Prenatal THC exposure and binge-like alcohol drinking in early adolescence: From sex-specific drinking vulnerability to abnormal endocannabinoid-dopamine nexus in the nucleus accumbens.

Background: Endocannabinoid (eCB) signalling is pivotal for brain programming, including the reward system neurodevelopment. Prenatal exposure to Δ9-tetrahydrocannabinol (THC), cannabis psychoactive component, can perturb eCB tone via CB1 receptor and alter the response to salient stimuli.

Aim: We hypothesise that prenatal THC exposure disrupts the eCB-dopamine nexus in the nucleus accumbens (NAc), predisposing the offspring to excessive alcohol drinking.

Methods: Using a 3-week intermittent access (IA) two-bottle choice paradigm, we tested binge-like alcohol drinking in prenatally exposed to THC (pTHC) rats of both sexes from early adolescence. NAc gene expression of cannabinoid receptor type 1 (CB1R), eCB enzymatic machinery (DAGLα, N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), monoacylglycerol lipase (MAGL), fatty-acid amide hydrolase (FAAH)), and D2 receptor was quantified before and after alcohol drinking.

Results: pTHC females consumed higher alcohol levels than controls from the first session onward. In contrast, pTHC males initially drank less than controls but progressively escalated alcohol consumption, although they did not reach females' drinking levels. Prior to drinking, pTHC females showed increased D2 and DAGLα mRNA expression when compared to controls and to pTHC males. pTHC males displayed CB1R upregulation and reduced DAGLα expression compared to controls and to pTHC females. Following alcohol drinking, both sexes displayed CB1R downregulation and increased NAPE-PLD expression; pTHC males exhibited DAGLα mRNA upregulation; pTHC females showed higher NAPE-PLD expression than pTHC males.

Conclusions: Prenatal THC exposure selectively predisposed the female offspring to alcohol vulnerability. The accumbal insight suggests a D2-driven reduced avoidance pathway in the females and a CB1R-driven avoidance behaviour in the males. Over the IA-paradigm, the potentiation in eCB synthesis plays a critical role in excessive alcohol drinking in pTHC offspring of both sexes.