scholarly journals 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

2021 ◽  
Vol 15 ◽  
Author(s):  
Alessandra Matzeu ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Priming Effect ◽  
Cocaine Dependence ◽  
Orexin A ◽  
Drug Seeking ◽  
Intermediate Period ◽  
Protracted Abstinence ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Long Access

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.

scholarly journals Administration of orexin A in the posterior paraventricular nucleus of the thalamus promotes cocaine-seeking behavior and is associated with hypothalamic activation

2017 ◽  
Author(s):  
Alessandra Matzeu ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Priming Effect ◽  
Cocaine Dependence ◽  
Activation Pattern ◽  
Neuronal Activation ◽  
Drug Seeking ◽  
Protracted Abstinence ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
History Of

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.

scholarly journals Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

2004 ◽  
Vol 29 (6) ◽  
pp. 1190-1202 ◽  
Author(s):  
Diana Martinez ◽  
Allegra Broft ◽  
Richard W Foltin ◽  
Mark Slifstein ◽  
Dah-Ren Hwang ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Cocaine Dependence ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

2019 ◽  
Author(s):  
William C. Buchta ◽  
Aubin Moutal ◽  
Bethany Hines ◽  
Constanza Garcia-Keller ◽  
Alexander C.W. Smith ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Treatment Options ◽  
Health Concern ◽  
Self Administration ◽  
Drug Seeking ◽  
Binding Partner ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Medial Pfc

AbstractCocaine addiction is a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug-seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to Yoked saline controls. By contrast, cued-reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.

scholarly journals Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence

2017 ◽  
Author(s):  
Alessandra Matzeu ◽  
Marsida Kallupi ◽  
Olivier George ◽  
Paul Schweitzer ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Glutamate Release ◽  
Critical Role ◽  
Brain Slices ◽  
Self Administration ◽  
Excitatory Transmission ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Male Wistar Rats ◽  
Behavioral Evidence

ABSTRACTThe orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA±DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seeking vs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.

scholarly journals Erratum: Cocaine Dependence and D2 Receptor Availability in Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

2004 ◽  
Vol 29 (9) ◽  
pp. 1763-1763 ◽  
Author(s):  
Diana Martinez ◽  
Allegra Broft ◽  
Richard W Foltin ◽  
Mark Slifstein ◽  
Dah-Ren Hwang ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Cocaine Dependence ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking

2019 ◽  
Vol 22 (9) ◽  
pp. 574-584
Author(s):  
Yue-Qing Zhou ◽  
Lan-Yuan Zhang ◽  
Zhi-Peng Yu ◽  
Xiao-Qin Zhang ◽  
Jie Shi ◽  
...  
Keyword(s):  
Training Session ◽  
Progressive Ratio ◽  
Drug Intake ◽  
Ratio Schedule ◽  
Progressive Ratio Schedule ◽  
Dosing Regimen ◽  
Self Administration ◽  
Drug Seeking ◽  
Cocaine Seeking ◽  
Long Access

AbstractBackgroundThe hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT3 receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing.MethodsRats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task.ResultsThe rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration.ConclusionsThese results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT3/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking.

Orexin/hypocretin in the paraventricular nucleus of the thalamus mediates cocaine-seeking behavior in rats

2015 ◽  
Vol 146 ◽  
pp. e198
Author(s):  
Alessandra Matzeu ◽  
Tony M. Kerr ◽  
Friedbert Weiss ◽  
Remi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Hadas Ahdoot-Levi ◽  
Ofri Croitoru ◽  
Tzofnat Bareli ◽  
Einav Sudai ◽  
Hilla Peér-Nissan ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Brain Cell ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Drug Seeking ◽  
Tissue Organization ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Dhea Treatment

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

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