Cannabinoids promote NREM sleep via inhibition of prefrontal cortico-hypothalamic projections

Cannabinoids promote non-rapid eye movement (NREM) sleep, but its underlying mechanism is not known. Here we find that cannabinoid promotion of NREM sleep is inhibited by cannabinoid antagonist injection systemically or into the dorsomedial hypothalamus (DMH), where cannabinoids selectively inhibit glutamatergic inputs synapsing with glutamatergic but not GABAergic neurons. Photoactivation of DMH-projecting ventromedial prefrontal cortical (vmPFC) neurons, their terminals, or their postsynaptic DMH neurons rapidly switches NREM sleep to wakefulness, which is blocked by photoinhibition of DMH outputs. Chemoactivation of DMH glutamatergic but not GABAergic neurons innervated by vmPFCs promotes wakefulness and suppresses NREM sleep, whereas chemoinhibition of vmPFC projections in DMHs produces opposite effects by mimicking cannabinoid effects. DMH-projecting vmPFC neurons are inhibited during NREM sleep and activated during wakefulness. Chemoactivation of DMH-projecting vmPFC neurons blocks cannabinoid promotion of NREM sleep and suppression of wakefulness. Thus, vmPFC neurons innervating DMHs represent the first identified set of cerebral cortical neurons for promotion of physiological wakefulness and suppression of NREM sleep, while cannabinoid inhibition of vmPFC projections in DMHs promotes NREM sleep and suppresses wakefulness.

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

ABSTRACTCocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8–12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates ‘extinction burst’ responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism. Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait

Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.