Biology subjects

Bocarsly, M. E.

Publications and source records attributed to Bocarsly, M. E..

4 recordsLinked to original sources

bioRxiv2026

Semaglutide Increases Striatal Leptin Sensitivity, Impacting Dopaminergic Response to Cocaine

There is accumulating evidence that the GLP-1 analog, semaglutide, might effectively curb intake of cocaine via brain dopaminergic functioning, despite limited brain penetrance. However, there is currently no established mechanism elucidating how chronic semaglutide treatment regulates the dopaminergic response to cocaine. Cocaine is a highly addictive substance that produces rewarding effects primarily through antagonism of the dopamine transporter (DAT). Therapeutics for cocaine use disorder (CUD) have long targeted DAT in the hope of reducing cocaine intake. Metabolic hormones such as leptin and insulin have been shown to influence DAT, and for that reason have been explored for the regulation of cocaine reward and behavior. Interestingly, while semaglutide does not penetrate the brain, it does peripherally modulate metabolic hormones that enter the brain. Through fast-scan cyclic voltammetry and behavioral experimentation, we examined the effects of chronic semaglutide treatment on dopamine signaling, cocaine-induced dopamine release, and locomotor sensitivity. We determined that chronic semaglutide inhibits dopaminergic reward induced by cocaine. Surprisingly, semaglutides effects on cocaine reward were blunted in mice fasted overnight, suggesting a mechanistic dependence on metabolic hormones. Semaglutide administration generated significant reductions in fasting blood leptin, as well as enhanced striatal leptin sensitivity compared to vehicle controls. Preceding cocaine exposure, application of leptin to fasted mice restored semaglutides regulation of cocaine. Our results exhibit a potential mechanism for semaglutide-induced cocaine reward inhibition, emphasizing the potential of central leptin signaling as a therapeutic target for CUD.

neuroscience↗

bioRxiv2026

D2 autoreceptors gate vulnerability to cocaine use disorder

A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability1. Reduced striatal dopamine D2/3 receptor availability is a robust PET correlate of problematic stimulant use2-5, but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type-specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2/3 binding, D1-like compensations diverged, resulting in different D1:D2/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.

neuroscience↗

bioRxiv2025

Susceptibility of Glucose Regulation to Social Isolation

Loneliness and social isolation strongly associate with increased incidence of diabetes in humans. However, it remains unclear if lack of meaningful social interactions represents a cause or a symptom of disease. In rodents, social isolation leads to metabolic dysregulation, however the dynamics and contributing factors remain poorly understood. Here we show that single-housing young adult male mice for at least three weeks led to fasting hyperglycemia, an effect that was maintained for the duration of single-housing, but was corrected within a week of reverting mice to co-housing conditions. Single-housing did not affect glucose regulation in females. Gonadectomy experiments revealed that testicular factors induced susceptibility to social isolation, as orchiectomy prevented isolation-induced fasting hyperglycemia in males. We did not find a protective role for ovarian hormones, as ovariectomized females were as resilient as intact females to isolation-induced fasting hyperglycemia. To understand the underlying mechanisms for susceptibility to isolation, we measured plasma levels of glucoregulatory hormones. Isolation did not affect the levels of insulin, epinephrine, and corticosterone. However, glucagon levels were distinctly modulated by social isolation in intact and orchiectomized mice. Social isolation induces increased immediate early gene expression in specific neurons of the ventromedial hypothalamus, a glucoregulatory brain structure that promotes glucagon release. Taken together, our findings show that testicular hormones make males susceptible to isolation-induced disruption of glucose regulation and suggest that brain glucoregulatory neurons play a role.

systems biology↗

bioRxiv2025

Brain insulin signaling restores deficits in striatal dopamine release in overweight male mice with preexisting low D2-receptor expression

Obesity is characterized by insulin resistance, motivational impairments, and, in some cases, reduced availability of dopamine D2 receptors in the brain. However, whether the low D2 receptor levels represent a predisposing factor or a consequence of obesity, and how these processes are mechanistically linked, remains unclear. Here, we directly tested this causal relationship by selectively reducing D2 receptor density in striatal neurons. Male, but not female, mice with a low density of striatal D2 receptors consumed more food, gained more weight, and developed metabolic features of peripheral insulin resistance despite being maintained on standard chow. Motivational deficits preceded weight gain, manifesting as delayed circadian locomotor onset, reduced physical activity, and diminished effort to obtain food. In the brain, male mice with low D2 receptor density showed reduced dopamine release capacity and age-dependent alterations in brain insulin sensitivity. Prior to weight gain, brain insulin responses were blunted compared to those of controls, in which insulin potentiates dopamine release and enhances striatal acetylcholine signaling. Once overweight, however, these mice exhibited brain insulin hypersensitivity, with insulin strongly restoring dopamine release capacity. Together, these findings demonstrate that low striatal D2 receptor density predisposes male mice to an obesity-like phenotype through early dopaminergic dysfunction that precedes weight gain and is later compensated by insulin hypersensitivity in the brain.

neuroscience↗