Abstract
Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as after a 2‐week period of abstinence, to relate the number of LH orexin cells to economic demand for cocaine. We also knocked down LH orexin expression with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. We found that animals with greater baseline motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a 2‐week abstinence from cocaine, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence, indicating that orexin expression is a persistent marker for demand. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual motivation for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.
Here, we show that animals with low demand elasticity (α; higher motivation) for cocaine have more orexin‐expressing neurons in lateral hypothalamus (LH) immediately following a behavioral economics paradigm, and knockdown of orexin protein expression in LH using morpholino antisense decreased motivation (increased α). When animals were sacrificed after 2 weeks of abstinence, LH orexin neuron number reflected motivation (α) for cocaine 2 weeks prior. Collectively, these studies point to the number of LH orexin neurons as a predictor of addiction susceptibility.