Context-Specific Reversal of Cocaine Sensitization by the CB1 Cannabinoid Receptor Antagonist Rimonabant

Abstract

The CB 1 cannabinoid receptor is implicated in the rewarding properties of many drugs of abuse, including cocaine. While CB 1 receptor involvement in the acute rewarding properties of cocaine is controversial, CB 1 antagonists such as SR141716 (rimonabant) have clearly been found to prevent cue-and cocaine-elicited reinstatement of cocaine self-administration in rodents. Here we demonstrate the novel involvement of CB 1 receptors in the maintenance of behavioral sensitization to cocaine in C57BL/6 mice. Consistent with previous reports, the induction of locomotor sensitization following repeated daily cocaine was not prevented by systemic pretreatment of either rimonabant, D 9 -tetrahydrocannabinol (THC), or a 1:1 mixture of THC and cannabidiol (CBD). In contrast, established cocaine sensitization was markedly disrupted following subchronic treatment with rimonabant alone. This effect was notably context-dependent, in that rimonabant did not diminish established cocaine sensitization if delivered in the home cage, but only if the rimonabant-injected mice were exposed to activity chambers previously paired with cocaine. These findings are consistent with CB 1 receptor involvement in conditioned cocaine-seeking behaviors, and further suggest that endocannabinoid (eCB)-mediated synaptic plasticity may act specifically within drug-paired environments to maintain cocaine-directed behavioral responses.

Sensitization to cocaine is inhibited after intra-accumbal GR103691 or rimonabant, but it is enhanced after co-infusion indicating functional interaction between accumbens D3 and CB1 receptors

“…This finding indicates that the induction or development of motor sensitization is normal if the CB 1 R ligand rimonabant is infused into the NAc, but the expression of cocaine's sensitization is impaired if NAc CB 1 -mediated neurotransmission is modified by rimonabant during this time period. The data are in agreement with previous results using systemic rimonabant because its injection does not affect the development of cocaine's sensitization (Lesscher et al 2005), but expression of behavioral sensitization is impaired (Filip et al 2006;Gerdeman et al 2008). Rimonabant effects could be accounted for by antagonism or inverse agonism of CB 1 R. In this context, Thiemann et al (2008a, b) have observed that AM251, an antagonist of CB 1 receptors, attenuates amphetamine-induced behavioral sensitization.…”

“…The NAc expresses CB 1 R, as reported by Pickel et al (2004) and was confirmed in our lab (Martín et al 2008). As regards to sensitization to cocaine, cannabinoid CB 1 R in the NAc appear to be involved in the persistence of cocaine addiction (Wiskerke et al 2008), affecting the expression, not induction, of sensitization (Lesscher et al 2005;Filip et al 2006;Gerdeman et al 2008). …”

“…CB 1 R and DRD 3 are known to be expressed in the shell of the NAc (Le Moine and Bloch 1996;Martín et al 2008). However, a role for the core region after infusions cannot be discarded, because infusions could easily reach this adjacent region that is also known to be involved in addictive processes (Nestler 2001;Gerdeman et al 2008;McClung and Nestler 2008), and the core also expresses CB 1 R and DRD 3 (Le Moine and Bloch 1996;Martín et al 2008). Repeated cocaine treatment is known to up-regulate expression of D 3 receptors in the NAc (Le Foll et al 2002, 2005, and this up-regulation of D 3 receptors could account for the development of association of drug effects with the particular context where drug is administered (Le Foll et al 2002).…”

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

“…Full pharmacological antagonism of CB1 decreases the influence of conditioned factors on cocaine seeking and on extracellular Glu and DA in the NAc (Caillé and Parsons, 2006;Cheer et al, 2007;Oleson and Cheer, 2012;De Vries et al, 2001;Xi et al, 2006), as well as expression of cocaine-induced behavioral sensitization in a context-specific manner (Gerdeman et al, 2008). Differently, full pharmacological blockade or complete genetic deletion of CB1 does not affect, or only marginally affect (Chaperon et al, 1998;Soria et al, 2005), the primary reinforcing (Cossu et al, 2001;De Vries et al, 2001;Caillé and Parsons, 2006) and rewarding properties of cocaine (Houchi et al, 2005;Martin et al, 2000), as well as the underlying DA and GABA mechanisms (Caillé and Parsons, 2006;Soria et al, 2005;De Vries and Schoffelmeer, 2005).…”

Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice

“…However, there are other studies that show the contrary (Li et al 2009 ;Soria et al 2005 ;Xi et al 2008). CB 1 receptors appear to be involved in the association of cocaine reward with environmental cues, reinstatement of cocaine self-administration and acquisition of behavioural sensitization (Adamczyk et al 2012 ;de Vries et al 2001 ;Gerdeman et al 2008). Additionally, a new role for cannabinoid CB 2 receptors in cocaine addiction is emerging (Xi et al 2011).…”