Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand.
Bi-acetylated l-stepholidine (l-SPD-A), a novel derivate of l-stepholidine (l-SPD), possesses a pharmacological profile of D(1)/5-HT(1A) agonism and D(2) antagonism. In the present study, we examined the potential antipsychotic effect of l-SPD-A in a phencyclidine (PCP)-induced rat model of schizophrenia. Pretreatment with l-SPD-A blocked acute PCP-induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Chronic l-SPD-A administration (i.p., 10mg/kg/day for 14 days) improved social interaction and novel object recognition impairments in rats that were pretreated with PCP (i.p., 5mg/kg/day for 14 days). Moreover, in a conditioned avoidance response (CAR) test, l-SPD-A, with either i.p. or oral administration, significantly decreased active avoidance without affecting the escape response of rats. Importantly, compared to that of the parent compound l-SPD, l-SPD-A showed stronger suppression of CARs. Lastly, using a [(35)S]GTPgammaS binding assay, we demonstrated that l-SPD-A improved impaired dopamine D(1) receptor function in the prefrontal cortex (PFC) in chronic PCP-treated rats. Taken together, these results indicate that l-SPD-A was not only effective against the hyperactivity, but also improved the sensorimotor gating deficit, social withdrawal and cognitive impairment in an animal model of schizophrenia. The present data suggest that l-SPD-A, a potential neurotransmitter stabilizer, is a promising novel candidate drug for the treatment of schizophrenia.
Guo
Yang
Y
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Zhang
Hai
H
Chen
Xuetao
X
Cai
Wenxian
W
Cheng
Jianjun
J
Yang
Yushe
Y
Jin
Guozhang
G
Zhen
Xuechu
X
D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007266:Inhibition, Psychological; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D001599:Berberine; C010513:stepholidine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010622:Phencyclidine