Changes in endocannabinoid and N-acylethanolamine levels in rat brain structures following cocaine self-administration and extinction training.

Preclinical investigations have demonstrated that drugs of abuse alter the levels of lipid-based signalling molecules, including endocannabinoids (eCBs) and N-acylethanolamines (NAEs), in the rodent brain. In addition, several drugs targeting eCBs and/or NAEs are implicated in reward and/or seeking behaviours related to the stimulation of dopamine systems in the brain. In our study, the brain levels of eCBs (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and NAEs (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) were analyzed via an LC-MS/MS method in selected brain structures of rats during cocaine self-administration and after extinction training according to the "yoked" control procedure. Repeated (14days) cocaine (0.5mg/kg/infusion) self-administration and yoked drug delivery resulted in a significant decrease (ca. 52%) in AEA levels in the cerebellum, whereas levels of 2-AG increased in the frontal cortex, the hippocampus and the cerebellum and decreased in the hippocampus and the dorsal striatum. In addition, we detected increases (>150%) in the levels of OEA and PEA in the limbic areas in both cocaine treated groups, as well as an increase in the tissue levels of OEA in the dorsal striatum in only the yoked cocaine group and increases in the tissue levels of PEA in the dorsal striatum (both cocaine groups) and the nucleus accumbens (yoked cocaine group only). Compared to the yoked saline control group, extinction training (10days) resulted in a potent reduction in AEA levels in the frontal cortex, the hippocampus and the nucleus accumbens and in 2-AG levels in the hippocampus, the dorsal striatum and the cerebellum. The decreases in the limbic and subcortical areas were more apparent for rats that self-administered cocaine. Following extinction, there was a region-specific change in the levels of NAEs in rats previously injected with cocaine; a potent increase (ca. 100%) in the levels of OEA and PEA was detected in the prefrontal cortex and the hippocampus, whilst a drop was noted in the striatal areas versus yoked saline yoked animals. Our findings support the previous pharmacological evidence that the eCB system and NAEs are involved in reinforcement and extinction of positively reinforced behaviours and that these lipid-derived molecules may represent promising targets for the development of new treatments for drug addiction.