L-822492 is a highly selective and high affinity antagonist for substance P at the rat neurokinin-1 receptor (NK1R). Earlier work has shown that substance P and NK1R are involved in alcohol-related behaviors. We have previously reported that NK1R antagonism attenuates stress-induced reinstatement of alcohol seeking and suppresses escalated alcohol self-administration, but does not affect primary reinforcement or cue-induced reinstatement. We administered L-821429 or vehicle prior to footshock-induced reinstatement of alcohol seeking, and mapped the resulting neuronal activation using Fos immunohistochemistry. As expected, vehicle treated animals exposed to footshock showed induction of Fos immunoreactivity in several regions of the brain stress circuitry, including the amygdala (AMG), nucleus accumbens (NAC), dorsal raphe nucleus (DR), prefrontal cortex (PFC), and bed nucleus of the stria terminalis (BNST). NK1R antagonism selectively suppressed the stress-induced increase in Fos in the DR and NAC shell. In the DR, Fos-induction by stress largely overlapped with tryptophan hydroxylase (TrpH), indicating activation of serotonergic neurons. Of NAC shell neurons activated during stress-induced reinstatement of alcohol seeking, about 30% co-expressed dynorphin (DYN), while 70% co-expressed enkephalin (ENK). Few (<1%) activated NAC shell neurons coexpressed choline acetyltransferase (ChAT), which labels the cholinergic interneurons of this region. Infusion of the NK1R antagonist L-822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L-822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, these results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking. We also examined the effect of L-822429, on alcohol intake and seeking behaviour in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. Systemic administration of L-822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. cL-822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L-822429 injected into the medial amygdala also significantly reduced anxiety-like behavior in the elevated plus maze test. No effects on alcohol intake were observed following injection of L-822429 into the dorsal or the ventral hippocampus. These results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Drug Abuse
Zip Code
Ayanwuyi, Lydia O; Stopponi, Serena; Ubaldi, Massimo et al. (2015) Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats. Br J Pharmacol 172:5136-46
Schank, J R; Nelson, B S; Damadzic, R et al. (2015) Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking. Neuropharmacology 99:106-14
Blasio, Angelo; Valenza, Marta; Iyer, Malliga R et al. (2015) Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats. Behav Brain Res 287:315-22
Corrigan, Frances; Wu, Yue; Tuke, Jonathan et al. (2015) Alcohol-induced sedation and synergistic interactions between alcohol and morphine: a key mechanistic role for Toll-like receptors and MyD88-dependent signaling. Brain Behav Immun 45:245-52
Schank, Jesse R; King, Courtney E; Sun, Hui et al. (2014) The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. Neuropsychopharmacology 39:1093-101
Augier, E; Flanigan, M; Dulman, R S et al. (2014) Wistar rats acquire and maintain self-administration of 20 % ethanol without water deprivation, saccharin/sucrose fading, or extended access training. Psychopharmacology (Berl) 231:4561-8
Bajo, Michal; Madamba, Samuel G; Roberto, Marisa et al. (2014) Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun 40:191-202
Sabino, Valentina; Kwak, Jina; Rice, Kenner C et al. (2013) Pharmacological characterization of the 20% alcohol intermittent access model in Sardinian alcohol-preferring rats: a model of binge-like drinking. Alcohol Clin Exp Res 37:635-43
Schank, Jesse R; Tapocik, Jenica D; Barbier, Estelle et al. (2013) Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats. Biol Psychiatry 73:774-81
Lewis, Susannah S; Hutchinson, Mark R; Zhang, Yingning et al. (2013) Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain. Brain Behav Immun 30:24-32

Showing the most recent 10 out of 17 publications