Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward prediction.

Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion from VTA dopamine neurons prevents depolarization-induced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cue-driven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.

Differential effects of intermittent and continuous exposure to novel environmental stimuli on the development of amphetamine-induced behavioral sensitization in mice: implications for addiction.

BACKGROUND: Previous studies have demonstrated a preventive effect of continuous environmental enrichment during early development on the vulnerability of rodents to drug addiction-related behaviors. Recently, it was demonstrated that a continuous environmental enrichment could eliminate already established addiction-related behaviors in mice. The present study compared the effects of intermittent or continuous exposure to novel stimuli during repeated amphetamine (Amp) treatment on the development of behavioral sensitization (an animal model of addiction-related neuroadaptations) in adult mice. METHODS: Three-month-old male Swiss mice were treated with 2.5mg/kg Amp every other day for 13 days in their home cages. Novel objects were presented in their home cages for 2h on non-drug treatment days (experiment 1) or for 24h/day during the 13 days of drug treatment (experiment 2). Seven days after the drug treatment had finished, the mice were challenged with 2.5mg/kg Amp, and their locomotor activity was quantified in a familiar open field for 10 min. RESULTS: Intermittent exposure to the novel objects did not modify the acute Amp locomotor stimulatory effect but potentiated the development of Amp-induced locomotor sensitization. This enhanced sensitization was due to increased locomotion in the central squares of the apparatus, which suggests anxiolysis or increased impulsiveness. Conversely, continuous exposure to the novel objects potentiated the acute Amp locomotor stimulatory effect and blunted the development of Amp-induced locomotor sensitization. CONCLUSIONS: We conclude that addiction-related behaviors can be differentially and critically modified depending on the schedule and period of the novelty exposure.

Acute and chronic ethanol differentially modify the emotional significance of a novel environment: implications for addiction.

Using open-field behaviour as an experimental paradigm, we demonstrated a complex interaction between the rewarding/stimulating effects and the anxiogenic/stressful effects of both novelty and acute or chronic amphetamine in mice. As a consequence of this interaction, acute amphetamine-induced hyperlocomotion was inhibited, whereas the expression of its sensitization was facilitated in a novel environment. In the present study, we aimed to investigate the interactions between exposure to a novel environment and the acute and chronic effects of ethanol (Eth), a drug of abuse known to produce anxiolytic-like behaviour in mice. Previously habituated and non-habituated male Swiss mice (3 months old) were tested in an open field after receiving an acute injection of Eth or following repeated treatment with Eth. Acute Eth administration increased locomotion with a greater magnitude in mice exposed to the apparatus for the first time, and this was thought to be related to the attenuation of the stressful effects of novelty produced by the anxiolytic-like effect of acute Eth, leading to a subsequent prevalence of its stimulant effects. However, locomotor sensitization produced by repeated Eth administration was expressed only in the previously explored environment. This result might be related to the well-known tolerance of Eth-induced anxiolytic-like behaviour following repeated treatment, which would restore the anxiogenic effect of novelty. Our data suggest that a complex and plastic interaction between the emotional and motivational properties of novelty and drugs of abuse can critically modify the behavioural expression of addiction-related mechanisms.