PT  - JOURNAL ARTICLE
AU  - Platt, Donna M.
AU  - Rowlett, James K.
AU  - Spealman, Roger D.
TI  - Noradrenergic Mechanisms in Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys
AID  - 10.1124/jpet.107.121806
DP  - 2007 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 894--902
VI  - 322
IP  - 2
4099  - http://jpet.aspetjournals.org/content/322/2/894.short
4100  - http://jpet.aspetjournals.org/content/322/2/894.full
SO  - J Pharmacol Exp Ther2007 Aug 01; 322
AB  - Norepinephrine (NE) uptake and NE receptor mechanisms play important modulating roles in the discriminative stimulus and stimulant effects of cocaine. The present study investigated the role of NE mechanisms in cocaine priming-induced reinstatement of extinguished drug seeking. Squirrel monkeys (Saimiri sciureus) were trained to stability under a second-order fixed interval, fixed ratio schedule of drug self-administration in which operant responding was maintained jointly by i.v. cocaine injections and presentations of a cocaine-paired stimulus. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In test sessions during which the cocaine-paired stimulus was reintroduced but only vehicle was available for self-administration, priming with cocaine, the dopamine transport inhibitor 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), and the NE transport inhibitors nisoxetine and talsupram induced dose-dependent reinstatement of drug seeking. The maximum effect of the NE transport inhibitors was less than half that of cocaine. Both nisoxetine and talsupram augmented the priming effects of a low but not a high dose of cocaine. The priming effects of nisoxetine were blocked by the α1-adrenoceptor antagonist prazosin, the α2-adrenoceptor agonist clonidine, and the β-adrenoceptor antagonist propranolol, but not by the dopamine receptor antagonist flupenthixol. The priming effects of cocaine were antagonized by clonidine and flupenthixol. Neither nisoxetine nor cocaine increased physiological (salivary cortisol) or behavioral (self-directed behaviors) markers of stress. These findings suggest that NE transporter inhibition and α2-adrenoceptor mechanisms play a significant role in cocaine-induced reinstatement of drug seeking that is not secondary to activation of brain stress pathways. The American Society for Pharmacology and Experimental Therapeutics