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D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine’s potency at the DAT. Male rats self-administered cocaine intermittently (5 min ON, 25 min OFF x10; 5-h/session) for 14 sessions, with or without concomitant D-amphetamine maintenance therapy during these 14 sessions (5 mg/kg/day via s.c. osmotic minipump). We then assessed responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. We also assessed the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core using fast scan cyclic voltammetry ex vivo. IntA cocaine self-administration produced psychomotor (locomotor) sensitization, strong motivation to take and seek cocaine, and it increased cocaine’s potency at the DAT. D-amphetamine co-administration suppressed the psychomotor sensitization produced by IntA cocaine experience. After cessation of D-amphetamine treatment, the motivation to take and seek cocaine was also reduced, and sensitization of cocaine’s actions at the DAT was reversed. Thus, treatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

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.

The global precedence effect is a phenomenon in which global aspects of visual and auditory stimuli are processed before local aspects. Individuals with musical experience perform better on all aspects of auditory tasks compared with individuals with less musical experience. The hemispheric lateralization of this auditory processing is less well-defined. The present study aimed to replicate the global precedence effect with auditory stimuli and to explore the lateralization of global and local auditory processing in individuals with differing levels of musical experience. A total of 38 college students completed an auditory-directed attention task while electroencephalography was recorded. Individuals with low musical experience responded significantly faster and more accurately in global trials than in local trials regardless of condition, and significantly faster and more accurately when pitches traveled in the same direction (compatible condition) than when pitches traveled in two different directions (incompatible condition) consistent with a global precedence effect. In contrast, individuals with high musical experience showed less of a global precedence effect with regards to accuracy, but not in terms of reaction time, suggesting an increased ability to overcome global bias. Further, a difference in P300 latency between hemispheres was observed. These findings provide a preliminary neurological framework for auditory processing of individuals with differing degrees of musical experience.