title: 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 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.
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Cooper
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Kimmel
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Manvich
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Schmidt
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-3678-6215
authors.initials: D
authors.lastname: Weinshenker
authors.affiliation: Yerkes National Primate Research Center, Division of Neuropharmacology and Neurologic Diseases (D.A.C., H.L.K., L.L.H.), Department of Pharmacology (H.L.K., L.L.H.), Department of Human Genetics (D.A.C., D.F.M., K.T.S., D.W.), and Department of Psychiatry and Behavioral Sciences (L.L.H.), Emory University, Atlanta, Georgia lhowell@emory.edu.
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Howell
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases; D016739:Behavior, Addictive / Q000139:chemically induced; D003042:Cocaine / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D003216:Conditioning, Operant / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000172:deficiency*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000172:deficiency*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D012453:Saimiri; D012646:Self Administration; D013871:Thiones / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004221:Disulfiram; C109487:nepicastat; D004298:Dopamine; D009638:Norepinephrine