title: Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking.
abstract: Substance P (SP) and its cognate neurokinin-1 receptor (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. Here, we administered an NK1R antagonist 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 L822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, our results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, 30602, Georgia. Electronic address: jschank@uga.edu.
authors.forename: J R
authors.initials: JR
authors.lastname: Schank
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, 30602, Georgia.
authors.forename: B S
authors.initials: BS
authors.lastname: Nelson
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: R
authors.initials: R
authors.lastname: Damadzic
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Tapocik
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yao
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: King
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Rowe
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Lab of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D004597:Electroshock; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012149:Restraint, Physical; D012646:Self Administration; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D064729:Neurokinin-1 Receptor Antagonists; D016760:Proto-Oncogene Proteins c-fos; D018040:Receptors, Neurokinin-1; D000431:Ethanol
keywords: Alcohol; Neurokinin-1; Nucleus accumbens; Reinstatement; Stress; Substance P