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.