Modulation of catecholamine release by α2-adrenoceptors and I 1-imidazoline receptors in rat brain

Abstract

The physiological and pharmacological effects of imidazoli(di) ne derivatives, such as Clonidine, have been related not only to the interaction with α 2-adrenoceptors but also to their activity on non-adrenoceptor sites termed imidazoline receptors. The modulation of catecholamine release by imidazoline drugs was studied by monitoring extracellular levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) with microdialysis in cingulate cortex of rats, with or without irreversible α 2-adrenoceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HVA levels were ≅100 nM. NE and DA levels were increased when the uptake blocker desipramine (1 μM) 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 c 2-adrenoceptor antagonist RX821002. After α 2-adrenoceptor irreversible blockade with the alkylating agent 7V-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), [ 3H] clonidine binding to α 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, DOPAC 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 (Iimidazoline receptor 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 manner to clonidine (11–82%). Idazoxan also abolished these responses to cirazoline or moxonidine. In contrast to systemic administration, local perfusion of clonidine (10–100 μM) through the microdialysis probe under α 2-adrenoceptor alkylating conditions, did not modify extracellular levels of NE and DA suggesting an indirect mechanism. The results demonstrate that clonidine and related imidazoli(di) ne drugs are able not only to inhibit NE release in rat cerebral cortex involving an α 2-adrenoceptor mechanism, but also to induce a paradoxical NE release through an indirect extracortical mechanism. The findings evidence that the indirect modulation of NE levels by imidazoline drugs is mainly due to a functional activity on I 1-imidazoline receptors.