Argatroban for The number of DBH alleles affects dopamine an

The number of DBH Argatroban for affects dopamine and norepinephrine levels in the prefrontal cortex of mice when they are treated with disulfiram (33). Disulfiram increased dopamine and decreased norepinephrine levels in their prefrontal cortex of mice with two normal alleles, whereas disulfiram showed relatively little effect on these levels in mice with null alleles (33). Like these mice, our human study participants with low DβH seemed less affected by disulfiram-induced inhibition of DβH than those with high DβH activity. Lowering DβH activity through disulfiram might increase aversive symptoms from acute cocaine use, as one mechanism for its efficacy. Although none of these outpatients reported aversive symptoms from cocaine as an adverse event, disulfiram has increased cocaine-associated negative effects, including anxiety and paranoia, and reduced positive subjective effects during acute laboratory cocaine administration in humans (63, 64, 65, 66). Low DBH levels have been associated with psychotic symptoms in psychiatric disorders (see review [67]). For instance, schizophrenic or depressed patients who have low plasma or cerebrospinal fluid levels of DβH exhibit more positive psychotic symptoms compared with those with higher levels of DβH (68, 69, 70, 71, 72). Moreover, patients diagnosed with unipolar depression plus psychotic features have lower DβH levels than those without psychotic features (73). In addition, the genetic predisposition for lower levels of DβH protein is associated with cocaine-induced paranoia (39). This trial has several limitations. First, the sample size is small for the genetic association studies, and larger replications of this preliminary study are needed. Second, the genetic associations reflect a modest reduction in cocaine use to a mean proportion of .56 cocaine-positive urines. However, this reduction for the normal DβH (CC genotype) patients treated with disulfiram was a 33% reduction, compared with no change with placebo. The low DβH patients showed only a 13% reduction, which was the same as the 13% reduction with placebo. Thus, we had at least a doubling in efficacy with this genetic selection. Third, most cocaine abusers are not also opioid-dependent, which limits the generalization of our findings. Fourth, alcohol abuse can be common among cocaine abusers, and our rates of alcohol abuse were low, reflecting our exclusion criteria. Fifth, an alternative rationale that might also explain the effectiveness of disulfiram involves aldehyde dehydrogenase 2 inhibition leading to generation of tetrahydropapaveroline (THP). This chemical inhibits activated tyrosine hydroxylase and suppresses cocaine-induced dopamine production and release (74). Future studies might examine the polymorphisms in the gene coding for aldehyde dehydrogenase 2 as well as the gene for tyrosine hydroxylase and the role of these as potential pharmacogenetic targets. Finally, disulfiram might not be the optimal medication for attaining DβH inhibition, but another DβH inhibitor—nepicastat—is being developed that does not inhibit aldehyde dehydrogenase or produce aversive interactions with alcohol (75). Future studies should investigate the efficacy of this more selective DβH inhibitor, because this compound attenuates cocaine-seeking during relapse-like behavior in rats (76) and reduces some positive subjective effects of cocaine in humans (77).
This work was supported by National Institutes of Health/National Institute on Drug Abuse5 P50 DA018197-05 (TK), the Veterans Health Administration, and the David Toomim Fund.
ClinicalTrials.gov: Pharmacogenetics of Disulfiram for Cocaine; clinicaltrials.gov/ct2/show/NCT00149630; NCT00149630.
Introduction The carotid body (CB) is located bilaterally at the bifurcation of the common carotid artery and is the peripheral chemoreceptor responsible for monitoring changes in PO2, PCO2 and pH in arterial blood (Nurse, 2005, Lahiri et al., 2006, Prabhakar, 2006). The decrease in PO2 is detected by glomus cells (type I cells) within CB, which are synaptically connected with carotid sinus nerve (CSN), leading to an increase in the afferent sensory discharge to the nucleus of the solitary tract (Gonzalez et al., 1994, Lahiri et al., 2006). As a result, appropriate autonomic changes including stimulation of breathing and a raise in blood pressure are caused under environmental hypoxia (Prabhakar, 2006).