The Role of Lateral Hypothalamic Neuropeptides in Drug Addiction and Feeding Behavior

A major goal of both feeding and drug abuse research is to understand the neural and molecular mechanisms that control intake and how dysfunction of these systems can lead to excessive food ingestion or addiction. Numerous studies have found synergistic effects of drugs of abuse and metabolism on reward related behaviors such as lateral hypothalamus self-stimulation (LHSS). The lateral hypothalamus (LH) is a brain structure with prominent roles in feeding, arousal and reward. Recent studies have found that melanin concentrating hormone (MCH), orexin A and orexin B are exclusively expressed in this brain area, opening the possibility that these LH neuropeptides could be involved in feeding behavior and drug addiction. This study shows that orexin neurons, and not the nearby LH neurons expressing MCH have 歯pioid receptors and respond with induction of cFos and CRE- mediated transcription to chronic morphine administration and opiate antagonist-precipitated morphine withdrawal. Additionally, orexin knockout mice and C57BL/6J mice that received a selective OX1R antagonist develop attenuated morphine dependence, as indicated by a less severe antagonistprecipitated withdrawal syndrome. These findings support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons. This study also establishes a role for MCH and its receptor (MCH1R) in mediating a hypothalamic- limbic circuit that regulates feeding and related behaviors. Particularly intriguing was the high density of MCH1R in nucleus accumbens shell (AcSh), a region important in the regulation of appetitive behavior. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant- like effect in the forced swim test, while intra-AcSh injection of MCH had opposite effects. Expression and biochemical studies demonstrated that MCH is modulating feeding behavior by interacting with the dopamine and glutamate pathways in the enkephalin and dynorphin positive neurons of AcSh. This work identifies a novel hypothalamic-AcSh circuit that may integrate the homeostatic and hedonic aspects of feeding. Together, these studies identify new roles for LH peptides in drug addiction, feeding and depression and help to define novel molecular mechanisms and neural circuits controlling complex behavior.