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-phenyl]-pyridine-5-carboxylate), an activator of dihydropyridine-sensitive Ca(2+) channels, injected in rats [2 mg/kg intraperitoneally (i.p.)], induces behavioral changes including ataxia, increased sensitivity to auditory stimulation, stiff tail, arched back, limb tonus and clonus, and rolling over. Neurochemical changes in the brain 45 min after application of 2 mg/kg were characterized by a significant decrease of noradrenaline in the amygdala (-27.8%, P<0.02) and piriform cortex (-16.3%, P<0.02). No significant changes of catecholamines were found in the hippocampal subregions CA1, CA3 and dentate gyrus or in the septum as compared to controls. The dopamine metabolites, 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), respectively. In the septum, a 52.6% (P<0.02) increase of HVA was observed. Analysis of amino acids revealed a marked increase of gamma-aminobutyric acid (GABA) content (+50.4%, P<0.001) in the septum. Pretreatment of the rats with the alpha(2)-adrenoceptor agonist, clonidine (0.1 mg/kg i.p.), 30 min before BAY K 8644 (2 mg/kg i.p.) injection completely abolished the behavioral and neurochemical changes. The data suggest that the Ca(2+)-dependent neurotransmitter release provoked by BAY K 8644 can be modulated by stimulation of presynaptic alpha(2)-adrenoceptors. The effect of clonidine on the GABAergic system may represent an important mechanism involved in the prevention of BAY K 8644-induced behavior.
Baran
H
H
Institute of Pharmacology and Toxicology, Veterinary University Vienna, A-1210, Vienna, Austria. halina.baran@vu-wien.ac.at
Kepplinger
B
B
Hörtnagl
H
H
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D002120:Calcium Channel Agonists; D018377:Neurotransmitter Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D003000:Clonidine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid