anandamide and Cocaine-Related-Disorders

The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory.. A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS).. The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p < .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele.. These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).

Topics: Adult; Amidohydrolases; Arachidonic Acids; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Endocannabinoids; Female; Humans; Male; Patient Reported Outcome Measures; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1

The endogenous cannabinoid system plays an important role in motivation, stress, and drug abuse. Pharmacologically, the endocannabinoid system can be stimulated by either agonists of CB1 receptors or inhibition of metabolic degradation of endogenous cannabinoids and consequent increases in their brain levels.. Here, we investigated whether chronic administration during a period of withdrawal of the fatty acid amide hydrolase inhibitor URB597, which increases anandamide levels, would decrease the risks of relapse to cocaine seeking. Rats were allowed to self-administer cocaine and then they underwent forced withdrawal for 28 days, during which they were treated with URB597 or vehicle. One day after the last injection, we investigated cocaine seeking in one 6h extinction session and relapse triggered by re-exposure to drug-associated cues or a pharmacological stressor.. We found that administration of URB597 significantly decreases cocaine-seeking behavior and cue- and stress-induced relapse.. These results suggest that stimulation of the endocannabinoid system could be helpful to prevent relapse to cocaine addiction.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Cocaine; Cocaine-Related Disorders; Cues; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug-Seeking Behavior; Endocannabinoids; Enzyme Inhibitors; Male; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Recurrence; Self Administration; Stress, Physiological; Yohimbine