Biology subjects

Lester, D. B.

Publications and source records attributed to Lester, D. B..

4 recordsLinked to original sources

bioRxiv2025

The Relationship between Social Reward Behavior and Mesolimbic Dopamine Release

Deficits in social behavior, such as reduced motivation and social avoidance, are key symptoms in several psychiatric disorders. Distinct modes of reward, such as drug and social, may rely on different dopamine release patterns in the mesolimbic pathway. We investigated the relationship between social reward behaviors and dopamine release elicited by phasic and tonic stimulation patterns in C57BL/6J mice. Social conditioned place preference was used to assess motivation for social interaction, and in vivo fixed potential amperometry was used to measure nucleus accumbens dopamine release before and after cocaine (10 mg/kg, ip). Additional measures included the frequency and duration of social interactions during conditioning sessions, with the first and last session representing novel and familiar social interactions respectively. No relationship was found between baseline (pre-cocaine) dopamine and social place preference in either sex. However, in males, social place preference negatively correlated with cocaine-induced phasic dopamine release, indicating that increased social motivation was associated with a reduced phasic dopaminergic response to cocaine. In contrast, greater novel interaction was associated with increased baseline dopamine elicited by tonic stimulations. These relationships were not observed in females. Overall, these findings suggest distinct, sex-dependent roles for phasic and tonic dopamine release in mediating social reward.

neuroscience↗

bioRxiv2020

Chronic Effects of Indirect and Direct Cannabinoid Receptor Agonists on Addiction-Related Behaviors and Dopamine Release

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase (FAAH) inhibition while also inhibiting transient receptor potential vanilloid type 1 (TRPV1) channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor type 1 (CB1R) agonist arachidonoyl-2-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with 7 daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA did not alter locomotor activity but did decrease phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference (CPP) then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a CPP or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct CB1R agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism.

neuroscience↗

bioRxiv2019

Cerebellar Modulation of Mesolimbic Dopamine Transmission is Functionally Asymmetrical

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.

neuroscience↗

bioRxiv2019

Risky Decision-Making Predicts Dopamine Release Dynamics in Nucleus Accumbens Shell

The risky decision-making task (RDT) measures risk-taking in a rat model by assessing preference between a small, safe reward and a large reward with increasing risk of punishment (mild foot shock). It is well-established that dopaminergic drugs modulate risk-taking; however, little is known about how differences in baseline phasic dopamine signaling drive individual differences in risk preference. Here, we used in vivo fixed potential amperometry in male Long-Evans rats to test if phasic nucleus accumbens shell (NACs) dopamine dynamics are associated with risk-taking. We observed a positive correlation between medial forebrain bundle-evoked dopamine release in the NACs and risky decision-making, suggesting that risk-taking is associated with elevated dopamine sensitivity. Moreover, \"risk-taking\" subjects were found to demonstrate greater phasic dopamine release than \"risk-averse\" subjects. Risky decision-making also predicted enhanced sensitivity to nomifensine, a dopamine reuptake inhibitor, quantified as elevated latency for dopamine to clear from the synapse. Importantly, this hyperdopaminergic phenotype was selective for risky decision-making, as delay discounting performance was not predictive of phasic dopamine release or dopamine supply. These data identify phasic NACs dopamine release as a possible therapeutic target for alleviating the excessive risk-taking observed across multiple forms of psychopathology.\n\nSignificance StatementExcessive risky decision-making is a hallmark of addiction, promoting ongoing drug seeking despite the risk of social, financial, and physical consequences. However, punishment-driven risk-taking is understudied in preclinical models. Here, we examined the relationship between individual differences in risk-taking and dopamine release properties in the rat nucleus accumbens shell, a brain region associated with motivation and decision-making. We observed that high risk taking predicted elevated phasic dopamine release and sensitivity to the dopamine transporter blocker nomifensine. This hypersensitive dopamine system was not observed in rats with high impulsive choice, another behavior associated with substance use disorder. This provides critical information about neurobiological factors underlying a form of decision-making that promotes vulnerability to substance abuse.

neuroscience↗