Dynamic Overrepresentation of Accumbal Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure.

The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined. Here, we characterize PCE rats during food (palatable pellets) or opioid (remifentanyl)-maintained reward seeking. We find that the supra motivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that in utero THC exposure leads to increased cue-evoked dopamine release responses and an overrepresentation of cue-aligned, effort-driven striatal patterns of encoding. Recapitulating findings in humans, drug-related neurobiological adaptations of PCE were more pronounced in males, who similarly showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders later in life.

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.

A multivariate regressor of patterned dopamine release predicts relapse to cocaine.

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopamine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics-in interaction with sex-for recapitulating persistent cocaine seeking and future relapse vulnerability.