Disulfiram has shown promise as a
pharmacotherapy for
cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of
disulfiram is inhibition of
dopamine β-
hydroxylase (DBH), the
enzyme that converts
dopamine (DA) to
norepinephrine (NE) in noradrenergic neurons. Thus,
disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both
disulfiram and the selective DBH inhibitor
nepicastat block
cocaine-primed reinstatement, a paradigm which is thought to model some aspects of
drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of
cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer
cocaine were pretreated with
disulfiram or
nepicastat prior to
cocaine-induced reinstatement sessions. Neither DBH inhibitor altered
cocaine-induced reinstatement. Unexpectedly,
nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated
cocaine-induced DA overflow in the NAc. Hence, the attenuation of
cocaine-induced changes in accumbal DA neurochemistry was not associated with altered
cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies.