Biology subjects

Westlake, J. G.

Publications and source records attributed to Westlake, J. G..

3 recordsLinked to original sources

bioRxiv2026

Negative affective states are not detected in rats following an intravenous self-administration regimen leading to incubation of oxycodone craving

In rats, cue-induced opioid craving intensifies (incubates) during abstinence from opioid self-administration and then remains high for a prolonged period. The prolonged plateau models persistent vulnerability to cue-induced craving and relapse in humans recovering from opioid use disorder. However, a very significant contributor to relapse vulnerability in these individuals is the presence of negative affective states that can persist for months to years, far beyond physical dependence. The goal of this study was to determine if the incubation of craving model recapitulates this aspect of relapse vulnerability. We began by comparing rats trained to self-administer oxycodone using a regimen leading to persistent elevation of cue-induced craving (6 h/d x 10 d) and rats trained to self-administer saline. We assessed somatic withdrawal signs in early abstinence and conducted behavioral tests modeling negative affect (open field, social preference, sucrose preference, and elevated plus maze) in late abstinence. Some somatic withdrawal signs were greater in oxycodone rats on abstinence day (AD)1, but cumulative scores did not differ between groups on AD1-3. On AD41-46, no group differences were found in behavioral tests modeling negative affect. To compare early and late abstinenceperiods, a second cohort of rats self-administered saline and oxycodoneand then received two cue-induced seeking tests (AD1 and AD40; oxycodone rats exhibited incubation of craving) and two series of negative affect tests (AD2-7 and AD41-48). While some time-dependent changes in affect were observed within each group, they were suggestive of reduced anxiety-like behavior in oxycodone rats. Finally, because rats are single-housed during our incubation studies, we compared drug-naive rats after 8-9 weeks of single vs pair housing and found no difference in behavioral tests modeling negative affect. We conclude that the persistence of elevated cue-induced craving observed after a standard opioid incubation regimen is not accompanied by negative affective states, probably due to lower drug intake during the intravenous regimen compared to non-contingent escalating dose regimens typically used to study withdrawal signs. This does not negate the utility of the incubation model for studying cue-induced opioid craving and its neurobiological basis.

neuroscience↗

bioRxiv2025

Dopamine and calcium dynamics in the nucleus accumbens core during food seeking

Extinction-reinstatement paradigms have been used to study reward seeking for both food and drug rewards. The nucleus accumbens is of particular interest in reinstatement due to its ability to energize motivated behavior. Indeed, previous work has demonstrated that suppression of neuronal activity or dopaminergic signaling in the nucleus accumbens reduces reinstatement to food seeking. In this study, we sought to further establish a connection between glutamatergic input, measured by proxy via a genetically encoded calcium indicator, and dopamine (DA) tone, measured simultaneously with a red-shifted DA biosensor. We performed this sensor multiplexing in the nucleus accumbens core in the classic extinction-reinstatement paradigm with food reward. We detected DA transients that changed in magnitude and/or temporally shifted over the course of self-administration training. In our calcium traces we observed a decrease from baseline time-locked to the lever press for food reward, which became more prominent with training. Both patterns were reduced in the first session of extinction with no deflections from baseline detected in either the DA or calcium traces in the last extinction session. When we recorded during reinstatement tests, bootstrapping analysis detected a calcium response when reinstatement was primed by cue or pellet+cue presentation, while a DA response was detected for pellet+cue reinstatement. These data further establish a role for nucleus accumbens core activity and DA in reinstatement of food seeking and represent the first attempt to simultaneously record the two during an extinction-reinstatement task.

neuroscience↗

bioRxiv2024

Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or incubates during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

neuroscience↗