The current study has revealed unique properties of the phytocannabinoid CBD and underscores the contrasting characteristics of the main constituents of cannabis in relation to addiction vulnerability. In comparison to the documented effects of THC to enhance heroin self-administration (Solinas et al., 2004
; Ellgren et al., 2007
), the present data demonstrated that CBD specifically inhibited reinstatement of cue-induced heroin seeking. The specificity of CBD to cue-induced reinstatement was also emphasized by the observation that the compound still inhibited drug relapse behavior in animals extinguished to the environmental context (self-administration chamber) previously associated with heroin. The results are striking given the very selective and protracted effects of CBD. Although CBD significantly altered drug-seeking behavior promoted by conditioned cue, it failed to influence drug seeking initiated by a heroin prime. Whether CBD induces some perceptual alterations that compromise cue- but not priming-induced reinstatement of drug seeking remains to be determined. The apparent diminished impact of CBD in the presence of heroin was also evident during the drug maintenance phase where CBD did not modify stable heroin intake behavior. Thus CBD does not appear to interfere with the reinforcing effects of heroin at least on a FR-1 schedule. Interestingly, the ability of CBD to reduce heroin-seeking behavior at least 2 weeks after exposure was nevertheless still observed when CBD had been administered during the active phase of heroin self-administration. These findings emphasize that CBD retains its effects to modulate neural mechanisms relevant to cue-induced drug relapse vulnerability even in the presence of heroin.
The observation that CBD’s effects on cue-induced drug seeking behavior was apparent 24 hr and two weeks, but not after 30 mins, following administration may suggest delayed pharmacological actions of the drug. However, it is important to note that behavioral effects have been observed immediately after administration of CBD at the dose range currently studied on, for example, its anxiolytic properties (Guimaraes et al., 1994
; Moreira et al., 2006
). Moreover, acute administration of CBD has been shown to enhance the extinction of cocaine- and amphetamine-induced conditioned place preference without affecting learning or retrieval (Parker et al., 2004
). There was also no evidence in our study that CBD affected extinction learning. CBD did not alter the extinction of heroin-seeking. The potential influence of CBD on psychostimulant-seeking behavior needs to be examined with an operant self-administration procedure to determine the specificity of CBD to different classes of drugs and different relapse models.
The protracted behavioral effects of CBD, in addition to its specific influence on heroin-seeking behavior, strongly implied a long-term impact on synaptic plasticity, the pathology of which is hypothesized to underlie compulsive disorders such as drug addiction. The endocannabinoid and glutamatergic systems have been tightly linked to synaptic plasticity (Kauer and Malenka, 2007
). In addition to its high potency at the CB1
R (Thomas et al., 2007
), CBD has also been reported to alter the hydrolysis of the endocannabinoid anandamide (Bisogno et al., 2001
). The reduction of CB1
R expression in the NAc when CBD was administered alone was short-term though its impact was enduring in heroin-seeking animals. Attenuation of the elevated expression CB1
R mRNA and protein levels in the NAc by CBD in heroin rats, which paralleled the behavioral alterations, is consistent with the observation that inhibition of the CB1
R inhibits cue-induced drug-seeking behavior (De Vries et al., 2003
Various lines of evidence have clearly documented the critical role of AMPA GluR1 in drug seeking behavior though most studies have focused on psychostimulant drugs (Anderson et al., 2008
; Conrad et al., 2008
). Of the few investigations that have evaluated opiates, the expression of AMPA receptors in prefrontal cortical synaptic membranes was reported to be reduced in heroin-abstinent animals after re-exposure to heroin cues (Van den Oever et al., 2008
) and glutamate arising from the prefrontal cortex was increased in the NAc core (LaLumiere and Kalivas, 2008
). The specific cellular localization of the GluR1 was not examined in the current study, which limits interpretations as to the dynamic cellular distribution of AMPA receptors relevant to drug-seeking behavior. Moreover, it is important to note that a similar alteration of glutamate levels was reported in the NAc core with both cue and heroin prime (LaLumiere and Kalivas, 2008
). Thus, other mechanisms than NAc core glutamatergic disturbances most likely underlie CBD’s apparent ability to alter cue- but not priming-induced reinstatement of drug seeking. Nevertheless, the observation that GluR1 disturbances in the NAc associated with heroin seeking were absent in those administered CBD is intriguing. Most studies have focused on the NAc core in relation to glutamatergic involvement in drug seeking behavior, but CBD’s effects on GluR1 were also apparent in the NAc shell, though to a weaker extent than the core. Further studies are required to determine the specific contribution of the NAc subregions as well as other brain regions implicated in cue-induced reinstatement to the actions of CBD. Although additional studies are needed to fully elucidate the molecular mechanisms of CBD in regard to its direct and indirect effects on heroin-seeking behavior, the mesolimbic specificity and protracted effects of CBD on CB1
R and GluR1 is interesting given the role of the limbic system in goal-directed behavior.
Of the over million opiate-dependent subjects today, only less than a quarter of such individuals receive treatment, which have traditionally targeted μ opioid receptors. Although such treatment strategies including methadone have improved substance abuse outcome, they do not effectively block opiate craving in all patients (Walter et al., 2008
) and thus are still associated with high rates of relapse and ultimately the continued cycle of opioid abuse. The fact that drug craving is generally triggered by exposure to conditioned cues makes the current results particularly fascinating. Moreover, the observation that CBD did not cause gross motor impairment as evident by a lack of effect on inactive lever presses or on locomotor behavior is consistent with the weak side effects that have been reported with this compound in humans (Consroe et al., 1991
; Tomida et al., 2006
). In addition, CBD lacks hedonic properties on its own (Parker et al., 2004
). Overall, the observations of this study suggest the potential for CBD as a treatment strategy given its specificity to attenuate cue-induced drug-seeking behavior, preferential impact on mesolimbic neuronal populations, and enduring neural actions. Clearly greater attention needs be given to the potential role of CBD in the treatment of addiction and other mental health disorders.