Neural circuits implicated in drug conditioning, craving, and relapse overlap with those involved in natural reward. Recently, the orexin/hypocretin (Orx/Hcrt) system has been identified to regulate a range of physiological processes, including feeding, energy metabolism, and arousal, and has been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus (LH), and accumulating evidence indicates an important role for these neurons in drug addiction. These Orx/Hcrt neurons project to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a """"""""way- station"""""""" that receives projections from the LH, processes information, and then modulates the mesolimbic and extrahypothalamic stress systems. While not thought to be part of the """"""""cocaine-seeking circuitry,"""""""" evidence implicates the PVT in the modulation of reward function in general and drug-directed behavior in particular. Importantly, a correlation between cocaine-seeking behavior and activation of the PVT has been detected, but not in the case of natural reward-seeking behavior. This suggests that cocaine dysregulates the neurotransmission within the PVT. Capitalizing on our findings, we hypothesize that following repeated cocaine use, the Orx/Hcrt system acquires a preferential role in mediating drug of abuse seeking vs. natural reward seeking. This proposal is designed to study the neurobiological basis of chronic vulnerability to relapse by focusing on Orx/Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the distinctly compulsive nature of cocaine seeking as opposed to behavior motivated by natural rewards essential for survival, well being, and """"""""healthy"""""""" hedonic pursuits. Specifically, this proposal will (i) behaviorally characterize the specific implication of the PVT in cocaine seeking, (ii) investigate cocaine-induced neuroplastic changes within Orx/Hcrt transmission and (iii) investigate the effects of dysregulated Orx/Hcrt-PVT transmission on the mesolimbic system.

Public Health Relevance

Currently, the available therapeutic approaches fail to completely treat and address the compulsive nature of drug seeking and drug taking associated with addiction. Preliminary evidence indicates that dysfunctional orexin/hypocretin transmission contributes to cocaine seeking vs. natural reward seeking. This project is likely to highlight a previously unrecognized mechanism in the etiology of cocaine dependence and may identify novel therapeutic targets for drug addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Volman, Susan
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Scripps Research Institute
La Jolla
United States
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Matzeu, Alessandra; Terenius, Lars; Martin-Fardon, Remi (2018) Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence. Alcohol Clin Exp Res 42:2466-2478
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
Martin-Fardon, Rémi; Cauvi, Gabrielle; Kerr, Tony M et al. (2018) Differential role of hypothalamic orexin/hypocretin neurons in reward seeking motivated by cocaine versus palatable food. Addict Biol 23:6-15
Matzeu, Alessandra; Cauvi, Gabrielle; Kerr, Tony M et al. (2017) The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine versus palatable food. Addict Biol 22:70-77
de Guglielmo, Giordano; Matzeu, Alessandra; Kononoff, Jenni et al. (2017) Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. J Pharmacol Exp Ther 362:378-384
Martin-Fardon, Rémi; Weiss, Friedbert (2017) Perseveration of craving: effects of stimuli conditioned to drugs of abuse versus conventional reinforcers differing in demand. Addict Biol 22:923-932
Matzeu, Alessandra; Kerr, Tony M; Weiss, Friedbert et al. (2016) Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2. J Pharmacol Exp Ther 359:273-279
Matzeu, A; Weiss, F; Martin-Fardon, R (2015) Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior. Neurosci Lett 608:34-9
Martin-Fardon, Rémi; Weiss, Friedbert (2014) Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking. Neuroreport 25:485-8
Matzeu, Alessandra; Zamora-Martinez, Eva R; Martin-Fardon, Rémi (2014) The paraventricular nucleus of the thalamus is recruited by both natural rewards and drugs of abuse: recent evidence of a pivotal role for orexin/hypocretin signaling in this thalamic nucleus in drug-seeking behavior. Front Behav Neurosci 8:117

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