The dopamine beta‐hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant‐induced dopamine release in the prefrontal cortex

Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Bini, Valentina; Gessa, Gian Luigi

doi:10.1111/adb.12026

Cited by 21 publications

(33 citation statements)

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“…Recent in vivo microdialysis studies in rats found that disulfiram or nepicastat alone produced robust increases in extracellular DA levels (approximately 300% above baseline) within the prefrontal cortex (PFC) (Devoto et al, 2012(Devoto et al, , 2013, a terminal region of DAergic mesocorticolimbic projections known to play a prominent role in the abuse-related effects of cocaine (Wise, 2009). In contrast, neither DBH inhibitor altered basal DA levels within the nucleus accumbens (NAc).…”

Section: Discussionmentioning

confidence: 99%

“…Because cocaine-induced increases in DA within the NAc rather than the PFC predominantly mediate the discriminative stimulus effects of cocaine (Callahan et al, 1997), it is not surprising that in the present studies, cocaine failed to generalize to either disulfiram or nepicastat. Importantly, our dose range (up to 100 mg/kg disulfiram and 56 mg/kg nepicastat) and pretreatment time (2 hours) were chosen based on our own previous work and the aforementioned microdialysis studies, which reported maximal increases in DA levels within the PFC and reductions of NE levels across multiple brain regions using these parameters (Schroeder et al, 2010;Devoto et al, 2012Devoto et al, , 2013. Thus, the experiments were optimized to detect the presence of a cocaine-like interoceptive stimulus.…”

Section: Discussionmentioning

confidence: 99%

“…Third, in rats trained to discriminate low (2.5 mg/kg) versus high (10.0 mg/kg) doses of cocaine, administration of 5.0 mg/kg produced full substitution for the high cocaine dose (Kleven and Koek, 1998). Finally, if DBH inhibition was suspected to functionally antagonize the noradrenergic component of the cocaine interoceptive stimulus via reductions of cocaine-induced increases of NE levels (Devoto et al, 2012(Devoto et al, , 2013, pretreatment with disulfiram or nepicastat would be predicted to produce a rightward shift of the cocaine dose-response function; however, the exact opposite effect was observed (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, DBH inhibition has been proposed to mediate the pharmacotherapeutic benefits of disulfiram observed in clinical cocaine-abusing populations (Weinshenker and Schroeder, 2007;Gaval-Cruz and Weinshenker, 2009). In support of this hypothesis, the effects of disulfiram on cocaineinduced neurochemical and behavioral phenotypes in rodents are mimicked by DBH knockout and/or the selective DBH inhibitor, nepicastat (Schank et al, 2008;Gaval-Cruz et al, 2008Devoto et al, 2013;Schroeder et al, 2013). However, the impact of disulfiram on the positive subjective effects of cocaine in humans has produced mixed results, with studies This work was previously presented at the following workshop: Manvich DF, DeBrouse L, and Weinshenker D (2013) Modulation of the discriminativestimulus effects of cocaine by dopamine beta-hydroxylase inhibitors in rats.…”

Section: Introductionmentioning

confidence: 98%

“…Second, we assessed whether pretreatment with disulfiram would alter the discriminative stimulus effects of cocaine. To confirm that any observed effects with disulfiram were mediated exclusively by actions on DBH, we examined the effects of nepicastat, a highly selective DBH inhibitor that acts via competitive antagonism at the active site on the DBH protein and also increases basal and cocaine-induced increases in DA overflow (Stanley et al, 1997;Kapoor et al, 2011;Devoto et al, 2013). Finally, to determine whether the modulatory effects of disulfiram and nepicastat were mediated by excess DA originating from noradrenergic neurons, we assessed their impact on the cocaine-like stimulus effects of the selective NE transporter inhibitor reboxetine.…”

Section: Introductionmentioning

confidence: 99%

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

Manvich

DePoy

2013

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Manvich

DePoy

2013

J Pharmacol Exp Ther

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Selective inhibition of dopamine‐beta‐hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

et al. 2015

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IntroductionDisulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine‐beta‐hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine‐induced increase. Concomitantly, in rats with cocaine self‐administration history, cocaine‐seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release.MethodsNoradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti‐DBH‐saporin (aDBH‐sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat–cocaine combination on extracellular DA levels and their regulation by α2‐adrenoceptors.ResultsFifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat–cocaine combination, while it was ineffective in denervated rats.ConclusionsThis research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2‐autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat‐induced DA release.

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Novel Pharmacological Agents for the Treatment of Cocaine Use Disorder

Hadizadeh

Flores

Nunes

et al. 2022

Curr Behav Neurosci Rep

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The dopamine beta‐hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant‐induced dopamine release in the prefrontal cortex

Cited by 21 publications

References 50 publications

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

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

Selective inhibition of dopamine‐beta‐hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

Novel Pharmacological Agents for the Treatment of Cocaine Use Disorder

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