Abstract
Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOHD and SCMD) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOHND and SCMND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOHD/ND and SCMD/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOHD and SCMD). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOHD and SCMD groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.
Highlights
Drugs neuroadaptively influence neural systems that regulate motivation that is normally directed toward natural rewards
Based on our data on cocaine- and SCMseeking behavior (Matzeu et al, 2016, 2018), the present study investigated whether the pharmacological manipulation of Orx transmission in the pPVT (i.e., OrxR1 and OrxR2 blockade with the dual Orx receptor antagonist TCS1102) prevents the stressinduced reinstatement of reward-seeking behavior toward EtOH and a highly palatable food reward (i.e., sweetened condensed milk (SCM)) in rats with a history of EtOH dependence
EtOHD animals exhibited significantly higher somatic withdrawal signs compared with withdrawal signs that were measured at the end of EtOH self-administration training and compared with the EtOHD groups during training and the air (EtOHND) group [p < 0.001, Tukey post hoc test following two-way analysis of variance (ANOVA): dependence (EtOHND vs. EtOHD), F(1,336) = 130.20, p < 0.001; time, F(3,228) = 44.46, p < 0.001; dependence × time interaction, F(3,228) = 39.52, p < 0.001; Figure 3B]
Summary
Drugs neuroadaptively influence neural systems that regulate motivation that is normally directed toward natural rewards. The neuroplasticity of this circuitry may be responsible for maladaptive compulsive behavior that characterizes addiction (e.g., Kelley and Berridge, 2002; Aston-Jones and Harris, 2004; Kalivas and O’Brien, 2008; Wanat et al, 2009). The reinstatement of EtOH seeking following intermittent footshock has been extensively used to mimic relapse-like behavior in rodents (e.g., Lê et al, 1998, 1999; Martin-Fardon et al, 2000; Liu and Weiss, 2002), demonstrating that stress-induced relapse is a valid model for testing possible therapeutic targets for the prevention of craving and relapse
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