Development of new neurobiological strategies to treat patients with cocaine dependence

Dopamine is a key neurotransmitter in the pathophysiology of substance dependence and low striatal dopamine D2 receptor availability is probably both a risk factor for and a consequence of repeated drug use. It was, therefore, hypothesized that increasing dopamine D2 receptor availability is a promising strategy to treat drug dependence (Part 1: Chapter 1). Varenicline (an a4ß2 nicotinic partial agonist registered for smoking cessation) and rimonabant (a cannabinoid CB1 receptor antagonist previously registered for obesity treatment) seem good candidates for further investigation as potential treatments of cocaine dependence, because our studies showed that both compounds increase dopamine D2/3 receptor availability in striatal brain regions of drug-naïve rats as measured by storage phosphor and SPECT imaging (Part 2: Chapters 2-6).
Approximately one out of every four patients with a substance use disorder has a comorbid attention-deficit/hyperactivity disorder (ADHD) (Part 3: Chapter 7). This comorbidity significantly worsens treatment outcome and has a negative influence on the pharmacotherapeutic effectiveness of methylphenidate in the treatment of ADHD. Our study showed that this may be attributed to lower availability of striatal dopamine transporters (DATs) and decreased DAT occupancy by methylphenidate in ADHD patients.