The Preliminary Study Of Antischizophrenic Effects Of Dopamine D₃ Receptor Antagonist Y-QA14

Schizophrenia is a chronic, debilitating psychotic mental disorder of unknown etiology that afflicts approximately 1 percent of the population. Schizophrenia has varied and ominous symptoms that generally begin in late adolescence or early adulthood and usually continue throughout life, seriously destroying human health and social stability. Generally, typical symptoms of schizophrenia cluster into positive symptoms (delusions, hallucinations, and thought disorder), negative symptoms (flattening of affect, poverty of speech, anhedonia, and social withdrawal) and cognitive deficits (impairments of attention, working memory, and executive functions). Many studies indicated that schizophrenia is considered to be a complex functional disorder of central nervous systems, to arise many hypotheses. Among them, functional disorder of dopaminergic system is one of the most important hypotheses. Currently, ideal therapies for schizophrenia are the combination of drug treatment, psychotherapy and supportive therapy of community. However, most of patients had to take antipsychotic drugs (APDs) which include typical and atypical APDs to control the symptoms and anti-relapse for the whole life. Unfortunately, there are many disadvantages of these two classes of drugs. Typical APDs such as chloropromazine, haloperidol (Haldol), as dopamine D₂ receptor (DAD₂R) antagonists, have good therapeutic effects on the positive symptoms of schizophrenia, but have no help to negative symptoms, and often result in serious extrapyramidal side effect (EPS). Atypical APDs such as clozapine (Clo) and risperidone have good therapeutic effects on positive symptoms, a little improvement on negative symptoms and cognitive deficits, and less EPS effect. However, some atypical APDs results in many other serious side effects such as agranulocytopenia, weight gain, and so on.Many studies proved that dopamine D₃ receptor (DAD₃R) plays an important role in etiology of schizophrenia, and selective DAD₃R antagonists improves both positive symptoms, negative symptoms and cognitive deficits of schizophrenia. More important, DAD₃R antagonists result in less or no EPS. In earlier stage, we screened a selective DAD₃R antagonist Y-QA14 with independent intellectual property rights. It has been proved that Y-QA14 had two high affinity binding sites for DAD₃R with 2.56×106–fold and 66-fold selectivity over DAD₂R and more than 100-fold over other 30 subtypes of receptors, moreover, its oral bioavalability was 40.46 percent. The present study is aimed to evaluate the pharmacological effects of Y-QA14, hoping to develop new potential APDs.Y-QA14 significantly prevented hyperactivity induced by methamphetamine (MA) in Kunming mice. MA (0.5 mg·kg^-1) significantly induced hyperactivity; haloperidol (0.3 mg·kg^-1) significantly prevented the hyperactivity induced by MA. Y-QA14 (0.1¹5 mg·kg^-1) had no effect on locomotor activity of mice, while prevented the hyperactivity induced by MA, especially at 10 and 15 mg·kg-1. These data indicated that Y-QA14 could improve the function of dopaminergic recetpor system.Y-QA14 prevented the climbing behavior induced by apomorphine (Apo) in mice. Apo (2 or 3 mg·kg^-1) significantly induced climbing behavior of mice. Haloperidol (0.2 or 0.3 mg·kg^-1)significantly prevented the climbing behavior induced by Apo (2 mg·kg^-1). Y-QA14 (5⁴0 mg·kg^-1) exhibited no effect on climbing behavior induced by Apo (3 mg·kg^-1). However, Y-QA14 (5, 10, 20 mg·kg^-1) prevented the climbing behavior induced by Apo (2 mg·kg^-1), especially at 5 and 20 mg·kg-1. These disparities might be related to the different central mechanism of climbing behavior induced by different dose of Apo.Y-QA14 prevented the hyperactivity induced by NMDA antagonist MK-801. MK-801 (0.25 mg·kg^-1) significantly induced the mice hyperactivity; Clozapine (1 mg·kg^-1) significantly prevented the hyperactivity induced by MK-801. Y-QA14 (5, 10, 20 mg·kg^-1) significantly prevented the hyperactivity induced by MK-801. These results indicated that Y-QA14 could regulate the function of glutamatergic receptor system.Y-QA14 significantly decreased the head twitches induced by 5-hydroxytryptophan (5-HTP). 5-HTP (150 mg·kg^-1) significantly induced the head twitches of mice; clozapine (1 mg·kg^-1) significantly prevented the head twitches induced by 5-HTP. Y-QA14 at 5, 10, 20 mg·kg-1 but not 0.5, 1, 2 mg·kg^-1 significantly prevented the head twitches induced by 5-HTP. These results indicated that Y-QA14 could regulate the function of serotoninergic receptor system.Y-QA14 prevented social withdrawal induced by MK-801. Acute and sub-acute administration of MK-801 (0.2 mg·kg^-1) could stably induce social withdrawal in mice, which could not be reversed by diazepam (DZP) and clozapine (2 mg·kg^-1), indicating specificity of this model. Y-QA14 (0.05³.2 mg·kg^-1) had no effect on social interaction of mice, while significantly prevented social withdrawal induced by MK-801 at the dose of 0.1, 1, 2 mg·kg-1. Moreover, co-administration of clozapine (0.2 mg·kg^-1) or Y-QA14 (1 mg·kg^-1) with MK-801 prevented social withdrawal induced by sub-acute administration of MK-801. All these data indicated that low dose of Y-QA14 might improve the negative symptoms through DAD₃R.Y-QA14 (1¹5 mg·kg^-1) did not influence the locomotor activity of mice. Y-QA14 did not induce catalepsy at the doses lower than 40 mg·kg^-1, while significantly induced catalepsy at the doses of 60 and 80 mg·kg^-1. Hypothermia induced by low dose Apo might be mediated by DAD₂R. Apo (2 mg·kg^-1) significantly decreased the body temperature of mice. Haloperidol (0.1 mg·kg^-1) significantly prevented the hypothermia induced by Apo. However, Y-QA14 (0.05⁵ mg·kg^-1) had no effect on hypothermia induced by Apo, indicating that Y-QA14 had no interaction with DAD₂R at the doses used. The results showed that Y-QA14 had less potential to induce EPS.Overall, Y-QA14 exhibited therapeutic effects on positive and negative symptoms of schizophrenia, with less potential to induce EPS.