title: The NK1 receptor antagonist L822429 reduces heroin reinforcement.
abstract: Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-1108, USA. barbieres@mail.nih.gov
authors.forename: Estelle
authors.initials: E
authors.lastname: Barbier
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Scott
authors.initials: S
authors.lastname: Edwards
authors.forename: Nathan
authors.initials: N
authors.lastname: Juergens
authors.forename: Paula E
authors.initials: PE
authors.lastname: Park
authors.forename: Kaushik K
authors.initials: KK
authors.lastname: Misra
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Jesse
authors.initials: J
authors.lastname: Schank
authors.forename: Gery
authors.initials: G
authors.lastname: Schulteis
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000517:prevention & control* / Q000523:psychology*; D003932:Heroin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism* / Q000502:physiology; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D003932:Heroin