Pregnenolone is considered the inactive precursor of all steroid hormones and its potential functional effects have been largely neglected. The administration of the main active principle of Cannabis sativa (marijuana) Δ9-tetrahydrocannabinol (THC) substantially increases the synthesis of pregnenolone in the brain via the activation of type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals an unknown paracrine/autocrine loop protecting the brain from CB1 receptor over-activation that could open an unforeseen novel approach for the treatment of cannabis intoxication and addiction.

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin2C receptor (5-HT2CR) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT2CR located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT2CRs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT2CR agonist Ro 60-0175 at 5 µg/0.2 µl, but not 1 µg/0.2 µl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT2CR antagonist SB 242084 (0.5 µg/0.2 µl) or SB 243213 (0.5 and 1 µg/0.2 µl). These results show that mPFC 5-HT2CRs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT2CRs on accumbal DA output is dependent on the functional balance among different 5-HT2CR populations located within the mesocorticoaccumbens system, and that 5-HT2CRs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.