Clonidine modulates BAY K 8644-induced rat behavior and neurotransmitter changes in the brain

BAY K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4[2-trifluoromethyl-phe nyl]-pyridine-5-carboxylate), an activator of dihydropyridine-sensitive Ca2 + channels, injected in rats [2 mg/kg intraperitoneally (i.p.)], induces be havioral changes including ataxia, increased sensitivity to auditory stimul ation, stiff tail, arched back, limb tonus and clonus, and rolling over. Ne urochemical changes in the brain 45 min after application of 2 mg/kg were c haracterized by a significant decrease of noradrenaline in the amygdala (-2 7.8%, P < 0.02) and piriform cortex (-16.3%, P < 0.02). No significant chan ges of catecholamines were found in the hippocampal subregions CA1, CA3 and dentate gyrus or in the septum as compared to controls. The dopamine metab olites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the amygdala were elevated by 60% (P < 0.02) and 66.7% (P < 0.02), resp ectively. In the septum, a 52.6% (P < 0.02) increase of HVA was observed. A nalysis of amino acids revealed a marked increase of gamma-aminobutyric aci d (GABA) content (+50.4%, P < 0.001) in the septum. Pretreatment of the rat s with the alpha(2)-adrenoceptor agonist, clonidine (0.1 mg/kg i.p.), 30 mi n before BAY K 8644 (2 mg/kg i.p.) injection completely abolished the behav ioral and neurochemical changes. The data suggest that the Ca2+-dependent n eurotransmitter release provoked by BAY K 8644 can be modulated by stimulat ion of presynaptic alpha(2)-adrenoceptors, The effect of clonidine on the G ABAergic system may represent an important mechanism involved in the preven tion of BAY K 8644-induced behavior. (C) 2000 Elsevier Science B.V. All rig hts reserved.