A history of bingeing on fat enhances cocaine seeking and taking.

ABSTRACTHypothalamic orexin (Orx) neurons that project to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. When injected in the posterior PVT (pPVT), OrxA reinstated extinguished cocaine-seeking behavior in rats that had long access (LgA) to cocaine for 6 h/day after an intermediate period of abstinence (I-Abst, 2-3 weeks). Considering the long-lasting nature of drug-seeking behavior and that the PVT sends projections to the hypothalamus, the present study examined whether (i) OrxA’s priming effect is preserved after a period of protracted abstinence (P-Abst, 4-5 weeks) in LgA rats and (ii) the neural activation pattern (i.e., Fos+ and Fos+/Orx+ cells) in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) following intra-pPVT OrxA administration that may explain OrxA-induced reinstatement in LgA animals. As reported previously, OrxA administration in the pPVT triggered cocaine-seeking behavior after I-Abst. With P-Abst, the priming effect of OrxA was absent. An intra-pPVT injection of OrxA produced a strong increase in neuronal activation (i.e., Fos expression) in the LH/DMH/PFA at I-Abst but not at P-Abst. The analysis of the activation (Fos+) of Orx neurons (Orx+) revealed an increase in Fos+/Orx+ expression in the LH/DMH/PFA at I-Abst only, thus paralleling the behavioral data. These data indicate that shortly after abstinence, PVT↔LH/DMH/PFA connections are strongly recruited in animals with a history of cocaine dependence. The lack of effect at P-Abst suggests that the function of Orx receptors and connectivity of the PVT↔LH/DMH/PFA circuit undergo significant neuroadaptations following P-Abst.SIGNIFICANCE STATEMENTA better understanding of the pathophysiological changes associated with cocaine addiction is needed to develop efficient pharmacotherapies. The paraventricular nucleus of the thalamus (PVT) and orexin (Orx) transmission within the PVT have been implicated in maladaptive (compulsive) behavior that is characteristic of drug addiction. The present study shows OrxA injections in the posterior PVT reinstates cocaine-seeking behavior in animals with a history of cocaine dependence, and this effect disappears after protracted abstinence, paralleled by the neuronal activation pattern in the hypothalamus. In subjects with a history of cocaine dependence, the function of Orx receptors and connectivity of the PVT↔ LH/DMH/PFA circuit undergo significant neuroadaptations.

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Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats

10.1101/2021.02.01.429216 ◽

2021 ◽

Author(s):

Maxime Fouyssac ◽

Yolanda Peña-Oliver ◽

Mickaёl Puaud ◽

Nicole Lim ◽

Chiara Giuliano ◽

...

Keyword(s):

Negative Urgency ◽

Great Tendency ◽

Cocaine Withdrawal ◽

Drug Seeking ◽

Dorsolateral Striatum ◽

Cocaine Seeking ◽

History Of ◽

Directed System ◽

Subsequent Relapse ◽

Dorsomedial Striatum

AbstractThe inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it.One Sentence SummaryInstrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.

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Neurobiological substrates of persistent working memory deficits and cocaine-seeking in the prelimbic cortex of rats with a history of extended access to cocaine self-administration

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2019.03.007 ◽

2019 ◽

Vol 161 ◽

pp. 92-105 ◽

Cited By ~ 9

Author(s):

Christina Gobin ◽

John Shallcross ◽

Marek Schwendt

Keyword(s):

Working Memory ◽

Memory Deficits ◽

Prelimbic Cortex ◽

Self Administration ◽

Cocaine Seeking ◽

Extended Access ◽

Neurobiological Substrates ◽

History Of

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Enhancement of the GluN2B subunit of glutamatergic NMDA receptors in rat brain areas after cocaine abstinence

Journal of Psychopharmacology ◽

10.1177/02698811211048283 ◽

2021 ◽

pp. 026988112110482

Author(s):

Irena Smaga ◽

Karolina Wydra ◽

Agata Suder ◽

Marek Sanak ◽

Lucia Caffino ◽

...

Keyword(s):

Nmda Receptors ◽

Dorsal Hippocampus ◽

Brain Structures ◽

Enriched Environment ◽

Self Administration ◽

Cocaine Use ◽

Cocaine Seeking ◽

Subunit Expression ◽

Seeking Behavior ◽

History Of

Background: Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas withdrawal in different environments may affect the intensification of relapse. Methods: The aim of this study was to examine the GluN2B subunit expression and its association with the postsynaptic density protein 95 (PSD95) in several brain structures in rats with a history of cocaine self-administration and housed either in an enriched environment or in an isolated condition. Furthermore, a selective antagonist of the GluN2B subunit—CP 101,606 (10 and 20 mg/kg) administered during exposure to cocaine or a drug-associated conditional stimulus (a cue) was used to evaluate seeking behavior in rats. Results: In rats previously self-administering cocaine, we observed an increase in the GluN2B expression in the total homogenate from the dorsal hippocampus under both enriched environment and isolation. Cocaine abstinence under isolation conditions increased the GluN2B and GluN2B/PSD95 complex levels in the PSD fraction of the prelimbic cortex in rats previously self-administering cocaine. Administration of CP 101,606 attenuated cue-induced cocaine-seeking behavior only in isolation-housed rats. Conclusion: In summary, in this study we showed region-specific changes in both the expression of GluN2B subunit and NMDA receptor trafficking during cocaine abstinence under different housing conditions. Furthermore, we showed that the pharmacological blockade of the GluN2B subunit may be useful in attenuating cocaine-seeking behavior.

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