Effects of Pharmacologic Dopamine β-Hydroxylase Inhibition on Cocaine-Induced Reinstatement and Dopamine Neurochemistry in Squirrel Monkeys

Abstract

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 b-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 cocaineinduced 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.

Norepinephrine at the nexus of arousal, motivation and relapse

“…In rodents and monkeys, α 1 -antagonists or α 2 -agonists, prevented the ability of noncontingent psychostimulant administration to reinstate cocaine self-administration (Zhang and Kosten, 2005; Platt et al, 2007). However, in other studies, neither α1-antagonists, β-antagonists, α 2 agonists (to suppress NE release) or NE synthesis inhibitors affected cocaine-induced reinstatement (Shaham et al, 2000a; Mantsch et al, 2010; Cooper et al, 2014). While the discrepant nature of the literature might indicate that NE does not play a prominent role in psychostimulant-induced reinstatement, there are a couple of important issues that need to be considered prior to drawing strong conclusions.…”

The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs—disulfiram and ritonavir

“…We have convincing evidence that both ritonavir and disulfiram or their active metabolites penetrate the blood–brain barrier effectively in sufficient concentrations [ 56 - 60 ]. The most common clinical use of disulfiram is to inhibit aldehyde dehydrogenase during the treatment of alcoholism [ 48 ].…”

“…The most common clinical use of disulfiram is to inhibit aldehyde dehydrogenase during the treatment of alcoholism [ 48 ]. A secondary use of disulfiram is to inhibit brain dopamine beta-hydroxylase during the treatment of certain addictions [ 56 , 57 ], thus indicating sufficient blood–brain penetration. The levels of ritonavir in the brain tissues and cerebrospinal fluid (CSF) tend to be low [ 58 ] when given orally, but can easily be increased from 2.4 to 6.6 ng/mL CSF with oral co-administration of ketoconazole [ 59 ].…”

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

“…In preclinical trials, nepicastat was found to attenuate reinstatement of cocaine-seeking behaviors in rats following exposure to all three reinstatement modalities, cocaine-related cues, food prompts and stress [99]. Interestingly, in a recent study in nonhuman primates, nepicastat failed to attenuate cocaineinduced reinstatement in squirrel monkeys, instead inducing a modest reinstatement effect [100]. In Phase I, human laboratory testing, nepicastat significantly attenuated subjective effects of cocaine (e.g., 'drug effect', 'high', 'good effects' and 'stimulated'), but failed to have an effect on craving and increased ratings of 'depressed' and 'anxious' [101].…”