Noradrenergic involvement in the discriminative stimulus (DS) effects of cocaine was investigated in squirrel monkeys by using a two-lever drug discrimination procedure in which responding was maintained by a fixed-ratio schedule of stimulus-shock termination. Monkeys initially were trained to discriminate a relatively high dose of cocaine (1.0 mg/kg i.m.) from saline and subsequently were retrained to discriminate a 3.3- to 5.6-fold lower dose of cocaine (0.30 or 0.18 mg/kg i.m.). The selective norepinephrine[fnc] uptake inhibitors talsupram, tomoxetine, nisoxetine and desipramine substituted for cocaine in the majority of subjects under the low-dose training condition, whereas the selective dopamine uptake inhibitor GBR 12909 [1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl) piperazine] substituted for cocaine under both training conditions and the selective serotonin uptake inhibitor citalopram failed to substitute for cocaine under either condition. Representative alpha-1 [St 587 (2-(2-chloro-5-trifluoromethyl-phenylimino)imidazolidine] and SDZ NVI 085 [(-)-(4aR, 10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4- methyl-4-methyl-9-(methylthio)-2H-naphth[2,3-b]-1,4-oxazine)], alpha-2 (clonidine and UK 14,304 (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine]) and beta (clenbuterol) adrenoceptor agonists did not consistently substitute for cocaine under either condition in which they were studied. Pretreatment with the alpha-1 adrenoceptor blocker prazosin antagonized the DS effects of cocaine under both training conditions as well as the cocaine-like effects of talsupram and tomoxetine, but not GBR 12909, under the low-dose training condition. Pretreatment with the alpha-2 blocker efaroxan, the nonselective alpha blocker phentolamine and the beta blocker propranolol failed to alter the DS effects of cocaine consistently under either condition in which they were studied. Pretreatment with talsupram, at doses that did not substitute for cocaine when administered alone, enhanced the cocaine-like effects of GBR 12909 under both training conditions. The results support a role for norepinephrine uptake and alpha-1 adrenoceptor mechanisms in the DS effects of cocaine, possibly reflecting a facilitory noradrenergic influence on mesocorticolimbic dopamine activity.