Disruptions in the brain reward system through postnatal exposure to GABA agonists and anesthetics

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Early developmental exposure to GABAergic drugs leads to lasting changes in brain reward systems and reward- related behaviors, possibly due to the protracted development of the brain GABA system which extends several years into postnatal development, presenting a long developmental vulnerability window. Exposed individuals are more vulnerable to mood and addiction disorders as adults. Over 1.5 million infants and toddlers go through procedures that require general anesthetics (GAs) each year. GAs achieve most of their therapeutic end-points through their interactions with GABAA receptors (GABAARs) and cause persistent changes in the expression and trafficking of GABAARs similar to those caused by other GABAergic drugs. However, there is a significant gap in knowledge when it comes to the question of whether limited early developmental exposure to GABAA-acting GAs may also induce molecular and plastic changes in brain reward systems and reward-related behaviors that last into adulthood. The overall objective of this application is to address this gap using mice as a model system, focusing on evolutionarily-conserved brain circuits in well-controlled experiments. Our central hypothesis is that early exposure to GAs, as a robust and well-controlled model of GABAergic drug exposure, induces per- manent changes in GABAAR expression and/or trafficking in the nucleus accumbens (NAc), disrupting neuro- transmission in intra-NAc microcircuits and affecting reward-related behaviors. As such, our specific aims are to determine early GA exposure induced changes at the molecular level (GABAAR expression and trafficking), circuit level (intra-NAc neurotransmission and PFC–NAc feedforward inhibition) and behavioral level (respon- sivity to natural and drug rewards, stress-susceptibility). Considering the diffuse and extensive molecular effects of early GA exposure across brain circuits, our specific aims also include establishing causality between the dif- ferent levels of analyses, by attempting to alleviate disruptions in neurotransmission and behavior by normaliz- ing NAc GABAAR expression and activity. We believe the contribution of these findings to the field will be signif- icant, as they will extend our fundamental knowledge of long-lasting changes in the GABAAR system induced by GABAAR manipulations during specific developmental vulnerability periods. Translationally, the findings will indicate whether early GA-exposed children may be at risk for addiction and mood disorders as adults and will identify a causal molecular, pharmacologically targetable culprit. The findings will have wide-ranging impli- cations for short-term postnatal exposure to other GABAergic drugs, such as anxiolytics, sedatives and antiepi- leptics. Our studies are innovative, we believe, as they represent a significant departure from the status quo in their focus on this significant, yet neglected question, in their approach that pertains to multiple levels of analyses and establishes causality between them, and in the use of state-of-the-art techniques, such as single-cell protein analysis and temporally-precise optogenetic control of receptor activity, which makes it possible to address the questions at hand with a level of detail and precision that is not possible with more conventional approaches.