Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review.

Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH's role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.

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

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.

Contrasting dose-dependent effects of acute intravenous methamphetamine on lateral hypothalamic extracellular glucose dynamics in male and female rats.

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovasculature with local metabolism. Although glucose metabolism is known to differ in humans with and without methamphetamine use disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD-like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single session after: 1) natural nondrug stimuli (novel object presentation and a tail-touch), 2) increasing cumulative doses of intravenous methamphetamine (0.025, 0.05, 0.1, and 0.2 mg/kg), and 3) an injection of 60 mg of glucose. We found second-scale fluctuations in LH glucose in response to natural stimuli that differed by both stimulus type and sex. Although rapid, second-scale changes in LH glucose during methamphetamine injections were variable, slow, minute-scale changes following most injections were robust and resulted in a reduction in LH glucose levels. Dose and sex differences at this timescale indicated that female rats may be more sensitive to the impact of methamphetamine on central glucose regulation. These findings suggest that the effects of MUD on healthy brain function may be linked to how methamphetamine alters extracellular glucose regulation in the LH and point to possible mechanisms by which methamphetamine influences central glucose metabolism more broadly.NEW & NOTEWORTHY Enzyme-linked glucose biosensors were used to monitor lateral hypothalamic (LH) extracellular fluctuations during nondrug stimuli and intravenous methamphetamine injections in drug-naive awake male and female rats. Second-scale glucose changes occurred after nondrug stimuli, differing by modality and sex. Robust minute-scale decreases followed most methamphetamine injections. Sex differences at the minute-scale indicate female central glucose regulation is more sensitive to methamphetamine effects. We discuss likely mechanisms underlying these fluctuations, and their implications in methamphetamine use disorder.