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Dopamine Transporter Allosteric Modulator SRI‐32743 Alters The Effects Of Cocaine On Dopamine Neurotransmission In Adult Mice
Author(s) -
Hager Audrey,
Daws Lynette,
Ananthan Sam,
Beckstead Michael
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.680.9
Subject(s) - dopamine transporter , dopamine , allosteric regulation , pharmacology , allosteric modulator , dopamine plasma membrane transport proteins , neuroscience , neurotransmission , dopamine uptake inhibitors , transporter , chemistry , medicine , receptor , biology , dopaminergic , biochemistry , gene
Cocaine is a highly abused psychostimulant that inhibits dopamine (DA) uptake by blockade of the dopamine transporter (DAT). Despite knowledge and understanding of cocaine's main mechanism of action, there are no FDA‐approved pharmacotherapies for treatment of cocaine‐use disorder. Recently novel allosteric modulators of DAT have been identified that have nanomolar potency to partially inhibit DAT uptake, which may be useful as probes of biogenic amine transporter function and may have therapeutic potential. Here we used both patch clamp electrophysiology in male and female mouse brain slices and high speed chronoamperometry in anesthetized mice to examine the effects of two novel ligands (SRI‐32743 and SRI‐35282) on dopamine neurotransmission and their ability to alter the effects of cocaine. Pretreatment with SRI‐32743 blunted the cellular effects of cocaine by altering DAT function in a concentration‐dependent manner. In addition, SRI‐32743 decreased D2 receptor‐mediated currents of midbrain DA neurons. In contrast, the ligand SRI‐35282 demonstrated less ability to reduce the effects of cocaine. These preliminary results are promising and further exploration of the effects of these allosteric DAT modulators on behavior will be important for determining their potential as pharmacotherapies for the treatment of cocaine‐use disorder. Support or Funding Information R01DA32701, T32DA031115, F32DA042569, R01MH106978 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .