Effects of imidazoline receptor ligands on monoamine synthesis in the rat brain in vivo

This study was designed to assess the effects of imidazoline drugs on putat ive presynaptic imidazoline receptors modulating brain monoamine synthesis in vivo. The accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydrox ytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of the rate of tyrosine and tryptophan hydroxylation in various brain regions of naive rats and after irreversible alpha(2)-adrenoceptor inactivation wi th EEDQ (1.6 mg/kg, i.p., 6 h). Clonidine (1-3 mg/kg), moxonidine (1-10 mg/kg) and rilmenidine (10 mg/kg) ( mixed I-1/alpha(2) agonists) decreased dopa and 5-HTP synthesis in the cere bral cortex (14%-81%), hippocampus (27%-84%) and/or striatum (29%-56%), but these inhibitory effects were abolished in N-ethoxycarbonyl-2-ethoxy- 1,2- dihydroquinoline (EEDQ)treated rats. Similarly, the stimulatory effect of e faroxan (mixed I-1/alpha(2) antagonist; 10 mg/kg) on dopa synthesis in the cortex (77%) and hippocampus (57%) was abolished by EEDQ. The selective I-1 -ligand 2-endo-amino-3-exoisopropylbicyclo-heptane (AGN-192403; 5-10 mg/kg) did not modify dopa or 5-HTP synthesis in any brain region in naive or EED Q-treated rats. Idazoxan (mixed I-2/alpha(2) antagonist; 20 mg/kg) increase d dopa synthesis in the cortex (111%) and hippocampus (87%), but the stimul atory effects were abolished by EEDQ. Moreover, idazoxan and efaroxan decre ased 5-HTP synthesis in the cortex (12%-34%) and hippocampus (30%-34%) in a manner sensitive to blockade by the 5-HT1A receptor antagonist WAY 100135. The selective I-2-ligands 2-(2-benzofuranyl)-2-imidazoline (2-BFI; 20 mg/k g) and 2-styryl-2-imidazoline (LSL 61122; 10 mg/kg) did not alter the synth esis of dopa or 5-HTP in the cortex or hippocampus. In striatum, 2-BFI (1-2 0 mg/kg) dose-dependently decreased dopa synthesis (ED50: 5.9 mg/kg), reduc ed dopamine levels (6%-36%) and increased those of its metabolites DOPAC (1 5%-95%) and HVA (24%-74%). The inhibitory effect of 2-BFI on dopa/dopamine synthesis in striatum remained unchanged after alkylation of imidazoline re ceptors with isothiocyanatobenzyl imidazoline (IBI; 60 mg/kg, 6 h) or block ade of these receptors with 2-(2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidaz ole (KU-14R; 7-20 mg/kg). Therefore, most imidazoline drugs modulated the synthesis of brain monoamin es through interaction with alpha(2)-adrenoceptors or 5-HT1A receptors. The results do not provide functional evidence for the existence of presynapti c imidazoline receptors regulating the synthesis of monoamines in the rat b rain.