A single amphetamine infusion reverses deficits in dopamine nerve-terminal function caused by a history of cocaine self-administration (2015)

Neuropsychopharmacology. 2015 Feb 18. doi: 10.1038/npp.2015.45.

Ferris MJ1, Calipari ES1, Rose JH1, Siciliano CA1, Sun H1, Chen R1, Jones SR1.


There are approximately 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA approved pharmacotherapies. Amphetamine-based dopamine releasing drugs have shown efficacy for reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels.

Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine naïve animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day x 5 days). Dopamine kinetics were measured 1 and 24 hours after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine naïve animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals.

Here, for the first time, we demonstrate pharmacologically-induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid time-scale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.