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 selfadministration. 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 anxietylike 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.

Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

“…In this escalation phase, all groups were allowed to nose poke for food and water on an FR1 schedule while in the test chambers. Rats were allowed 15 days of daily escalation sessions, at the end of which ShA rats displayed stable levels of heroin self-administration, whereas LgA rats displayed an escalation of heroin intake as repeatedly reported by our laboratory (data not shown; Ahmed et al, 2000b;Barbier et al, 2013;Greenwell et al, 2009a,b;Schlosburg et al, 2013;Vendruscolo et al, 2011;Walker et al, 2000).…”

“…Escalation of heroin intake is thought to reflect an important aspect of the transition from initial controlled drug use to uncontrolled drug dependence or addiction, and has been associated with dysfunction of brain reward and stress systems (Ahmed et al, 2000b;Barbier et al, 2013;Edwards et al, 2012;Kenny et al, 2006;Lenoir and Ahmed, 2007;Lenoir et al, 2013;Vendruscolo et al, 2011). Here, we report that the HCRT-R2 antagonist NBI-80713 selectively decreased heroin, but not food, self-administration speci- Figure 2 NBI-80713, a HCRT-receptor 2 antagonist, has no effect on responding for food pellet self-administration in either long-access (LgA) or shortaccess (ShA) rats.…”

“…The escalation of heroin intake observed in LgA animals contrasts with the lower, more stable intake levels observed in ShA animals (Ahmed et al, 2000b;Barbier et al, 2013;Greenwell et al, 2009a, b;Schlosburg et al, 2013;Vendruscolo et al, 2011;Walker et al, 2000). It is hypothesized that escalated heroin taking is mediated, in part, by the dysregulation of brain reward and stress systems (eg, HCRT, dynorphin, substance P and corticotropin-releasing factor; CRF) particularly within subregions of the extended amygdala via negative reinforcement mechanisms (for review, see Koob et al, 2014) Effects of acute heroin withdrawal on Hcrtr2 mRNA expression levels in reward/stress-related brain regions of heroin-naive, short access (ShA) and long access (LgA) to heroin rats.…”

“…Intravenous self-administration sessions were conducted in standard operant conditioning chambers (Med Associates) as previously described (Barbier et al, 2013;Vendruscolo et al, 2011). In brief, rats were trained to press one of the two levers (the active lever) on a fixed-ratio 1 (FR1) schedule of reinforcement (each response resulted in fluid delivery) to obtain 0.1 ml of heroin (60 mg/kg/infusion) in 1 h sessions.…”

“…In rats, short access (1 h per day; ShA) to heroin produces stable levels of drug intake, whereas long access (6-23 h per day; LgA) to heroin self-administration can lead to escalated self-administration, which reproduces several key symptoms of heroin dependence reminiscent of the human condition (Ahmed et al, 2000a;Barbier et al, 2013;Vendruscolo et al, 2011). It has long been hypothesized that during limited access conditions, drug intake is mainly driven by the positive reinforcing properties of heroin, whereas during extended access, negative reinforcement mechanisms predominate, in which brain stress systems are recruited and the drug is taken to alleviate negative affective states associated with drug withdrawal (for review, Koob et al, 2014).…”