Cocaine abuse and midbrain circuits: Functional anatomy of hypocretin/orexin transmission and therapeutic prospect.

Brain Research
Steven J Simmons, Taylor A Gentile

Abstract

Cocaine abuse remains a pervasive public health problem, and treatments thus far have proven ineffective for long-term abstinence maintenance. Intensive research on the neurobiology underlying drug abuse has led to the consideration of many candidate transmitter systems to target for intervention. Among these, the hypocretin/orexin (hcrt/ox) neuropeptide system holds largely untapped yet clinically viable therapeutic potential. Hcrt/ox originates from the hypothalamus and projects widely across the mammalian central nervous system to produce neuroexcitatory actions via two excitatory G-protein coupled receptor subtypes. Functionally, hcrt/ox promotes arousal/wakefulness and facilitates energy homeostasis. In the early 2000s, hcrt/ox transmission was shown to underlie mating behavior in male rats suggesting a novel role in reward-seeking. Soon thereafter, hcrt/ox neurons were shown to respond to drug-associated stimuli, and hcrt/ox transmission was found to facilitate motivated responding for intravenous cocaine. Notably, blocking hcrt/ox transmission using systemic or site-directed pharmacological antagonists markedly reduced motivated drug-taking as well as drug-seeking in tests of relapse. This review will unfold the current ...Continue Reading

Citations

Aug 29, 2019·Proceedings of the National Academy of Sciences of the United States of America·Kathryn G PowersRichard E Mains
Jan 28, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Morgan H JamesGary Aston-Jones
Apr 16, 2020·Brain Sciences·Alessandra Matzeu, Rémi Martin-Fardon
Aug 11, 2020·Drugs·Reda M Chalhoub, Peter W Kalivas
May 4, 2021·Drug and Alcohol Dependence·Natalie E ZlebnikMarilyn E Carroll
Jan 20, 2022·Journal of Internal Medicine·Laura H JacobsonLuis de Lecea

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