NORADRENERGIC INVOLVEMENT IN THE DISCRIMINATIVE STIMULUS EFFECTS OF COCAINE IN SQUIRREL-MONKEYS

Noradrenergic involvement in the discriminative stimulus (DS) effects of cocaine was investigated in squirrel monkeys by using a two-lever d rug discrimination procedure in which responding was maintained by a f ixed-ratio schedule of stimulus-shock termination. Monkeys initially w ere 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 o f subjects under the low-dose training condition, whereas the selectiv e dopamine uptake inhibitor GBR 12909 [1 henyl)methoxy]ethyl)-4-(3-phe nylpropyl)piperazine] substituted for cocaine under both training cond itions and the selective serotonin uptake inhibitor citalopram failed to substitute for cocaine under either condition. Representative alpha -1 [St 587 hloro-5-trifluoromethyl-phenylimino)imidazolidine) and SDZ NVI 085 thyl-9-(methylthio)-2H-naphth[2,3-b]-1,(oxazine)], alpha-2 (cl onidine and UK 14,304 (4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine )) and beta (clenbuterol) adrenoceptor agonists did not consistently s ubstitute for cocaine under either condition in which they were studie d. Pretreatment with the alpha-1 adrenoceptor blocker prazosin antagon ized the DS effects of cocaine under both training conditions as well as the cocaine-like effects of talsupram and tomoxetine, but not GBR 1 2909, under the low-dose training condition. Pretreatment with the alp ha-2 blocker efaroxan, the nonselective alpha blocker phentolamine and the beta blocker propranolol failed to alter the DS effects of cocain e consistently under either condition in which they were studied. Pret reatment with talsupram, at doses that did not substitute for cocaine when administered alone, enhanced the cocaine-like effects of GBR 1290 9 under both training conditions. The results support a role for norep inephrine uptake and alpha-1 adrenoceptor mechanisms in the DS effects of cocaine, possibly reflecting a facilitory noradrenergic influence on mesocorticolimbic dopamine activity.