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An estimated 50–90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to ‘self-medicate’ against the negative emotional side effects of the cocaine ‘crash’, including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol- and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use. This article is part of the special issue on Neurocircuitry Modulating Drug and Alcohol Abuse.

Psychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. It has recently been appreciated that reinforcement may be separated into consummatory (hedonic), motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, motivation to avoid or escape foot shock or to acquire sucrose was not altered by mTBI. Our results suggest that individuals experiencing mTBI find avoidance of aversive events less reinforcing, and therefore are less apt to utilize proactive control of stress.