Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors

Abstract

The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad-yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p < 0.01), nucleus accumbens (p < 0.01), and medial globus pallidus (p < 0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus.

Cocaine-Induced Reinstatement of Cocaine Seeking Provokes Changes in the Endocannabinoid and N-Acylethanolamine Levels in Rat Brain Structures

“…Parallel immunohistochemical analyses revealed that cocaine priming enhanced the expression of the CB1 and CB2 receptors in the prefrontal cortex and lateral septal nuclei. The upregulation of the CB1 receptors observed in the prefrontal cortex and the lateral septal nuclei was present during cocaine self-administering rats and should be linked to the drug rewarding properties [7]. The lateral septum is the middle of the relay for connections from the CA3 hippocampus to the ventral tegmental area, which makes it possible to link the reward signals with the context in which they occur [4].…”

“…In recent years, the changes in the lipid signaling molecules such as endocannabinoids and N -acetylethyloamines (NAEs) in cocaine reward and the drug’s withdrawal have been demonstrated [2,3,4,5,6]. In fact, self-administration of cocaine induced both a potent decrease of the anandamide (AEA) levels in the cerebellum and in the 2-arachidonoylglycerol (2-AG) levels in the hippocampus and striatum with fewer cannabinoid CB1 receptors, while increased 2-AG levels were observed in the frontal cortex and cerebellum and were was linked with cocaine reward in rats [2,7]. A cocaine-free period with extinction training resulted in a potent reduction of the endocannabinoid levels in the limbic and subcortical areas with the cannabinoid CB2 receptor downregulation [7].…”

“…PEA and OEA levels could strengthen the effect of AEA on the cannabinoid receptor or TRPV1 (“entourage effect”) [9] and consequently potentiate the effect of endocannabinoids [10]. Contingent cocaine administration upregulated the NAEs (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) levels in the limbic areas [2], while the levels of these molecules were also seen to increase during extinction in the prefrontal cortex and the hippocampus only during the rats’ self-administered cocaine phase [2,7].…”

Progress in brain cannabinoid CB2 receptor research: From genes to behavior

“…Cocaine addiction: Growing evidence suggests that cannabinoids or medical marijuana may be useful for the treatment for drug addiction (Gonzalez-Cuevas et al, 2018). Prolonged or acute exposure to drugs of abuse, including cocaine and morphine, increases brain CB2R mRNA expression by up to five-fold in key reward-related regions such as the VTA, NAc, PFC, and striatum (Figure 4; Bystrowska et al, 2018;Onaivi et al, 2008a;, suggesting that CB2R ligands may have therapeutic potential for cocaine abuse (Zhang et al, 2017b). Accordingly, systemic and local administration of CB2R agonists (JWH133 or GW405833) into the VTA or NAc dose-dependently reduced intravenous cocaine self-administration in WT and CB1-KO mice, an effect that was blocked by the CB2R antagonist AM630 and absent in CB2-KO mice (Xi et al, 2011;Zhang et al, 2015;Zhang et al, 2014).…”

“…Although brain CB2R levels are low in healthy subjects under basal conditions, many studies suggest that brain CB2Rs are inducible or up-regulated in response to various insults (Atwood and Mackie, 2010;Mechoulam and Parker, 2013), including chronic pain (Beltramo et al, 2006;Luongo et al, 2010), ischemia-induced hypoxia (Ashton and Glass, 2007), drug addiction (Bystrowska et al, 2018;Onaivi et al, 2008b;Zhang et al, 2003), Alzheimer's disease, HIV-induced encephalitis and multiple sclerosis (Benito et al, 2008;Lopez et al, 2018;Schmole et al, 2015). Brain CB2R upregulation may be a common neuroprotective response to various central nervous system insults.…”