Clonidine and related drugs not only interact with alpha 2-adrenoceptors but also recognise non-adrenoceptor sites in the brain. The involvement of these imidazoline-preferring receptors in the regulation of the activity of locus coeruleus noradrenergic neurones (NA-LC) was investigated after inactivation of alpha 2-adrenoceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). In EEDQ-pretreated rats (6 mg/kg, i.p., 6 h), the characteristic inhibitory effect of low doses of clonidine on these neurones was abolished and a paradoxical, dose-dependent increase in firing rate was observed at higher doses (640-5120 micrograms/kg, i.v.) (ED50 = 702 micrograms/kg, Emax = 83%, n = 14). Guanfacine (0.3-20 mg/kg) did not modify neuronal activity but antagonised the stimulatory effect of clonidine. Cirazoline (80-640 micrograms/kg) and rilmenidine (0.3-10 mg/kg) also stimulated neuronal activity (ED50 = 192 micrograms/kg, Emax = 102%, n = 5; ED50 = 1563 micrograms/kg, Emax = 70%, n = 1-5, respectively) by an alpha 2-adrenoceptor-independent mechanism. The results suggest that these drugs can modulate the activity of locus coeruleus noradrenergic neurones through the activation of I1-imidazoline-preferring receptors.