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The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior.
- Source :
-
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2013 May; Vol. 38 (6), pp. 1032-8. Date of Electronic Publication: 2013 Jan 03. - Publication Year :
- 2013
-
Abstract
- Although norepinephrine (NE) does not typically modulate cocaine self-administration under traditional schedules of reinforcement, it is required for different inducers of the reinstatement of cocaine-seeking behavior via activation of multiple adrenergic receptor subtypes. We predicted that blockade of NE synthesis would attenuate all known modalities of reinstatement and showed previously that the selective dopamine β-hydroxylase inhibitor, nepicastat, had no effect on either maintenance of operant cocaine self-administration maintained on a fixed-ratio 1 schedule or reinstatement of food seeking but did abolish cocaine-primed reinstatement. In the present series of studies, we first evaluated the dose-dependent effect of nepicastat (5, 50, or 100 mg/kg) on novelty-induced locomotor activity and found that it blunted exploration only at the highest dose. Next, we assessed the ability of nepicastat (50 mg/kg) to reduce breakpoint responding for cocaine on a progressive ratio schedule and reinstatement induced by drug-associated cues and stress. We found that nepicastat significantly lowered the breakpoint for cocaine, but not for regular chow or sucrose, and attenuated cue-, footshock-, and yohimbine-induced reinstatement. Combined, these results indicate that nepicastat can reduce the reinforcing properties of cocaine under a stringent schedule and can attenuate relapse-like behavior produced by cocaine, formerly cocaine-paired cues, and physiological and pharmacological stressors. Thus, nepicastat is one of those rare compounds that can reduce reinforced cocaine seeking as well as all three reinstatement modalities, while sparing exploratory behavior and natural reward seeking, making it a promising pharmacotherapy for cocaine addiction.
- Subjects :
- Animals
Conditioning, Operant drug effects
Conditioning, Operant physiology
Dopamine beta-Hydroxylase metabolism
Imidazoles pharmacology
Male
Motor Activity drug effects
Motor Activity physiology
Rats
Rats, Long-Evans
Rats, Sprague-Dawley
Thiones pharmacology
Cocaine administration & dosage
Cocaine-Related Disorders drug therapy
Cocaine-Related Disorders enzymology
Dopamine beta-Hydroxylase antagonists & inhibitors
Imidazoles therapeutic use
Thiones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1740-634X
- Volume :
- 38
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23303068
- Full Text :
- https://doi.org/10.1038/npp.2012.267