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.

Figure 1

L822429 decreases heroin intake and motivation to consume heroin in both short access (ShA) and long access (LgA) rats. The bars or dots and vertical lines represent mean values and SEM. (a) Extended periods of drug access result in significantly increased heroin intake over time. (b) L822429 (30 mg/kg) significantly decreases responding (fixed-ratio 1 (FR1)) for heroin in the ShA and LgA rats during the first hour of heroin intake. (c) L822429 (30 mg/kg) significantly decreases responding (FR1) for heroin in the LgA rats in the entire 12-h session. (d) L822429 (30 mg/kg) significantly decreases responding (FR3) for food self-administration in the ShA and LgA rats. (e) L822429 (30 mg/kg) significantly decreases responding for heroin on a PR schedule of reinforcement in the ShA and LgA rats. *P<0.05 vehicle vs L822429; ⁺P<0.05 different from first session. N=10 per group.

Figure 2

Anxiolytic-like effect of L822429 measured by the elevated plus maze. The bars and vertical lines represent mean values and SEM. (a) % Time spent and (b) % entries in the open arms. (c) Number of entries in the closed arms. *P<0.05 vehicle vs L822429; ^#P<0.05 short access (ShA) or long access (LgA) rats vs naïve rats. N=8–14 per group.

Figure 3

Paw withdrawal thresholds are significantly decreased in short access (ShA) rats, and to a significantly greater degree in long access (LgA) rats compared with naïve rats. The bars and vertical lines represent mean values and SEM. L822429 (30 mg/kg) did not alter mechanical hypersensitivity in either ShA or LgA rats. ^#P<0.05 ShA or LgA rats vs naïve rats; ^&P<0.05 ShA vs LgA rats. N=6 to 7 per group.

Figure 4

Expression of TacR1 in stress/reward-related brain areas are presented as the percentage of control (naïve) values. The bars or dots and vertical lines represent mean values and SEM. (a) Heroin self-administration by short access (ShA) and long access (LgA) rats used for mRNA expression measurements. (b) TacR1 mRNA levels in stress/reward-related brain areas of ShA, LgA, and naïve rats. (c) Mechanical sensitivity of rats repeatedly injected with saline, heroin, or escalated doses of heroin. (d) TacR1 mRNA levels in stress/reward-related brain areas of rats repeatedly injected with saline, heroin, or escalated doses of heroin. ^#P<0.05 ShA or LgA rats vs naïve rats and repeated heroin or escalated heroin vs repeated saline, ^&P<0.05 repeated heroin vs escalated heroin, and ⁺P<0.05 different from first session. N=6–8 per group.