Lateral septum and lateral hypothalamus orexin neurons mediate motivation for cocaine through interactions with the mesolimbic dopamine system

Drug addiction is a disorder characterized by pathological motivation for drug. Our laboratory has recently developed a behavioral economics (BE) paradigm that uniquely assesses demand for drugs of abuse. Animals’ individual lever-pressing data can be fitted to demand curves to determine two important measures of cocaine demand: baseline consumption (Q0) and motivation (α). As α is the slope of the demand curve, it inversely scales with motivation, such that animals with greater demand elasticity (α) have lower motivation for cocaine. Here, we utilized our BE paradigm with pharmacological, morpholino antisense, and retrograde tracing approaches and determined that lateral septum (LS) and lateral hypothalamus (LH) orexin neurons are important neuronal populations for cocaine demand elasticity (α). We demonstrate that inhibiting LS reduced motivation (increased demand elasticity; α) and that the benzodiazepine diazepam blocked this effect, pointing to opposing roles of the two manipulations on ventral tegmental area (VTA) dopamine signaling. The two manipulations were similarly found to be anxiolytic, indicating that changes in drug taking occurred independently of effects on anxiety. Similarly, we show that orexin signaling contributes to motivation for cocaine (α) and that the involvement of orexin in motivated drug taking is mediated primarily by orexin neurons in LH. Animals sacrificed after BE had greater expression of orexin neurons in LH, and unilateral knockdown of LH orexin cells attenuated motivation during BE. The number of spared LH orexin neurons predicted α value in antisense-infused animals and in animals sacrificed two weeks after BE testing. We then blocked orexin-1 receptor signaling in VTA using the oreceptor antagonist SB-334867 (SB) and found that intra-VTA SB reduced motivation. The effects of SB specifically occurred in animals trained and tested on BE with cues and removing cocaine-paired cues reduced SB efficacy. Finally, using retrograde tract tracing, we observed that a greater proportion of LH orexin neurons project to VTA than do other subregions of the orexin cell field. Collectively, these studies implicate two important neuronal populations in motivation for cocaine and indicate that both LS and LH orexin connections to the mesolimbic dopamine system mediate their effects on motivation.Ph.D.Includes bibliographical reference