Endocannabinoids mediate long-lasting behavioural and physiological changes in male rats induced by the repeated activation of the mesolimbic system by copulation to satiety.

Sexually satiated male rats exhibit long-lasting physiological changes, suggestive of brain plasticity, the most conspicuous of which are a sexual behaviour inhibition and a generalised drug hypersensitivity. Copulation activates the mesolimbic circuit increasing dopamine (DA) release in the nucleus accumbens (NAcc) and, enhanced midbrain DA neuron activity promotes endocannabinoid (eCB) release in the ventral tegmental area (VTA). The objective of this work was to explore the possible participation of DA and/or eCB transmission in the induction of these two long-lasting phenomena. To this aim we analysed the effect of blocking DA or CB1 receptors during the process of copulation to exhaustion, on the expression 24 h later, of the sexual inhibitory state and the hypersensitivity to two different drugs: 8-OH-DPAT, a 5-HT receptor agonist, and yohimbine, an α-adrenoceptor antagonist. Blockade of DA receptors failed to prevent these phenomena, while blockade of CB1 receptors interfered with the appearance of the sexual inhibition and the hypersensitivity to both drugs in the sexually satiated animals. Specific blockade of CB1 receptors in the VTA during copulation to satiety mimicked these results, suggesting that both eCB-mediated effects were exerted in this brain region. It is concluded that eCBs play a role in the induction of behavioural and physiological changes, triggered by copulation to satiety, by acting at the VTA, while increased NAcc DA levels appear not to contribute to the changes induced by intense copulation. Results pose sexual satiety as a useful model for the study of brain plasticity phenomena induced by natural rewards.