The antipsychotic-like effects in rodents of YQA31 involve dopamine D3 and 5-HT1A receptor.

BACKGROUND: We previously reported that YQA31 is a dopamine D3 receptor antagonist with modest 5-HT1A receptor affinity and that it exhibits antipsychotic properties in animal models of schizophrenia. However, the contributions of D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31 are not clear. The current study evaluated the role of these two receptors in the effect of YQA31 on the hyperactivity and novel object recognition deficit in mice. METHODS: We used dopamine D3 receptor knockout mice and 5-HT1A receptor antagonist WAY100635 pretreatment, respectively, to investigate the involvement of these receptors in the effects of YQA31. The anti-psychotic effects were tested by inducing hyperlocomotion with methamphetamine or MK-801 and by inducing novel object recognition deficit with MK-801, which are the animal models to represent a positive symptom and a cognitive disorder. RESULTS: YQA31 significantly inhibited MK-801-induced hyperlocomotion and novel object recognition deficit in WT mice, which was significantly inhibited by dopamine D3 receptor knockout. The 5-HT1A receptor antagonist, WAY100635, also blocked the effect of YQA31 in MK-801-induced novel object recognition deficit but not hyperlocomotion. The effect of YQA31 on methamphetamine-induced hyperlocomotion was not reversed by either dopamine D3 receptor knockout or WAY100635 pretreatment. CONCLUSIONS: These results demonstrate the different roles of dopamine D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31. Both dopamine D3 and 5-HT1A receptors contributed to the effects of YQA31 on the inhibition of MK-801-induced novel object recognition deficit, and the dopamine D3 receptor mediated the inhibiting effect of YQA31 on hyperlocomotion induced by MK-801.

Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia.

AIM: To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. METHODS: A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein-coupled receptors. [(35)S]GTPγS-binding assays and Ca(2+) imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. RESULTS: In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT1A receptor partial agonist and α1A adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors (100-fold lower than for the D3 receptor). In vivo, Y-QA31 (10-40 mg/kg, po) significantly inhibited MK-801-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose (1 mg/kg, po). Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. CONCLUSION: Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.

[Analysis of the diagnosis and treatment of cervical minimal deviation adenocarcinoma].

OBJECTIVE: To analyze the characteristics of cervical minimal deviation adenocarcinoma (MDA) and the methods of diagnosis and treatment. METHODS: A retrospective study was carried out to evaluate the clinical and pathological data of 15 patients with MDA treated from 1992 to 2007. RESULTS: The average age of the 15 patients was 42.3 years. The main symptoms were increased discharge and irregular vaginal bleeding. Preoperative Pap smears showed adenocarcinoma in 3 cases (27.3%). The diagnosis of MDA was confirmed in 8 cases by cervical punch biopsies (53.3%) and 2 cases by conization. Several cysts were noted in sections of the endocervix. Microscopic examination showed glands irregular in size and shape. However, the deviation of tumor cells was minimal. Immunohistochemistry revealed positive expression of CEA and alpha-SMA. The mean follow-up time was 51.0 months. The overall 5-year survival rate was 85.7%. Four cases experienced recurrence in the vagina and pelvis at 2 years after operation. Three cases died of the disease relapse with an average survival time of 36.3 months. CONCLUSION: Cervical minimal deviation adenocarcinoma is rare, with minimal deviation of cell shape from the normal cervical cells and difficult in diagnosis. A deep biopsy or conization is necessary when punch biopsy is not sufficient for diagnosis. Immunohistochemistry is helpful to make an accurate diagnosis. Surgery is the first choice for cervical minimal deviation adenocarcinoma. Radiotherapy and/or chemotherapy should be given if needed. The prognosis can be improved if a proper treatment plan is carried out.