Dopamine beta-hydroxylase inhibition induced blunting of dopaminergic response to psychostimulant administration. A PET exploration of the mechanism of action of a new therapeutic strategy in cocaine addicts – RAPID

Dopamine beta-hydroxylase (DHB) inhibition has shown promise as a treatment of cocaine dependence. This enzyme is responsible of the hydroxylation of dopamine into norepinephrine. DBH inhibition results in the lack of norepinephrine synthesis. Animal studies suggest that DBH inhibition efficacy in psychostimulant use is related to the decrease of dopaminergic response, possibly associated to postsynaptic dopaminergic receptors hypersensibility. In humans, the clinical efficacy of DBH inhibition, achieved with disulfiram treatment, is close to be established. The mechanism of action is however not yet fully understood: some studies have shown an increase of aversive reactions to cocaine, as other studies have shown a decrease of positive effects of cocaine. The effect of DBH inhibition on dopaminergic response to psychostimulants has not yet been studied in humans.
Our study is a randomized double-blind placebo-controlled trial. Thirty subjects with cocaine dependence will be included after inpatient admission for cocaine detoxification. They will be randomized at a 1/1 ratio to receive disulfiram 250 mg/d or placebo during 15 days while hospitalized. Judgment criteria measurements will take place during a double PET session with 11Craclopride, before and after stimulation with methylphenidate. This double imaging session will be programmed 8 to 15 days after randomization. The primary outcome will be the 11Craclopride binding change in the nucleus accumbens from baseline to post methylphenidate (20 mg) PET.
The primary objective of this randomized controlled trial is to show that DBH inhibition induces a decrease of dopaminergic response to methylphenidate stimulation. Secondary objectives are to show that:
1. methylphenidate stimulation induces less craving and more aversive responses when subjects are treated with disulfiram compared to placebo.
2. disulfiram DBH inhibition increases D2 dopaminergic receptors availability at baseline
3. D2 dopaminergic receptors availability at baseline is related to DBH activity
4. disulfiram treatment decreases DBH activity compared to placebo in cocaine dependent subjects after detoxification
5. subjects with a low DBH activity report more aversive reactions to cocaine.
Up to now, disulfiram is the unique DBH inhibitor on the market. Another DBH inhibitor, more specific, is currently in phase 2 as a treatment for cocaine dependent subjects. It is likely that other new DBH inhibitors will be developed for the treatment of psychostimulant or other psychiatric or somatic disorders in the near future. The development of this new therapeutic approach in cocaine dependence treatment requires a better knowledge of its mechanism of action.