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Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.
- Source :
-
The European journal of neuroscience [Eur J Neurosci] 2024 May; Vol. 59 (10), pp. 2436-2449. Date of Electronic Publication: 2024 Mar 05. - Publication Year :
- 2024
-
Abstract
- Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.<br /> (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)
- Subjects :
- Animals
Male
Rats
Benzhydryl Compounds pharmacology
Microdialysis methods
Modafinil pharmacology
Piperidines pharmacology
Rats, Sprague-Dawley
Cocaine pharmacology
Dopamine metabolism
Dopamine Plasma Membrane Transport Proteins antagonists & inhibitors
Dopamine Uptake Inhibitors pharmacology
Nucleus Accumbens drug effects
Nucleus Accumbens metabolism
Receptors, sigma antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1460-9568
- Volume :
- 59
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The European journal of neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 38444104
- Full Text :
- https://doi.org/10.1111/ejn.16293