Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine
Article first published online: 20 OCT 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 128, Issue 2, pages 224–232, January 2014
How to Cite
J. Neurochem. (2014) 128, 224–232.
- Issue published online: 6 JAN 2014
- Article first published online: 20 OCT 2013
- Accepted manuscript online: 18 SEP 2013 11:47PM EST
- Manuscript Accepted: 9 SEP 2013
- Manuscript Revised: 5 SEP 2013
- Manuscript Received: 1 AUG 2013
- NIH. Grant Numbers: R01 DA021325, R01 DA030161, P50 DA006634, K99 DA031791, T32 DA007246, F31 DA031533
Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self-administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Furthermore, we report reductions in cocaine-induced uptake inhibition and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (Ki) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. In addition, cocaine-induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here, we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts.
We demonstrate tolerance to the neurochemical and behavioral effects of cocaine following extended-access cocaine self-administration. With respect to neurochemistry, we show reduced cocaine-induced dopamine uptake inhibition, an increased dose of cocaine required for 50% inhibition of the dopamine transporter, and reduced cocaine-induced dopamine overflow. In addition, we show escalation of cocaine intake and reduced cocaine-induced locomotor activity following cocaine self-administration.