Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142
| Autor: | Jose M. Eltit, Subramaniam Ananthan, S. Stevens Negus, Megan J. Moerke, Matthew L. Banks, Amy R. Johnson, Tyler W.E. Steele, Surendra K. Saini, Kelen Freitas |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Microdialysis Serotonin Dopamine Allosteric regulation Nucleus accumbens Pharmacology Ligands Nucleus Accumbens Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Neurochemical Neuropharmacology Cocaine Dopamine Uptake Inhibitors In vivo parasitic diseases medicine Animals Dopamine transporter Dopamine Plasma Membrane Transport Proteins biology Chemistry Rats 030104 developmental biology biology.protein Molecular Medicine 030217 neurology & neurosurgery medicine.drug |
| Popis: | Drugs that inhibit the dopamine (DA) transporter (DAT) include both therapeutic agents and abused drugs. Recent studies identified a novel series of putative allosteric DAT inhibitors, but the in vivo effects of these compounds are unknown. This study examined the abuse-related behavioral and neurochemical effects produced in rats by SRI-31142 [2-(7-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine], one compound from this series. In behavioral studies, intracranial self-stimulation (ICSS) was used to compare the effects produced by SRI-31142, the abused and nonselective DAT inhibitor cocaine, and the selective DAT inhibitor GBR-12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine]. In neurochemical studies, in vivo microdialysis was used to compare the effects of SRI-31142 and cocaine on levels of DA and serotonin in nucleus accumbens (NAc). The effects of SRI-31142 in combination with cocaine were also examined in both procedures. In contrast to cocaine and GBR-12935, SRI-31142 failed to produce abuse-related increases in ICSS or NAc DA; instead, SRI-31142 only decreased ICSS and NAc DA at a dose that was also sufficient to block cocaine-induced increases in ICSS and NAc DA. Pharmacokinetic studies suggested low but adequate brain penetration of SRI-31142, in vitro binding studies failed to identify likely non-DAT targets, and in vitro functional assays failed to confirm DA uptake inhibition in an assay of DAT-mediated fluorescent signals in live cells. These results indicate that SRI-31142 does not produce cocaine-like abuse-related effects in rats. SRI-31142 may have utility to block cocaine effects and may warrant further study as a candidate pharmacotherapy; however, the role of DAT in mediating these effects is unclear, and side effects may be a limiting factor. |
| Databáze: | OpenAIRE |
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