COCAINE CUES AND DOPAMINE IN DORSAL STRIATUM: MECHANISM OF CRAVING IN COCAINE ADDICTION? The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and 11Craclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of 11Craclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine).? ? 11CRacloprides specific binding in dorsal (caudate and putamen) but not in ventral striatum (where nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation), is involved with craving and is a fundamental component of addiction. Inasmuch as craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.? ? DOPAMINE TRANSPORTER LEVELS IN TREATMENT AND DRUG NAIVE ADULTS WITH AND WITHOUT ADHD ? Attention deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, yet data are sparse on its pathophysiology. Great interest was generated by imaging studies showing increases in dopamine transporter levels in subjects with ADHD. However, not all studies confirmed this and the role of dopamine transporters on the neurobiology of ADHD remains unclear. The purpose of this study was to investigate the levels of dopamine transporters in the brain of ADHD subjects with control of potentially confounding factors (previous medication and/or drug histories, co-morbidity) and to investigate the significance of the variability in transporters levels on clinical measures of inattention and hyperactivity.? ? Positron emission tomography and 11Ccocaine were used to measure dopamine transporters in 20 never medicated adults with ADHD and 25 controls. Images were analyzed using regions of interest and statistical parametric mapping (SPM). Symptoms of inattention and hyperactivity were quantified using the Conners Adult Attention Rating Scale (CAARS). Dopamine transporters were lower in left caudate (13%, p < 0.05) and in left nucleus accumbens (p < 0.005) in ADHD subjects than in controls. However, dopamine transporter levels in putamen, which did not differ between groups, were positively associated with inattention (CAARS A and E) both in ADHD and control subjects. Thus, for a given transporter level the scores for inattention were on average five times greater in ADHD subjects than in controls.? ? These results do not support increases in dopamine transporters in ADHD but instead document decreases in left caudate and nucleus accumbens/ventral cingulate. The data also provide evidence that dopamine transporter levels modulate attention, but suggest that additional pathology (e.g prefrontal or cingulostriatal pathways, noradrenergic neurotransmission) is necessary to account for the large differences in inattention observed between controls and ADHD subjects.? ? ? DEPRESSED DOPAMINE ACTIVITY IN CAUDATE AND LIMBIC REGIONS IN ADULTS WITH ADHD? Attention deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disorder of childhood. There is considerable evidence that brain dopamine is involved in ADHD but it is unclear whether dopamine activity is enhanced or depressed. The purpose of this study was to test the hypotheses that striatal dopamine activity is depressed in ADHD and that this contributes to symptoms of inattention. Subjects were 19 with ADHD that had never been medicated and 24 healthy controls. They were scanned with positron emission tomography and 11Craclopride (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine) after placebo and after intravenous methylphenidate, a stimulant that increases extracellular dopamine by blocking dopamine transporters. The difference in 11Craclopride binding (estimated as Bmax/Kd) between placebo and methylphenidate was used as marker of dopamine release. Symptoms were quantified using the Conners Adult Attention Rating Scale.? ? On Placebo, dopamine D2/D3 receptor availability in left caudate was lower (p < 0.05) in ADHD subjects than controls. Methylphenidate induced smaller decrements in 11Craclopride binding in caudate (blunted DA increases)(p < 0.05) and higher scores on self-reports of drug liking in ADHD than in control subjects. The blunted response to methylphenidate in caudate was associated with symptoms of inattention (p < 0.005) and with higher self-reports of drug liking (p < 0.01). Exploratory analysis using statistical parametric mapping (SPM) revealed that methylphenidate also decreased 11Craclopride binding in hippocampus and amygdala and that these decrements were smaller in ADHD subjects (p < 0.001).? ? This study provides evidence that dopamine activity is depressed in caudate and limbic regions in adults with ADHD and that in caudate it is associated with inattention. The enhanced reinforcing effects of intravenous methylphenidate in ADHD subjects, which were associated with depressed dopamine responses, suggest that dopamine dysfunction may contribute to substance abuse comorbidity in ADHD.
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