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CNS‐Permeant Tamoxifen Analog Modulates The Dopamine Transporter And Reduces Amphetamine Reinforcing Effects
Author(s) -
Carpenter Colleen,
Zestos Alexander,
Altshuler Rachel,
Sorenson Roderick,
Guptaroy Bipasha,
Jutkiewicz Emily,
Kennedy Robert,
Showalter Hollis,
Gnegy Margaret
Publication year - 2017
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.31.1_supplement.986.7
Subject(s) - dopamine transporter , amphetamine , dopamine , chemistry , pharmacology , nucleus accumbens , dopamine plasma membrane transport proteins , dopamine receptor d2 , dopamine receptor d1 , tamoxifen , dopamine receptor d3 , endocrinology , medicine , biology , dopaminergic , cancer , breast cancer
Amphetamine (AMPH) is the second most widely abused drug worldwide, yet an effective therapeutic for AMPH abuse and addiction remains elusive. The reinforcing properties of amphetamine are due to its ability to increase extracellular dopamine in the nucleus accumbens. This process is facilitated by protein kinase C (PKC) activation and blocking PKC reduces AMPH activities. The selective estrogen receptor modulator tamoxifen remains the only available brain‐permeant PKC inhibitor. We have created a small library of novel tamoxifen analogs with increased selectivity for PKC inhibition and reduced affinity at the estrogen receptor. With an IC 50 of 80 nM, our lead compound ( 6c ) inhibits PKC 250 times more potently than tamoxifen and displays no binding at the estrogen receptor α. In determining the efficacy of 6c to reduce the neurochemical and behavioral effects of AMPH, we firstly investigated the ability of the compound to modulate the dopamine transporter in both cellular and rat striatal synaptosomal preparations. 6c showed negligible effects in blocking dopamine uptake or AMPH‐induced dopamine release in HEK cells stably expressing the dopamine transporter. However, 0.3–3 μM 6c dose dependently inhibits dopamine release stimulated by 10 μM AMPH in synaptosomes. 6c less potently blocks dopamine uptake and does not displace [ 3 H]WIN 35428 binding at the dopamine transporter in synaptosomes, showing that it does not bind near the active site. 6 mg/kg 6c s.c. does not affect baseline dopamine levels or locomotion but significantly reduces both dopamine release and locomotion induced by 2 mg/kg i.p. AMPH as measured with microdialysis in freely‐moving rats. 6 mg/kg s.c. 6c reduces i.v. AMPH self‐administration (0.032 mg/kg AMPH per infusion) by ~40% but does not affect food self‐administration in rats. 6c effectively reduces the actions of AMPH both in vitro and in vivo . The fact that 6c modulates the dopamine transporter in synaptosomes but not in cells overexpressing DAT, suggests its action is via a mediator versus a direct action at the transporter. This study also highlights the importance of choosing appropriate models of the dopaminergic terminal in screening compounds for AMPH abuse. Support or Funding Information NIH grant 1R01 DA11697, HHMI International Student Research Fellowship