Sex and dose-dependent effects of cannabidiol on cocaine consumption in mice

Cocaine use disorder (CUD) is a neuropsychiatric disorder marked by compulsive drug-seeking and loss of control over cocaine intake, with women experiencing a faster addictive development and greater adverse outcomes despite lower incidence compared to men. Currently, there are no effective pharmacological treatments for CUD. Cannabidiol (CBD), a multitarget compound acting mainly on mediators of the expanded endocannabinoid system, has emerged as a potential therapeutic agent for substance use disorders. Though its effects have been researched in preclinical studies with males, its role in females remains underexplored. Here, we investigated the effect of CBD on distinct phases of cocaine-seeking and taking behaviour using the intravenous self-administration (SA) paradigm in female mice. First, CBD's pharmacological profile was evaluated on anxiety-like and cognitive-task models. Consequently, animals received CBD at 10 or 20 mg/kg to assess its effects on the acquisition of cocaine-consummatory behaviours and compulsive drug-seeking following association to negative consequences like an electric foot-shock. Our findings reveal that CBD modulates cocaine-seeking behaviour in a dose-dependent manner: 10 mg/kg CBD attenuated the acquisition of SA by alteration of reward- and cognitive-related markers within the mesocorticolimbic pathway. Conversely, 20 mg/kg increased cocaine consumption post-punishment but reduced cocaine-seeking upon re-exposure to punishment-associated cues and induced an upregulation of Htr1a expression in the medial prefrontal cortex. Parallel studies in males found no effects after punishment. These results highlight the complex, dose-dependent effects of CBD on cocaine consumption patterns and underscore its potential as a modulator of specific neurobehavioral processes in CUD in female mice.