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Low and high affinity dopamine transporter inhibitors block dopamine uptake within 5 sec of intravenous injection
Journal article   Open access   Peer reviewed

Low and high affinity dopamine transporter inhibitors block dopamine uptake within 5 sec of intravenous injection

Jordan T Yorgason, Sara R Jones and Rodrigo A España
Neuroscience, v 182
19 May 2011
DOI: https://doi.org/10.1016/j.neuroscience.2011.03.017
PMID: 21402130
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1016/j.neuroscience.2011.03.017View
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Abstract

methylphenidate voltammetry nucleus accumbens nomifensine rat cocaine
Extensive evidence suggests that the reinforcing effects of cocaine involve inhibition of dopamine transporters (DAT) and subsequent increases in dopamine (DA) levels in the striatum. We have previously reported that cocaine inhibits the DAT within 4–5 sec of intravenous injection, matching the temporal profile of the behavioral and subjective effects of cocaine. Intravenous injection of GBR-12909, a high affinity, long-acting DAT inhibitor, also inhibits DA uptake within 5 sec. Given that high affinity, long-acting drugs are considered to have relatively low abuse potential, we found it intriguing that GBR-12909 had an onset profile similar to that of cocaine. To further explore the onset kinetics of both low and high affinity DAT inhibitors, we examined the effects of intravenous cocaine (1.5 mg/kg), methylphenidate (1.5 mg/kg), nomifensine (1.5 mg/kg), GBR-12909 (1.5 mg/kg), PTT (0.5 mg/kg), and WF23 (0.5 mg/kg) on electrically-evoked DA release and uptake in the nucleus accumbens core. Results indicate that all of the DAT inhibitors significantly inhibited DA uptake within 5 sec of injection. However, the timing of peak uptake inhibition varied greatly between the low and high affinity uptake inhibitors. Uptake inhibition following cocaine, methylphenidate, and nomifensine peaked 30 sec following injection. In contrast, peak effects for GBR-12909, PTT, and WF23 occurred between 20 and 60 min following injection. These observations suggest that the initial onset for intravenous DAT inhibitors is extremely rapid and does not appear to be dictated by a drug’s affinity.

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