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.
Footnotes
- Received January 21, 2014.
- Accepted May 8, 2014.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA012514, K05-DA031246, R01-DA027535, R03-DA034867, R01-DA017963, and T32-DA015040]; the National Institutes of Health National Institute of General Medical Sciences [Grants P51-RR00165 and UL1-RR025008]; the Office of Research Infrastructure Programs [Grant ODP51OD11132]; and the Howard Hughes Medical Institute [Grant 56006762].
This article was prepared while H.L.K. was employed at the National Institutes of Health. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
With the exception of income received from their primary employers, D.A.C., H.L.K., D.F.M., K.T.S., and L.L.H. have received no financial support or compensation from any individual or company entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a conflict of interest. D.W. is coinventor on a patent concerning the use of selective dopamine β-hydroxylase inhibitors for the treatment of cocaine dependence [Weinshenker D and Malison RT (2012) inventors, Yale University and Emory University, assignee. Methods and compositions for treatment of drug addiction. US patent US-2013-0274303-A1. 2012 Oct 2].
Parts of this study represent partial fulfillment dissertation: Cooper DA (2014) Pharmacologic Dopamine β-Hydroxylase Inhibition: Effect On Cocaine-Induced Behavior and Neurochemistry. Doctoral dissertation, Emory University, Atlanta, GA.
Preliminary findings from these experiments were previously presented as follows: Cooper DA, Kimmel HK, and Howell LL (2012) Effects of dopamine beta-hydroxylase (DBH) inhibition on cocaine seeking behavior in squirrel monkeys. Society for Neuroscience Meeting; 2012 October 13–17; New Orleans, LA.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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