Melanin-concentrating hormone receptor antagonism differentially attenuates nicotine experience-dependent locomotor behavior in female and male rats

Isabel R K Kuebler; Youxi Liu; Bárbara S Bueno Álvarez; Noah M Huber; Joshua A Jolton; Raaga Dasari; Ken T Wakabayashi

doi:10.1016/j.pbb.2023.173649

Melanin-concentrating hormone receptor antagonism differentially attenuates nicotine experience-dependent locomotor behavior in female and male rats

Pharmacol Biochem Behav. 2023 Oct 2:232:173649. doi: 10.1016/j.pbb.2023.173649. Online ahead of print.

Authors

Isabel R K Kuebler¹, Youxi Liu¹, Bárbara S Bueno Álvarez¹, Noah M Huber¹, Joshua A Jolton¹, Raaga Dasari¹, Ken T Wakabayashi²

Affiliations

¹ Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, 1220 T St., Lincoln, NE 68588, United States of America.
² Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, 1220 T St., Lincoln, NE 68588, United States of America; Rural Drug Addiction Research Center, University of Nebraska-Lincoln, 660 N 12th St., Lincoln, NE 68588, United States of America. Electronic address: kwakabayashi2@unl.edu.

PMID: 37793486
PMCID: PMC10985048 (available on 2025-04-02)
DOI: 10.1016/j.pbb.2023.173649

Abstract

Nicotine is a significant public health concern because it is the primary pharmacological agent in tobacco use disorder. One neural system that has been implicated in the symptoms of several substance use disorders is the melanin-concentrating hormone (MCH) system. MCH regulates various motivated behaviors depending on sex, yet little is known of how this interaction affects experience with drugs of abuse, particularly nicotine. The goal of this study was to determine the effect of MCH receptor antagonism on experience-dependent nicotine-induced locomotion after chronic exposure, particularly on the expression of locomotor sensitization. Adult female and male Wistar rats were given saline then cumulative doses of nicotine (0.1, 0.32, 0.56, and 1.0 mg/kg) intraperitoneally to determine the acute effects of nicotine (day 1). Next, rats were treated with 1.0 mg/kg nicotine for 6 days, given an identical series of cumulative doses (day 8), and then kept in a drug-free state for 6 days. On day 15, rats were pretreated with vehicle or the MCH receptor antagonist GW803430 (10 or 30 mg/kg) before another series of cumulative doses to assess response to chronic nicotine. After vehicle, male rats increased nicotine locomotor activation from day 1 to day 15, and both sexes showed a sensitized response when normalized to saline. The lower dose of GW803430 decreased locomotion compared to vehicle in females, while the higher dose decreased locomotion in males. Both sexes showed nicotine dose-dependent effects of GW803430, strongest at lower doses of nicotine. Controlling for sex-based locomotor differences revealed that females are more sensitive to GW803430. The high dose of GW803430 also decreased saline locomotion in males. Together, the results of our study suggest that MCH is involved in the expression of nicotine locomotor sensitization, and that MCH regulates these nicotine behavioral symptoms differently across sex.

Keywords: Hypolocomotion; Locomotion; Non-contingent administration; Sensitization; Sex differences; Tobacco use disorder.

Grants and funding

P20 GM130461/GM/NIGMS NIH HHS/United States