Search

Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling in vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine's reinforcing efficacy in resilient subjects.

Hypocretin- (also known as orexin) containing neurons of the lateral hypothalamus project widely throughout the brain and are implicated in a range of behaviors via signaling at hypocretin receptor 1 (HCRTr1) and hypocretin receptor 2. These neurons send a moderate, but influential, projection to the dopaminergic ventral tegmental area which—as part of the mesolimbic dopamine system—is highly implicated in motivated behavior and substance abuse. In this chapter, we will explore the contribution of HCRTr1 to dopamine neurotransmission and its consequential importance to addiction-related processes. Following, we review evidence for HCRTr1 involvement in supporting drug-associated behavior across behavioral models of addiction. We then discuss HCRTr1 regulation of ventral tegmental dopamine neuron activity and its impact on dopamine neurotransmission in the nucleus accumbens, and address hypocretin-dopamine interactions and their effects in females. Finally, we propose that HCRTr1 regulation of dopamine release influences behavioral responses to drug-associated cues.