The alpha 2-adrenoceptor antagonist idazoxan reverses catalepsy induced by haloperidol in rats independent of striatal dopamine release: role of serotonergic mechanisms.
The alpha(2)-adrenoceptor antagonist idazoxan may improve motor symptoms in Parkinson's disease and experimental Parkinsonism. We studied the effect of idazoxan on haloperidol-induced catalepsy in rats, an animal model of the drug-induced extrapyramidal side effects in man. Catalepsy was induced by a subcutaneous (s.c.) injection of haloperidol (1 mg/kg) and measured by the bar test for a maximum of 5 min. At 3 h after haloperidol, rats were given 0.16-5.0 mg/kg s.c. idazoxan, and descent latency was measured 1 h later. Idazoxan potently reversed haloperidol-induced catalepsy with an ED(50) of 0.25 mg/kg. This effect was mimicked by the selective alpha(2)-adrenoceptor antagonist RS-15385-197 (0.3 and 1 mg/kg orally). We assessed how dopaminergic mechanisms were involved in the anticataleptic effect of idazoxan by studying its effect on dopamine (DA) release in the striatum, with the microdialysis technique in conscious rats. Idazoxan (0.3 and 2.5 mg/kg) had no effect on extracellular DA and did not modify the rise of extracellular DA induced by haloperidol, indicating that changes of striatal DA release were not involved in the reversal of catalepsy. The anticataleptic effect of 2.5 mg/kg idazoxan (haloperidol+vehicle 288+/-8 s, haloperidol+idazoxan 47+/-22 s) was attenuated in rats given an intraventricular injection of 150 microg of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (haloperidol+vehicle 275+/-25 s, haloperidol+idazoxan 137+/-28 s). The 5-HT(1A) receptor antagonist WAY100 635 (0.1 mg/kg s.c.) did not affect the anticataleptic effect of idazoxan. The results suggest that idazoxan reversed haloperidol-induced catalepsy by a mechanism involving blockade of alpha(2)-adrenoceptors and, at least in part, 5-HT neurons.
Invernizzi
Roberto W
RW
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. rinvernizzi@marionegri.it
Garavaglia
Claudio
C
Samanin
Rosario
R
D058669:Adrenergic alpha-2 Receptor Antagonists; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000633:toxicity; D019329:Idazoxan / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*
D058669:Adrenergic alpha-2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D006220:Haloperidol; D004298:Dopamine; D019329:Idazoxan