Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition

Abstract

The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DAT occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximately 2% of maximal DAT blockade. Overall our data indicate that abused doses of cocaine produce a relatively modest degree of DA uptake inhibition, and suggest that the relationship between DAT occupancy and functional blockade of DAT is more complex than originally posited.

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

“…Voltammetry experiments were carried out as previously described (Brodnik and España, 2015; Brodnik et al, 2017b), and performed on the day after behavioral segregation. Rats were anesthetized for 3 min with 2.5% isoflurane before decapitation.…”

Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

“…DA release was evoked every 5 min using a single electrical pulse (400 μA, 4 ms, monophasic). After recording 3 stable baseline responses (3 stimulations with <10% variation), cocaine was cumulatively applied to the tissue (0.3–30 μM) as previously described (Brodnik and España 2015; Brodnik et al 2016). Stimulated DA release and DA uptake measures ( V max and K m ) were determined as described for the anesthetized FSCV experiments.…”

Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

“…It is also possible that there is a non-linear relationship between the ability of an i.v. infusion of cocaine to occupy dopamine transporters and its ability to block the reuptake of dopamine, and thus increase dopamine overflow (Brodnik et al, 2017). Brain cocaine and dopamine concentrations were tightly coupled across time, at all infusion rates.…”

“…However, i.v. cocaine-induced inhibition of dopamine reuptake can increase with repeated exposure (Brodnik et al, 2017). This being said, studying brain cocaine and dopamine pharmacokinetics after a single cocaine exposure is important.…”