MODULATION OF CATECHOLAMINE RELEASE BY ALPHA(2)-ADRENOCEPTORS AND I-1-IMIDAZOLINE RECEPTORS IN RAT-BRAIN

The physiological and pharmacological effects of imidazoli(di)ne deriv atives, such as clonidine, have been related not only to the interacti on with alpha(2)-adrenoceptors but also to their activity on non-adren oceptor sites termed imidazoline receptors, The modulation of catechol amine release by imidazoline drugs was studied by monitoring extracell ular levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) with microdialysis in cingulate cortex of rats, with or without irreversible alpha(2)-adreno ceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HVA levels were congruent to 100 nM. NE and DA levels were increa sed when the uptake blocker desipramine (1 mu M) or KCl (100 mM) were added to the perfusion medium. Clonidine induced a dose-dependent (0.3 -1.2 mg/kg i.p.) decrease in NE (max 61%) and DA (max 40%) levels that was reversed by the alpha(2)-adrenoceptor antagonist RX821002. After alpha(2)-adrenoceptor irreversible blockade with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), [H-3]clonidine binding to alpha(2)-adrenoceptors was reduced by 94 +/- 1%. Under such conditions, clonidine elicited a paradoxical dose-dependent (0.6-2.4 mg/kg i.p.) increase of NE (max 56%) without modifications in DA, DOPA C and HVA levels. The stimulatory effect of clonidine was prevented by the imidazoline receptor antagonist idazoxan (10 mg/kg i.p.) but not by RX821002 (5 mg/kg i.p.). In rats pretreated with EEDQ, cirazoline ( I-1/I-2-imidazoline receptor agonist), moxonidine (I-1-imidazoline rec eptor agonist), but not guanabenz (I-2-imidazoline receptor agonist) ( 1.2-2.4 mg/kg i.p,) elicited an increase of NE levels in a similar man ner to clonidine (11-82%). Idazoxan also abolished these responses to cirazoline or moxonidine. In contrast to systemic administration, loca l perfusion of clonidine (10-100 mu M) through the microdialysis probe under alpha(2)-adrenoceptor alkylating conditions, did not modify ext racellular levels of NE and DA suggesting an indirect mechanism. The r esults demonstrate that clonidine and related imidazoli(di)ne drugs ar e able not only to inhibit NE release in rat cerebral cortex involving an alpha(2)-adrenoceptor mechanism, but also to induce a paradoxical NE release through an indirect extracortical mechanism. The findings e vidence that the indirect modulation of NE levels by imidazoline drugs is mainly due to a functional activity on I-1-imidazoline receptors.