1. Alterations in rat striatal dopamine transporters produced by long-access cocaine self-administration. Our laboratory has been documenting the consequences of chronic, high-dose, long-access cocaine self-administration under a variety of schedules of reinforcement for more than a decade. We have focused on two major adaptation categories - hypodopaminergia and cocaine tolerance. Hypodopaminergia describes the reduced function of dopamine terminals in striatal regions, and cocaine tolerance refers to a marked reduction in cocaine's ability to inhibit dopamine uptake, which leads to escalating cocaine intake over time.
2. Chronic alcohol and stress exposure produces hypodopaminergia in the mesolimbic reward system of mice, rats and monkeys. We have documented that ethanol plus withdrawal stress or repeated stress alone cause a blunting of dopamine signaling, at least in part mediated by increased activity of kappa opioid receptors. We have had the unique opportunity to measure dopamine in striatal slices from chronic alcohol drinking monkeys, which have provided translational information on these changes.
3. The acute and chronic effects of amphetamine have been explored in our laboratory over the last 15 years. There is an ongoing controversy about whether a low-dose, long-lasting amphetamine formulation would make a viable therapeutic agent for the treatment of cocaine addiction. Our studies support this notion, and we have been exploring several different aspects of amphetamine action, from its acute effects on release vs uptake to its long term effects on cocaine self-administration.
4. Intermittent cocaine self-administration produces sensitization of dopamine and behavior. In contrast to the tolerance and low function of the dopamine system after long access paradigms (6+ hours), allowing only brief access for a few minutes at time increases motivation to seek cocaine and dopamine responses to cocaine. These manuscripts have challenged the dogma that long, continuous exposure to cocaine is required to create relevant translational models of drug addiction.
5. High fat diet-induced obesity is associated with dramatic changes in dopamine signaling that in some ways resemble drug and alcohol addiction. We have recently begun exploring the effects of chronic continuous access or limited binge-like access to a high fat diet in mice. We have found that neurochemical and behavioral effects of these paradigms modify responses to abused drugs such as amphetamine and produce a withdrawal syndrome similar to that produced by chronic ethanol exposure.
6. Methylphenidate self-administration produces opposite neurochemical, dopamine terminal and behavioral effects from cocaine. Methlyphenidate, or Ritalin, is a dopamine transporter blocker, in the same drug class as cocaine, but it has very different effects on the dopamine transporter and dopamine terminals in the striatum. We have published a series of well-cited manuscripts on methlyphenidate interactions with the dopamine system and continue to explore this topic.