stepholidine and Disease-Models--Animal

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinson's disease (PD) drug therapy. In the present study, we examined the effect of L-stepholidine (L-SPD), a known dual dopamine receptor agent, on LID in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model. Daily administration of L-DOPA to PD rats for 22 days induced steady expression of LID, co-administration of L-SPD with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA, indicating that L-SPD attenuated LID development. L-SPD alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of L-SPD to rats with established LID produced significant relief of dyskinesia; this effect was mimicked by D(2) receptor antagonist haloperidol, but blunted by 5-HT(1A) receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT(1A) decreased significantly on 6-OHDA-lesioned striata, whereas chronic L-SPD treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata. The present data demonstrated that L-SPD elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analysis of Variance; Animals; Antiparkinson Agents; Antipsychotic Agents; Benzazepines; Berberine; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Disease Models, Animal; Dopamine Agents; Drug Administration Schedule; Drug Interactions; Dyskinesias; Gene Expression Regulation; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; RNA, Messenger; Serotonin Receptor Agonists; Transfection; Tritium

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.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Berberine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Guanosine 5'-O-(3-Thiotriphosphate); Inhibition, Psychological; Interpersonal Relations; Locomotion; Male; Phencyclidine; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Serotonin; Recognition, Psychology; Reflex, Startle; Schizophrenia