Abstract The effects of chronic cocaine (50 mg/kg per day for two weeks) administration on two α 2-adrenoceptor-mediated responses were studied in rats. Chronic administration of cocaine significantly (compared to sham controls) attenuated the α 2-adrenoceptor-mediared inhibition of noradrenergic locus coeruleus (LC) neurons as well as α 2-adrenoceptor elicited mydriasis. Noradrenergic LC neurons from the cocaine treated and sham groups differed significantly in their responsiveness to the inhibitory effects of clonidine (ED 50 values μg/kg: sham 7.35 ± 1.13 and cocaine-treated 17.17 ± 4.40, P < 0.05). The ED 50 values for the mydriatic response were sham 5.71 ± 0.49 and cocaine-treated 16.42 ± 0.69 μg/kg, respectively, P < 0.001. No differences in cardiovascular responses to systematically injected clonidine between the chronic cocaine- and sham-treated groups were observed. Chronic cocaine treatment attenuates the two α 2-adrenoceptor-mediated responses most likely via an interaction with central catecholaminergic neurotransmission.