Sex-biased, region-specific regulation of DA release and clearance

Project Summary / Abstract Virtually all neuropsychiatric disorders display sex bias, with the prevalence, age of onset, and clinical symptomology differing significantly between males and females. Historically, female subjects have been excluded from preclinical research, with male-only studies in neuroscience research outnumbering those of females by 5.5:1, a discrepancy attributed to concern over the impact of estrus cycling on population homogeneity or the assumption that sexual dimorphism is absent, such that results obtained with males extrapolate to females. However, accumulating evidence demonstrates that genetic/gonadal sex and sex hormones influence several critical brain functions including the release, reuptake, and signaling response to the neurotransmitter dopamine (DA). DA is heavily implicated in substance use disorders and, notably, when compared to men, women typically report experiencing greater subjective effects from psychostimulants, are nearly twice as likely to abuse these drugs, and display enhanced dopamine release in the nucleus accumbens (NAc), a critical component of the mesolimbic dopaminergic reward circuit, following psychostimulant exposure. Similarly, in rodents, there are robust sex differences in the behavioral impacts of the psychostimulant amphetamine with females exhibiting greater amphetamine place preference scores but blunted hyperlocomotion relative to males. Though existing evidence points to a critical role for gonadal hormones in determining differential psychostimulant responses in females, the neural substrate(s) linking steroid hormone signaling to synaptic DA availability remain unelucidated. We recently described a sex-biased and region-specific functional coupling between the dopamine transporter (DAT), a direct target of psychostimulants and primary mediator of synaptic DA clearance. More specifically, the ability of D2 autoreceptors (D2ARs) to promote phosphorylation and surface trafficking of DAT occurs in the dorsal striatum, the critical efferent target of nigrostriatal dopamine neurons heavily implicated in DA-driven locomotor behavior but is absent in the reward- linked NAc of male mice. In contrast, a functional coupling between D2AR and DAT is observed only in the ventral striatum (NAc) in females. The central hypothesis of this proposal is that gonadal hormone signaling differentially enhances D2AR-dependent DAT regulation in the nigrostriatal vs mesolimbic dopaminergic circuits translating into sex-selective impacts of AMPH on synaptic DA and behavior. First, we will establish if/when the actions of gonadal hormones in the brain define sex-biased patterns of D2AR effector coupling and the specific hormone/receptor signaling involved. Second, we will investigate how circuit-specific DAT regulation via D2AR shapes amphetamine-dependent DA outflow and behavior in a sex-biased manner. Ultimately, delineating the mechanisms contributing to the sex biased architecture of the dopaminergic circuitry is imperative and has the potential to identify novel therapeutic targets for the treatment of mental illnesses including psychostimulant dependence for which there are currently no available pharmacotherapies.