Physical Activity Across the Clinical Trajectory of Chronic Kidney Disease and in Patients Undergoing Peritoneal Dialysis: A Cross-Sectional Study Using Accelerometry.

Relapse is a hallmark of substance use disorder (; ). Relapse-inducing triggers include cues previously associated with the drug, stressful events and/or environments, and taking the drug itself (i.e. drug priming). These triggers can result in resumption of drug-taking (relapse), despite negative consequences (; ; ; ). Several preclinical models of relapse have been developed, and the model most closely mimicking the human condition involves drug self-administration, an operant behavior in which the animal is required to press a lever to obtain the drug and can, therefore, regulate its drug intake. To specifically assess relapse-like behavior, animals undergo a period of ‘forced abstinence’ after several weeks of drug self-administration. During forced abstinence, the animals are returned to their home cage without access to the drug (). When animals are re-introduced to the self-administration behavioral chambers after forced abstinence, they engage in rapid lever pressing, even though no drug is delivered in response. This time-dependent increase in motivation to seek out the drug is referred to as ‘incubation of craving’ that leads to relapse (; ; ; ; ). Following extended periods of abstinence, incubated craving generally remains elevated before gradually stabilizing and declining (). The use of extinction training is also a common approach to study relapse after self-administration. In contrast to forced abstinence, extinction training prompts animals to learn that the drug is no longer available based on their actions (instrumental responding, e.g. lever presses or nose pokes), leading to a gradual reduction in drug-seeking behavior. Both models can trigger relapse when animals are reintroduced to drug-associated cues, but the neural pathways involved and the behavioral outcomes differ (; ; ). In these models, extinction training teaches animals that lever pressing no longer results in drug delivery. However, the drug-paired cues (contextual or discrete) are not extinguished. When presented during relapse, the cues elicit increased lever pressing based on the prior drug association formed during self-administration. Recent studies suggest that glutamatergic projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens shell (NAcSh) are necessary for the expression of opioid withdrawal signs (; ) and for cue-induced relapse after abstinence but not extinction (). The nucleus accumbens (NAc) is an important node involved in cue-driven reward-seeking behaviors (; ; ; ). Multiple factors, including synaptic plasticity, contribute to behavioral changes over time. For example, increased synaptic strength in projections from the PVT to D2R-expressing NAc MSNs contributes to naloxone-induced withdrawal behaviors following morphine administration (), which are evident in the first few days of abstinence and then dissipate. In addition, increased synaptic strength in projections from the PVT to D1R-expressing NAc MSNs is associated with relapse to heroin-seeking after 14 days of abstinence (). It has also been found that glutamatergic strength decreases from PVT to parvalbumin interneurons (PV-IN) after self-administration and during extinction and that rescuing this projection prevents heroin relapse (). Although it is clear that changes in glutamatergic inputs onto MSNs and other interneurons may contribute to opioid withdrawal and reinstatement of drug-seeking (; ; ; ), the relationships between NAcSh MSN circuitry functions, length of abstinence from oxycodone self-administration, level of drug-seeking, and sex specificity remain unclear. We aimed to determine whether synaptic strength in PVT-NAcSh projections is affected following oxycodone abstinence and whether such changes are associated with cue-induced relapse and drug-seeking. Additionally, we examined whether there are sex-specific differences in either cue-induced relapse or PVT-NAcSh synaptic transmission after either 1 (acute) or 14 (prolonged) days of forced abstinence. Our results demonstrate that sex-specific enhancement in cue-induced relapse emerges after prolonged abstinence but not during acute abstinence from oxycodone self-administration. Although both males and females show increased cue-induced relapse after prolonged abstinence, females exhibited a greater relapse rate compared to males. Both sexes showed similar increases in PVT-NAcSh synaptic strength after prolonged abstinence, while synaptic strength was not altered after acute abstinence compared to saline controls. Together, these findings reveal a time-dependent increase in PVT-NAcSh synaptic strength and a sex-specific effect of prolonged abstinence on cue-induced relapse, while synaptic enhancements after prolonged abstinence were not sex-specific.