Exposure to drugs of abuse results in changes throughout reward-related neuronal circuits, contributing to the development of substance use disorders (SUD). Recently, it has been suggested that the olfactory tubercle (OT), the ?ventral most portion? of the ventral striatum, acts as a critical interface for processing multi-sensory inputs and integrating information from the reward/motivation/addiction systems to mediate subsequent behavioral responses. The OT receives dense dopamine (DA) innervation from the ventral tegmental area (VTA) and may have a distinct role in reward as it has been shown that the OT-DA system is more vulnerable to psychostimulants than other well known DA rich brain areas such as the nucleus accumbens. However, only a handful of studies have investigated whether the VTA-DA system could be involved in the modulation of OT neuronal function and psychostimulant-induced reward, primarily due to its complicated structure, small size, and anatomical location thus limiting the application of conventional behavioral assays and in vivo neurochemical analyses. Our long-term goal is to determine the functional role of the OT-DA system in reward/aversion learning, SUD-related behaviors, and experience-dependent neurochemical plasticity.
Aim 1 of this proposal will first determine the different contributions of the amOT and alOT in the acquisition of METH-induced conditioned place preference by selectively inhibiting VTA-DA projections to the OT subregions via activation of inhibitory designer receptors exclusively activated by designer drugs (DREADDs). Second, we will map the distribution of VTA-DA projections to the amOT and alOT through viral neural tracing.
Aim 2 of this proposal will determine how VTA-DA neurons and DA signaling are differentially regulated in subregions of the OT using a novel combination of in vivo fast-scan cyclic voltammetry (FSCV) coupled with optogenetic and local pharmacological manipulation of OT-DA neurons and receptors/transporters, respectively. These results will fill a gap in our knowledge of a poorly understood brain reward area that is part of reward circuits implicated in drugs of abuse, and may point to novel therapeutic targets for SUD.
Substance use disorder (SUD) is a serious health concern with no effective pharmacotherapies due, in part, to a limited understanding of the brain circuits underlying this disease. The poorly understood olfactory tubercle (OT)-dopamine (DA) circuit is implicated in SUD, therefore, the goal of this proposal is to determine i) the regulatory mechanisms of DA transmission in the subregions of the OT and ii) the role of the OT-DA system in SUD related rewarding effects and behavioral changes. Together these experiments will help define the role of the OT in mediating SUD related neurochemical and behavioral phenomena and will provide more effective therapeutic targets.
