Profile of action of a novel 5-hydroxytryptamine1A receptor ligand E-4424 to inhibit aversive behavior in the mouse, rat and marmoset.
E-4424 (2-(4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl)pyrimidine) was shown to be a 5-hydroxytryptamine1A receptor ligand in radioligand binding assays and in an in vitro guinea pig ileum preparation had both 5-hydroxytryptamine1A antagonist and agonist effects. The antagonist/agonist ratio of E-4424 was greater than in the case of buspirone and ipsapirone. E-4424 was compared to diazepam, buspirone and ipsapirone to inhibit the behavioral response to an aversive situation in the mouse black and white test box, the rat social interaction test and a marmoset human threat test. The acute administration of E-4424 (0.0001-0.5 mg/kg, i.p.) to the mouse decreased aversion to the white area of the test box and was as effective as diazepam (0.125-1.0 mg/kg, i.p.) and much more potent than buspirone (0.25-1.0 mg/kg, i.p.) or ipsapirone (0.5-5.0 mg/kg, i.p.). E-4424 was also effective in enhancing rat social interaction and reducing anxiety-related behaviors in the marmoset and was again more potent than diazepam, buspirone or ipsapirone. Withdrawal from a 14-day administration of diazepam, cocaine, nicotine or alcohol exacerbated the response to the aversive situation in the mouse test. This was not observed after withdrawal from a chronic treatment with E-4424, buspirone or ipsapirone. However, E-4424 administered during drug withdrawal prevented the response caused by withdrawal from cocaine, alcohol, nicotine and diazepam: buspirone was ineffective and ipsapirone only attenuated that syndrome after alcohol withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
Costall
B
B
Postgraduate Studies in Pharmacology, School of Pharmacy, University of Bradford, West Yorkshire, England.
Domeney
A M
AM
Farre
A J
AJ
Kelly
M E
ME
Martinez
L
L
Naylor
R J
RJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002065:Buspirone / Q000494:pharmacology; D002144:Callithrix; D003975:Diazepam / Q000009:adverse effects; D005260:Female; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C043077:ipsapirone; C075568:lesopitron; D003975:Diazepam; D002065:Buspirone