Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats.
Compounds possessing 5-HT(1A) agonist properties attenuate catalepsy induced by D(2) receptor blockade. Here we examined the role of 5-HT(1A) receptor agonism in the reduced cataleptogenic potential of several novel antipsychotic agents in the crossed leg position (CLP) and the bar catalepsy tests in rats. When administered alone, ziprasidone produced marked catalepsy, whereas aripiprazole, bifeprunox, SLV313, SSR181507 and sarizotan did not. However, when 5-HT(1A) receptors were blocked with the selective antagonist, WAY100635 (0.63 mg/kg, SC), robust cataleptogenic properties of SLV313, bifeprunox and sarizotan were unmasked and the catalepsy induced by ziprasidone was accentuated. In contrast, only modest catalepsy was induced by aripiprazole and SSR181507, even following a higher dose of WAY100635 (2.5 mg/kg). This suggests that these compounds possess other anti-cataleptic properties, such as partial agonism at dopamine D(2) receptors. The capacity to reverse neuroleptic-induced catalepsy was investigated in interaction studies with haloperidol (2.5 mg/kg, SC). Whereas ziprasidone and aripiprazole did not markedly reduce the effects of haloperidol, SLV313 and sarizotan attenuated CLP catalepsy. In contrast, SSR181507 and bifeprunox potently inhibited both CLP and bar catalepsy. Taken together, these data show that 5-HT(1A) receptor activation reduces the cataleptogenic potential of novel antipsychotic agents but indicate marked diversity in the contribution of 5-HT(1A) and/or other mechanisms to the profiles of the drugs.
Pierre Fabre Research Centre, Neurobiology 2 Division, 17 ave. Jean Moulin, 81106 Castres, France.
Mark S
MS
Kleven
Catherine
C
Barret-Grévoz
Liesbeth
L
Bruins Slot
Adrian
A
Newman-Tancredi
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy*; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009930:Organic Chemicals; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*
C504317:1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-((5-(4-fluorophenyl)-3-pyridinyl)methyl)piperazine; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D009930:Organic Chemicals; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C443959:sarizotan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide