Cocaine-Seeking Behavior Induced by Orexin A Administration in the Posterior Paraventricular Nucleus of the Thalamus Is Not Long-Lasting: Neuroadaptation of the Orexin System During Cocaine Abstinence.

Alessandra Matzeu,Rémi Martin-Fardon

doi:10.3389/fnbeh.2021.620868

Abstract

Hypothalamic orexin (Orx) projections to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. Using an established model of cocaine dependence (i.e., long access [LgA] to cocaine), we previously showed that OrxA injections in the posterior PVT (pPVT) reinstated extinguished cocaine-seeking behavior in rats after an intermediate period of abstinence (2–3 weeks). Considering the long-lasting nature of drug-seeking behavior, the present study examined whether the priming effect of intra-pPVT OrxA administration was preserved after a period of protracted abstinence (4–5 weeks) in rats that self-administered cocaine under LgA conditions. Furthermore, to better understand whether a history of cocaine dependence affects the Orx system—particularly the hypothalamic Orx↔pPVT connection—the number of Orx-expressing cells in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) and number of orexin receptor 1 (OrxR1)- and OrxR2-expressing cells in the pPVT were quantified. Orexin A administration in the pPVT induced cocaine-seeking behavior after intermediate abstinence, as reported previously. At protracted abstinence, however, the priming effect of OrxA was absent. A higher number of cells that expressed Orx was observed in the LH/DMH/PFA at both intermediate and protracted abstinence. In the pPVT, the number of OrxR2-expressing cells was significantly higher only at intermediate abstinence, with no changes in the number of OrxR1-expressing cells. These data build on our previous findings that the hypothalamic Orx↔pPVT connection is strongly recruited shortly after cocaine abstinence and demonstrate that the priming effect of OrxA is not long lasting. Furthermore, these findings suggest that throughout abstinence, the Orx↔pPVT connection undergoes neuroadaptive changes, reflected by alterations of the number of OrxR2-expressing cells in the pPVT.

Highlights

The paraventricular nucleus of the thalamus (PVT) plays a major role in regulating arousal, attention, awareness states, food consumption, and energy balance (Bentivoglio et al, 1991; Groenewegen and Berendse, 1994; Van der Werf et al, 2002; Colavito et al, 2015; Kirouac, 2015)
The number of posterior PVT (pPVT) OrxR2+ cells was significantly higher at intermediate abstinence compared with naive and protracted abstinence, but no differences were detected at protracted abstinence compared with naive (p < 0.001; Tukey post hoc test following two-way analysis of variance (ANOVA); abstinence [intermediate abstinence, protracted abstinence], F1,16 = 12.76, p < 0.05; group [naive, cocaine], F1,16 = 44.40, p < 0.001; abstinence × group interaction, F1,16 = 15.72, p < 0.01; Figures 4D–F)
To further understand whether a history of cocaine dependence affects the Orx system and explain the reinstating effect of OrxA when injected in the pPVT at intermediate abstinence vs. protracted abstinence, we analyzed the number of Orx+ cells in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) and the number of orexin receptor 1 (OrxR1)+ and OrxR2+ cells in the pPVT

Summary

Introduction

The paraventricular nucleus of the thalamus (PVT) plays a major role in regulating arousal, attention, awareness states, food consumption, and energy balance (Bentivoglio et al, 1991; Groenewegen and Berendse, 1994; Van der Werf et al, 2002; Colavito et al, 2015; Kirouac, 2015). Orx-containing neurons represent a relatively small proportion of cells, their projections are widely distributed throughout the brain (Peyron et al, 1998), explaining how they can play diverse roles in physiological functions, including energy homeostasis, arousal, sleep/wake cycles (Sutcliffe and de Lecea, 2000; Mieda and Yanagisawa, 2002; de Lecea, 2012), and reward function (e.g., drug-seeking behavior; Harris et al, 2005; Dayas et al, 2008; Martin-Fardon et al, 2010, 2016; Jupp et al, 2011; Sakurai and Mieda, 2011). Orexin neurons project to structures that control behavior that is motivated by drugs of abuse, such as septal nuclei, the central nucleus of the amygdala, the ventral tegmental area, the medial prefrontal cortex, the nucleus accumbens shell, and the PVT, especially its posterior part (pPVT; Peyron et al, 1998; Baldo et al, 2003; Kirouac et al, 2005; Hsu and Price, 2009). Remaining unknown are whether the priming effect of OrxA is long lasting and whether a history of cocaine dependence affects the Orx system, the hypothalamic Orx↔pPVT connection

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