Anticataleptic 8-OH-DPAT preferentially counteracts with haloperidol-induced Fos expression in the dorsolateral striatum and the core region of the nucleus accumbens.
We studied the effects of the 5-HT(1A/7) agonist 8-OH-DPAT on haloperidol-induced catalepsy and forebrain Fos expression in mice to clarify its mechanism in modulating extrapyramidal motor disorders. 8-OH-DPAT (0.1-1mg/kg, i.p.) markedly attenuated haloperidol-induced catalepsy in a dose-dependent manner with a potency greater than that of the antiparkinsonian agent trihexyphenidyl. The anticataleptic action of 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT(1A) antagonist), but not by SB-269970 (a selective 5-HT(7) antagonist). Depletion of cerebral 5-HT by p-chlorophenylalanine (300mg/kg, i.p. for 3 days) did not attenuate, but rather potentiated the action of 8-OH-DPAT. Furthermore, the anticataleptic dose of 8-OH-DPAT showed a regionally specific reduction of haloperidol-induced Fos expression in the dorsolateral striatum (dlST) and the core region of the nucleus accumbens (AcC), without affecting that in the medial prefrontal cortex, the shell region of the nucleus accumbens or the lateral septal nucleus. These results suggest that 8-OH-DPAT alleviates antipsychotic-associated extrapyramidal motor disorders by stimulating the postsynaptic 5-HT(1A) receptors, which specifically counteracts the D(2) receptor blocking actions of antipsychotics in the dlST and AcC.
Ohno
Yukihiro
Y
Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan. yohno@gly.oups.ac.jp
Shimizu
Saki
S
Imaki
Junta
J
Ishihara
Shizuka
S
Sofue
Nobumasa
N
Sasa
Masashi
M
Kawai
Yoshiko
Y
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010134:Fenclonine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol; D008297:Male; D051379:Mice; D009714:Nucleus Accumbens / Q000187:drug effects*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D016761:Oncogene Proteins v-fos; D010879:Piperazines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006220:Haloperidol; D010134:Fenclonine