Efeitos do antagonista do receptor canabinoide do tipo 1, AM4113, nas respostas comportamentais e celulares induzidas pela cocaína

Abstract

Substance Use Disorder is a characterized by compulsive drug-seeking behavior, high vulnerability to relapse, and functional impairments. The endocannabinoid system modulates the reward circuitry and represents a promising therapeutic target. Previous studies have shown that inverse agonists of the cannabinoid type 1 receptor (CB1R), such as Rimonabant, reduce cocaine-seeking and relapse, although their clinical use was discontinued due to anxiety- and depression-relatd effects. In this context, the present study investigated whether AM4113, a selective CB1R antagonist, could attenuate cocaine-induced neurobehavioral alterations without producing adverse psychiatric effects. Male and female C57BL/6J mice received AM4113 (0.3, 1, 3, or 10 mg/kg, i.p.) prior to cocaine administration (15 mg/kg, i.p.) to evaluate: acute locomotor activity and glutamate release in synaptosomal preparations from the hippocampus (HPC) and striatum (STR); behavioral sensitization and conditioned hyperlocomotion, as well as the expression of genes related to the reward pathway in the striatum (STR); and Conditioned Place Preference (CPP) paradigm and dendritic spine density was assessed using Golgi-Cox staining in the prefrontal cortex (PFC), HPC, and STR. Anxiety- and depression- like behaviors were assessed using the Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Forced Swim Test (FST). All experimental procedures were approved by the Institutional Ethics Committee (Protocol No. 262/2023). AM4113 (10 mg/kg) reduced cocaine-induced hyperlocomotion and glutamate release induced by cocaine; attenuated behavioral sensitization (3 mg/kg) and normalized most of gene expression changes; and prevented CPP induction (10 mg/kg) and concaine-induced increase in dendritic spine density in the HPC. Importantly, AM4113 did not promoted anxiety- or depression-like behaviors in the EPM, TST, or FST compared to the control group. In conclusion, AM4113 effectively mitigated cocaine-induced neurobehavior effects without producing anxiety- or depressive-like behaviors. These finds highlight the role of CB1R in modulating maladaptive responses to cocaine, with an improved profile for antagonists compared to inverse agonists.