Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Publisher: Wiley-Blackwell Country of Publication: France NLM ID: 8918110 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-9568 (Electronic) Linking ISSN: 0953816X NLM ISO Abbreviation: Eur J Neurosci Subsets: MEDLINE

Publication: : Oxford : Wiley-Blackwell
Original Publication: Oxford, UK : Published on behalf of the European Neuroscience Association by Oxford University Press, c1989-

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; Animals ; Male ; Rats ; Benzhydryl Compounds/pharmacology ; Microdialysis/methods ; Modafinil/pharmacology ; Piperidines/pharmacology ; Rats, Sprague-Dawley

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.
(Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

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R01 DA058018 United States DA NIDA NIH HHS; ZIA DA000611 United States ImNIH Intramural NIH HHS; R01DA058018 (TH) U.S. Public Health Service; Z1A DA000611 (GT) United States DA NIDA NIH HHS

Keywords: addiction; dopamine (DA); dopamine transporter (DAT); rimcazole; sigma receptor; substance use disorder

0 (Benzhydryl Compounds)
I5Y540LHVR (Cocaine)
VTD58H1Z2X (Dopamine)
0 (Dopamine Plasma Membrane Transport Proteins)
0 (Dopamine Uptake Inhibitors)
R3UK8X3U3D (Modafinil)
0 (Piperidines)
0 (Receptors, sigma)

Date Created: 20240306 Date Completed: 20240521 Latest Revision: 20240726

20240726

PMC11108740

10.1111/ejn.16293

38444104