested with the COC S+ but not rats tested with the SCM S+ . These findings point toward a role for the Orx/Hcrt system in perseverating, compulsive-like COC seeking but not behavior motivated by palatable food. Moreover, analysis of the Orx/Hcrt recruitment patterns suggests that failure of Orx/Hcrt neurons in the lateral hypothalamus to respond to inhibitory inputs from Orx/Hcrt neurons in the dorsomedial hypothalamus/perifornical area may contribute to the perseverating nature of COC seeking.

The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine versus palatable food.

The paraventricular nucleus of the thalamus (PVT) is not traditionally considered part of the brain addiction neurocircuitry but has received growing attention with regard to a role in the modulation of drug-seeking behavior. This study sought to establish the pattern of neural activation induced by a response-reinstating discriminative stimulus (SD ) conditioned to either cocaine (COC) or a conventional reinforcer using a palatable food substance, sweetened condensed milk (SCM). Male Wistar rats were trained to associate one SD (S+ ; COC or SCM availability) and a distinctly different SD (S- ; non-reward; i.e. the availability of saline or the absence of SCM). Following extinction of COC- and SCM-reinforced responding, rats were presented with the respective S+ or S- alone and tested for the reinstatement of reward seeking. The COC S+ and SCM S+ elicited identical reinstatement, whereas the non-reward S- was behaviorally ineffective. PVT sections were obtained following completion of the reinstatement tests and labeled for Fos. The number of Fos+ neurons was compared among rats that were presented with the COC S+ , SCM S+ or S- . Rats that were presented with the COC S+ exhibited a significant increase in Fos expression compared with rats that were presented with the S- . Moreover, Fos expression was significantly correlated with the number of reinstatement responses that were induced by the COC S+ . In contrast, the SCM S+ and S- produced identical increases in Fos expression, without behaviorally relevant correlations. The findings implicate the PVT as an important site that is selectively recruited during COC-seeking behavior.

Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system.

Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Environmental conditioning factors are among the major determinants of relapse in abstinent cocaine users. Here we describe a role of the neuropeptide S (NPS) system in regulating relapse. In rats with a history of cocaine self-administration, presentation of stimuli predictive of drug availability reinstates drug seeking, triggering relapse. Intracerebroventricular (ICV) injection of NPS increased conditioned reinstatement of cocaine seeking, whereas peripheral administration of the NPS receptor antagonist SHA 68 reduced it. Manipulation of the NPS receptor system did not modify cocaine self-administration. We also found that ICV NPS administration activates c-Fos expression in hypocretin-1/orexin-A (Hcrt-1/Ox-A) immunoreactive neurons in the lateral hypothalamus (LH) and in the perifornical area (PeF). Of note, intra-LH and intra-PeF administration of NPS increased conditioned reinstatement of cocaine responding, an effect that was selectively blocked with the Hcrt-1/Ox-A receptor selective antagonist SB334867. Finally, results showed that intra-LH injection of the NPS antagonist [D-Cys(tBu) (5)]NPS blocked cue-induced cocaine seeking, indicating a role for this system in the pathophysiology of drug relapse.

Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse.

BACKGROUND: There has been a recent upsurge of interest in the role of hypothalamic feeding peptides, in particular, orexin (hypocretin), in drug-seeking behavior. However, the potential role of other hypothalamic feeding peptides, such as cocaine- and amphetamine-regulated transcript (CART), in conditioned reinstatement has yet to be explored. METHODS: Animals were exposed to environmental stimuli previously associated with ethanol availability (EtOH S+), and sections from the hypothalamus and paraventricular thalamus (PVT), a recipient of CART and orexin innervation, were dual labeled for Fos-protein and either CART or orexin. RESULTS: Significantly larger numbers of Fos-positive arcuate nucleus CART and hypothalamic orexin neurons were seen in animals exposed to the EtOH S+ compared with nonreward S- animals. Presentation of the EtOH S+ also increased numbers of Fos-positive PVT neurons. Fos-positive PVT neurons were observed to be closely associated with orexin and CART terminal fields. CONCLUSIONS: Taken together, these findings suggest that activation of hypothalamic neuropeptide systems may be a common mechanism underlying drug-seeking behavior.

Subchronic cannabinoid agonist (WIN 55,212-2) treatment during cocaine abstinence alters subsequent cocaine seeking behavior.

The co-abuse of marijuana with cocaine is widespread, but it has not been until recently that the relationship between the behavioral effects of cannabinoids and cocaine has begun to be unveiled in animal models. Male Wistar rats were trained to intravenously self-administer cocaine until a stable baseline was reached. Rats then were subjected to a 5-day cocaine deprivation period during which they were treated daily with the cannabinoid receptor agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.3, 1, and 3 mg/kg; i.p.). Following this subchronic treatment, rats were tested, in counterbalanced order, in a test of anxiety (elevated plus-maze), as well as extinction and cue-induced reinstatement tests, the latter conducted according to a between-within procedure. Subchronic administration of WIN 55,212-2 was found to produce dose-dependent alterations of performance in the extinction, reinstatement, and anxiety tests with the lowest dose of WIN 55,212-2 producing the highest resistance to extinction and reinstatement, and the highest dose of WIN 55,212-2 producing the highest anxiolytic activity. Subchronic treatment with WIN 55,212-2 in rats without a history of cocaine self-administration did not affect anxiety levels. The results suggest an important role of the cannabinoid system in neuronal processes underlying cocaine seeking behavior. However, further studies will be necessary to understand possible implications of these findings for a role of the cannabinoid system as a treatment target for human cocaine abuse.