The NK1 antagonist L822429 inhibits stress-induced reinstatement of alcohol seeking behavior in rats

INTRODUCTIONCONCLUSIONS REFERENCESSubstance P (SP) and its preferred neurokinin-1 (NK1)receptor play a significant role in stress and anxiety-relatedbehaviors. While the influence of the NK1 receptor onstress responses is well documented, less is known aboutits role in reward and addiction. Recent studies havesuggested a critical role of the SP/NK1 system in therewarding properties of morphine, but not that of cocaine.Furthermore, our lab was the first to demonstrate thatalcohol consumption is decreased by a genetic deletion ofthe NK1 gene in mice, and that administration of NK1antagonists to human alcoholics can alleviate craving. Inthe studies presented here, we utilize the well-validatedmodels of rat self-administration and reinstatement toassess the effects of a specific NK1 antagonist, L822429.This antagonist has anxiolytic properties in rodent modelswhen administered systemically, and therefore representsan intriguing agent for altering alcohol-related behaviors.NK1 antagonism has presented a rather complicated targetthus far, as receptor affinity shows significant interspeciesvariation and many antagonists that are effective in humansare inactive in rat. We found that while L822429 had littleeffect on baseline alcohol self-administration or cue-inducedreinstatement of alcohol seeking behavior, it dose-dependently blocked the expression of stress-inducedreinstatement. Importantly, this drug had no effect onlocomotor activity or self-administration of sucrose solution.To our knowledge, this is the first exploration of the effectsof NK1 receptor antagonists on alcohol-related behaviors inrats. Taken together, these results indicate NK1 antagonistsgenerally, and L822429 specifically, as promisingcandidates for pharmacotherapy for alcoholism. -Substance P (SP) is a neuropeptide that signalsprimarily through the neurokinin-1 (NK1) receptorand is highly involved in stress, anxiety, andaddiction1-2. -Manipulations of the SP/NK1 system have beenshown to impact rewarding and reinforcingproperties of morphine, but notcocaine3-5. -NK1 -/mice drink less alcohol, show bluntedalcohol associated reward, and do not escalatealcohol consumption following intermittentaccess6-7. -NK1 antagonists decrease alcohol consumptionin wildtype mice and attenuate craving inalcoholics6-7. -L822429 is a highly specific NK1 antagonist thathas central activity when delivered systemicallyand has anxiolyticproperties8-9. -The studies outlined here attempt to assessthe effect of L822429 on alcohol self-administration and reinstatement.-L822429 induces a small, butstatistically significant, reductionin alcohol self administration. -L822429 induced a potent,dose dependent suppression ofalcohol seeking behavior duringfootshock-inducedreinstatement testing. However,this drug does not affect cue-induced reinstatement ofalcohol seeking behavior. -L822429 does not effect self-administration of 10% sucroseor general locomotor activity(data not shown). -The experiments outlinedabove indicate an important roleof the NK1 receptor in alcohol-induced behaviors. Animals: Male Wistar rats weighing approximately 400 to 500 grams at the time of experimentation were used in these studies. Rats were housed in a reversed light cycle (lights on 20:30,lights off 08:30), and all testing took place during the dark phase.Alcohol Self-Administration: 10% ethanol (v/v) was available during self-administration sessions on an FR1 schedule. Alcohol was dissolved in tap water and delivered in a 0.1 mlvolume onto a tray within the self-administration chamber, from which the rat consumed the alcohol solution. A 5 second time out was initiated following alcohol delivery during which ahouse light was illuminated. During time out, alcohol delivery was not activated following active lever press, but these responses were recorded. Following the timeout, the sessionreturned to the FR1 schedule of reinforcement. For cue-induced reinstatement experiments, orange scent was also present in the self-administration chambers during alcohol sessions.Self-Administration Experiments: After a stable level of responding was reached for at least three consecutive days, rats were injected with L822429 (0, 15, or 30 mg/kg) 60 minutesbefore the next self-administration session.Extinction & Reinstatement: After 14-16 days of self-administration, extinction sessions were begun where responding on the active lever did not result in a delivery of alcohol. In thestress-induced reinstatement experiment, the time out light cue remained in place during the extinction sessions. For the cue-induced reinstatement experiment, the light cue and orangescent were removed during extinction sessions. Extinction conditions were in place for 15-19 sessions. To reinstate responding, specific stimuli were delivered to induce active leverpressing behavior. In the stress-induced reinstatement experiment, 15 minutes of intermittent footshock (0.5 sec shock, 0.6 mA) was delivered immediately before the reinstatementsession. In cue-induced reinstatement experiments, presentation of orange scent and contingent house light illumination served as the reinstatement stimuli. In both experiments L822429was injected 60 minutes prior to reinstatement testing.Drugs: L822429 was synthesized from the literature by K. Rice and K. Cheng. L822429 was dissolved in 45% (w/v) 2-hydroxypropyl β-cyclodextrin and pH was adjusted with 1 N NaOH.L822429 was injected i.p. at a volume of 2 ml/kg.METHODSRESULTSThe NK1 antagonist L822429 inhibits stress-inducedreinstatement of alcohol seeking behavior in rats ExtinctionReinstatement020406080100