Dopamine β-Hydroxylase Inhibitors Enhance the Discriminative Stimulus Effects of Cocaine in Rats

Abstract

Inhibitors of dopamine b-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic cells, have shown promise for the treatment of cocaine abuse disorders. However, the mechanisms underlying the beneficial effects of these compounds have not been fully elucidated. We used the drug discrimination paradigm to determine the impact of DBH inhibitors on the interoceptive stimulus properties of cocaine. Sprague-Dawley rats were trained to discriminate cocaine (5.6 mg/kg) from saline using a multicomponent, food-reinforced discrimination procedure. On test days, subjects were pretreated with the nonselective DBH inhibitor disulfiram (0-100.0 mg/kg i.p.) or the selective DBH inhibitor nepicastat (0-56.0 mg/kg i.p.) 2 hours prior to a test session either alone or in combination with cumulatively administered cocaine (0-5.6 mg/kg i.p.). Neither disulfiram nor nepicastat substituted for the cocaine stimulus when tested up to doses that nonspecifically reduced responding. However, in combination studies, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose-response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor, reboxetine (0.3-5.6 mg/kg i.p.). These results indicate that pharmacological inhibition of DBH does not produce cocaine-like interoceptive stimulus effects alone, but functionally enhances the interoceptive stimulus effects of cocaine, possibly due to facilitated increases in DA released from noradrenergic terminals. These findings suggest that DBH inhibitors have low abuse liability and provide support to clinical reports that some subjective effects produced by cocaine, particularly aversive effects, are enhanced after DBH inhibition.

The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice

“…Rats and mice were trained to discriminate 1.25 mg/kg clozapine from its vehicle using a two-lever, food-reinforced drug discrimination procedure based on methods published previously 15 , 21 – 23 and described in detail in the Supplementary Materials and Methods. Briefly, each animal was assigned one lever as the “clozapine-appropriate lever”, and the other lever as the “vehicle-appropriate lever.” When the subject was injected with clozapine, only responses on the “clozapine-appropriate lever” were reinforced, whereas only responses on the “vehicle-appropriate lever” were reinforced following injection of vehicle.…”

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder

“…Furthermore, genetic reduction of DBH enhances cocaine-induced paranoia in humans (Cubells et al, 2000; Kalayasiri et al, 2007) and transforms a cocaine conditioned place preference into a place aversion in mice (Schank et al, 2006). This is important since a preferential increase in the aversive effects of cocaine could explain why a medication that enhances cocaine responses (e.g., Haile et al, 2003; Hameedi et al, 1995; Manvich et al, 2013;McCance-Katz et al, 1998a, 1998b) reduces cocaine use. The reason for a lack of effect nepicastat on cocaine-induced negative subjective effects in the current study may be a function of the small sample size, but also the relatively low doses of cocaine evaluated.…”

“…In a drug discrimination study, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose–response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor reboxetine. These results suggest that pharmacological inhibition of DβH functionally enhances the interoceptive stimulus effects of cocaine possibly due to facilitated increases in DA released from noradrenergic terminals (Manvich et al, 2013). …”

Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys

“…For example, NE reuptake inhibitors can substitute for and/or enhance the discriminative stimulus effects of low doses of cocaine in rats and monkeys (Kleven and Koek 1997; Spealman 1995) and partially reinstate extinguished cocaine self-administration in monkeys (Platt et al 2007). Dopamine β-hydroxylase (DβH) inhibition, which decreases neuronal NE and increases extracellular dopamine levels by blocking the conversion of DA to NE, also has been reported to enhance the discriminative-stimulus effects of cocaine in rats and to reinstate extinguished cocaine self-administration in monkeys (Manvich et al 2013; Schroeder et al 2013) but not rats (Cooper et al 2014). Although further work is needed to clarify species-related differences in the neurochemical and behavioral effects of DβH inhibition, it seems evident that modulating NE neuronal activity can directly influence the behavioral effects of cocaine (see also Kohut et al 2013).…”