The orexin-1 antagonist SB-334867 blocks antipsychotic treatment emergent catalepsy: implications for the treatment of extrapyramidal symptoms.
We have previously shown that the orexin-1 antagonist SB-334867 blocks the electrophysiological effects of haloperidol and olanzapine on the activity of A9 and A10 dopamine neurons. To evaluate if orexin-1 antagonists might block other effects of antipsychotic drugs in animals, we examined the effects of SB-334867 on behavioral, neurochemical, and neuroendocrine effects of antipsychotic drugs. Pretreatment with SB-334867 (0.01-10 mg/kg, intraperitoneal [IP]) significantly decreased the catalepsy produced by the administration of haloperidol (1 mg/kg, subcutaneous [SC]), risperidone (2 mg/kg, SC), and olanzapine (10 mg/kg, SC). Administration of SB-334467 also reversed catalepsy after it had been established in animals pretreated 2 hours earlier with haloperidol. However, pretreatment with SB-334867 (1-10 mg/kg, IP) did not block the decreases in exploratory locomotor activity produced by administration of haloperidol (0.1 mg/kg, SC) or risperidone (0.3 mg/kg, SC). In addition, pretreatment with SB-334867 (1-10 mg/kg, IP) neither blocked the increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or striatum nor the elevation in serum prolactin produced by administration of haloperidol (0.1 mg/kg, SC) and risperidone (1 mg/kg, SC). Administration of SB-334867 alone neither changed locomotor activity and DOPAC or prolactin levels nor produced catalepsy. These results show that orexin-1 antagonists block the catoleptogenic effects of antipsychotics but do not block other locomotor, neurochemical, or neuroendocrine effects of antipsychotics. Because catalepsy is thought to be a good predictor of extrapyramidal symptoms in humans, treatment with orexin-1 antagonists might decrease the occurrence or severity of antipsychotic treatment-emergent extrapyramidal symptoms in humans.
Rasmussen
Kurt
K
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. rasmussen_kurt@lilly.com
Hsu
Mei-Ann
MA
Noone
Stephen
S
Johnson
Bryan G
BG
Thompson
Linda K
LK
Hemrick-Luecke
Susan K
SK
D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors*; D001480:Basal Ganglia Diseases / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D001583:Benzoxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D002375:Catalepsy / Q000188:drug therapy*; D006220:Haloperidol / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D000077152:Olanzapine; D000068797:Orexins; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D014150:Antipsychotic Agents; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D001569:Benzodiazepines; D014508:Urea; D011388:Prolactin; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine