Cannabis can be rewarding or aversive. Cannabis reward is believed to be mediated by activation of cannabinoid CB1 receptors (CB1Rs) on GABAergic neurons that disinhibit dopaminergic neurons in the ventral tegmental area (VTA). However, little is known about the mechanisms underlying cannabis aversion in rodents. In the present study, CB1Rs are found not only on VTA GABAergic neurons, but also on VTA glutamatergic neurons that express vesicular glutamate transporter 2 (VgluT2). We then used Cre-Loxp transgenic technology to selectively delete CB1Rs in VgluT2-expressing glutamatergic neurons (VgluT2-CB1 −/−) and Cre-dependent viral vector to express light-sensitive channelrhodopsin-2 into VTA glutamatergic neurons. We found that photoactivation of VTA glutamatergic neurons produced robust intracranial self-stimulation (ICSS) behavior, which was dose-dependently blocked by DA receptor antagonists, but enhanced by cocaine. In contrast, Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component of cannabis, produced dose-dependent conditioned place aversion and a reduction in the above optical ICSS in VgluT2-cre control mice, but not in VgluT2-CB1 −/− mice. These findings suggest that activation of CB1Rs in VgluT2-expressing glutamate neurons produces aversive effects that might explain why cannabinoid is not rewarding in rodents and might also account for individual differences in the hedonic effects of cannabis in humans.

Rationale Stress experiences have been shown to be a risk factor for alcohol abuse in humans; however, a reliable mouse model using episodic social stress has yet to be developed. Objectives The current studies investigated the effects of mild and moderate social defeat protocols on plasma corticosterone, voluntary alcohol drinking, and motivation to drink alcohol. Methods Outbred CFW mice were socially defeated for 10 days during which the intruder mouse underwent mild (15 bites: mean = 1.5 min), or moderate (30 bites: mean = 3.8 min) stress. Plasma corticosterone was measured on days 1 and 10 of the defeat. Ethanol drinking during continuous access to alcohol was measured 10 days following the defeat or 10 days prior to, during and 20 days after the defeat. Motivation to drink was determined using a PR operant conditioning schedule during intermittent access to ethanol. Results Plasma corticosterone was elevated in both stress groups on days 1 and 10. Ethanol consumption and preference following moderate social stress was higher than both the mild stress group and controls. Mice with previously acquired ethanol drinking showed decreased ethanol consumption during the moderate stress followed by an increase 20 days post-defeat. Moderately stressed mice also showed escalated ethanol intake (11g/kg/day) and ethanol self-administration during a schedule of intermittent access to alcohol. Conclusion Social defeat experiences of moderate intensity and duration led to increased ethanol drinking and preference in CFW mice. Ongoing work investigates the interaction between glucocorticoids and dopaminergic systems as neural mechanisms for stress-escalated alcohol consumption.

Background Most studies with corticotropin releasing factor (CRF) and ethanol consumption have focused on CRF type 1 (CRF1) receptors; less is known about other components of the CRF system, such as the CRF type 2 (CRF2) receptors and the CRF binding protein (CRFBP). In humans, several nucleotide polymorphisms in the CRFBP gene have been associated with ethanol abuse. Methods The role of the CRFBP within the ventral tegmental area (VTA) and the central nucleus of the amygdala (CeA) was investigated in C57BL/6J mice exposed to an ethanol binge drinking paradigm (drinking-in-the-dark, DID), or to a dependence-producing drinking protocol (two-bottle choice, intermittent access to alcohol, IAA) for 4 weeks. Potential interactions between VTA CRFBP and CRF2 receptors on ethanol binge drinking were also assessed. Mice were microinjected with the CRFBP antagonist CRF6–33 into the VTA or CeA, or with the CRF2 antagonist Astressin2-B (A2B) alone or in combination with CRF6–33 into the VTA, and had access to 20% (w/v) ethanol for 4 h (DID). Separate cohorts of mice received vehicle and doses of CRF6–33 into the VTA or CeA and had access to ethanol/water for 24 h (IAA). Blood ethanol concentrations (BECs) were measured, and signs of withdrawal by handling-induced convulsion were determined. Results Intra-VTA CRF6–33 and A2B reduced ethanol intake dose-dependently in mice during DID. Furthermore, a combination of a sub-effective dose of CRF6–33 and a lower dose of A2B promoted additive effects in attenuating ethanol binge drinking. Intra-VTA CRF6–33 did not affect ethanol consumption in mice given IAA, and intra-CeA CRF6–33 did not change alcohol consumption in both models of drinking. DID and IAA promoted pharmacologically relevant BECs, however, only mice given IAA exhibited convulsive events during withdrawal. Conclusions These findings suggest that VTA CRFBP is involved in the initial stages of escalated ethanol drinking by mechanisms that may involve CRF2 receptors.

These findings support a model in which ketamine induces aberrant cell cycle reentry, leading to apoptotic cell death in the developing rat brain.