Role of Glucagon-like peptide-1 Expressing Ventral Tegmental Area Neurons in Morphine Behavior

Abstract

<b>Abstract ID 17034</b> <b>Poster Board 74</b> Although opioid dependence and addiction continue to constitute a major health and economic burden, our limited understanding of the underlying neurobiology limits better diagnostics and interventions. Dysregulation of the mesocorticolimbic reward circuit is acknowledged to contribute to various aspects of drug addiction, with alteration in the activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) known to contribute to the rewarding aspects of drug use. However, the molecular mechanisms underlying these changes in VTA DA function remain relatively unexplored. Thus, we used translating ribosome affinity purification (TRAP) to identify gene expression changes in mice that specifically occur in VTA DA neurons following chronic morphine exposure. We found that expression of several neuropeptides not traditionally described in the VTA are robustly induced by morphine exposure. Glucagon-like peptide-1 (GCG) was of particular interest as it was enriched in VTA DA neurons and its expression was robustly increased following chronic morphine exposure. These data support increased GCG expression in the VTA following multiple types of opioid exposure and form a strong premise for studying GCG function. Thus, we hypothesize that activity of VTA GCG neurons contributes to morphine-elicited behaviors. To test this, we have begun to characterize the expression and functional impact of VTA DA neurons that co-express GCG using GCG-Cre mice and Cre-dependent viral vectors. Specifically, we are using DREADDs, designer receptors exclusively activated by designer drugs, to selectively activate or inhibit VTA-GCG neurons. We stereotaxically injected the excitatory DREADD hM3Dq (AAV-DIO-hM3Dq-mCherry) into the VTA of male and female wild-type and GCG-Cre mice and found that acute activation of VTA-GCG neurons via i.p. injection of clozapine-N-oxide (CNO, 0.3 mg/kg) does not affect general locomotor activity or elicit conditioned place preference or aversion (n = 5,9). We are now assessing whether activation of VTA-GCG neurons alters morphine-elicited behaviors (conditioned place preference, locomotor sensitization). Our preliminary data suggest there9s a decrease in morphine-induced locomotion and morphine CPP in animals whose VTA-GCG neurons were activated. Studies are currently underway to assess these behaviors in a second cohort of mice. Together, these studies are expected to set the stage for future work investigating the role of specific VTA-DAGCG circuits, their activity during behavior, and their potential as targets for therapeutic intervention.