Meana J J, Herrera-Marschitz M, Goiny M, Silveira R
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Brain Res. 1997 Jan 9;744(2):216-26. doi: 10.1016/s0006-8993(96)01080-3.
The physiological and pharmacological effects of imidazoli(di)ne derivatives, such as clonidine, have been related not only to the interaction with alpha 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 alpha 2-adrenoceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HIVA levels were approximately equal to 100 nM. NE and DA levels were increased when the uptake blocker desipramine (1 microM) 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), [3H]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, 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 (I1/I2-imidazoline receptor agonist), moxonidine (I1-imidazoline receptor agonist), but not guanabenz (I2-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 microM) through the microdialysis probe under alpha 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 alpha 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 I1-imidazoline receptors.
咪唑啉（二）酮衍生物，如可乐定，其生理和药理作用不仅与α2-肾上腺素能受体的相互作用有关，还与其对称为咪唑啉受体的非肾上腺素能受体位点的活性有关。通过在大鼠扣带回皮质中用微透析监测去甲肾上腺素（NE）、多巴胺（DA）、3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的细胞外水平，研究了咪唑啉药物对儿茶酚胺释放的调节作用，实验分为有或没有不可逆α2-肾上腺素能受体阻断的情况。NE和DA水平在1 nM范围内，而DOPAC和HIVA水平约等于100 nM。当将摄取阻断剂地昔帕明（1 μM）或氯化钾（100 mM）添加到灌注培养基中时，NE和DA水平升高。可乐定以剂量依赖性（0.3 - 1.2 mg/kg腹腔注射）降低NE（最大61%）和DA（最大40%）水平，这一作用可被α2-肾上腺素能受体拮抗剂RX821002逆转。在用烷基化剂N-乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ）进行α2-肾上腺素能受体不可逆阻断后，[3H]可乐定与α2-肾上腺素能受体的结合减少了94±1%。在这种情况下，可乐定引起了剂量依赖性（0.6 - 2.4 mg/kg腹腔注射）的NE升高（最大56%），而DA、DOPAC和HVA水平没有变化。可乐定的刺激作用可被咪唑啉受体拮抗剂伊达唑胺（10 mg/kg腹腔注射）阻断，但不能被RX821002（5 mg/kg腹腔注射）阻断。在预先用EEDQ处理的大鼠中，西拉唑啉（I1/I2-咪唑啉受体激动剂）、莫索尼定（I1-咪唑啉受体激动剂），但不是胍那苄（I2-咪唑啉受体激动剂）（1.2 - 2.4 mg/kg腹腔注射）以与可乐定相似的方式（11 - 82%）引起NE水平升高。伊达唑胺也消除了对西拉唑啉或莫索尼定的这些反应。与全身给药相反，在α2-肾上腺素能受体烷基化条件下通过微透析探针局部灌注可乐定（10 - 100 μM），并未改变NE和DA的细胞外水平，提示存在间接机制。结果表明，可乐定及相关的咪唑啉（二）酮药物不仅能够通过α2-肾上腺素能受体机制抑制大鼠大脑皮质中的NE释放，还能够通过间接的皮质外机制诱导反常的NE释放。这些发现证明，咪唑啉药物对NE水平的间接调节主要是由于对I1-咪唑啉受体的功能活性。
