THPP-1 PDE10A inhibitor reverses the cognitive deficits and hyperdopaminergic state in a neurodevelopment model of schizophrenia

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research Pub Date : 2024-10-21 DOI:10.1016/j.schres.2024.10.003

Daniela L. Uliana, Angela Martinez, Anthony A. Grace

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引用次数: 0

Abstract

Schizophrenia (SCZ) is a complex neuropsychiatric disorder characterized by positive, negative, and cognitive symptoms. The neurodevelopmental methylazoxy-methanol acetate (MAM) rodent model replicates key neurobiological features of SCZ which includes hyperdopaminergic states in the ventral tegmental area (VTA) and cognitive deficits. Typical and atypical antipsychotics are primarily effective in treating the positive symptoms of SCZ but often fall short of addressing cognitive deficits. A promising therapeutic approach for treating all symptoms of SCZ has emerged through the inhibition of phosphodiesterase 10 A (PDE10A). Our study aim was to investigate the impact of acute and chronic THPP-1 (PDE10A inhibitor) treatment, in MAM rats, focusing on cognitive deficits and VTA dopamine (DA) activity. Adult offspring of pregnant rats treated with Saline or MAM (20 mg/kg) on gestational day 17 were treated with THPP-1 acutely (male/female rats; 3 mg/kg) at postnatal day (PD) 70–80 or chronically (males; 3 weeks; 2-3 mg/kg) from PD 70–91 and tested in the novel object recognition test and electrophysiological recording of DA neurons in the VTA. Acute THPP-1 treatment reversed cognitive impairments and normalized the increased number of active DA neurons in the VTA of male and female MAM rats, without affecting control rats. Also, chronic THPP-1 treatment reversed cognitive deficits and normalized DA hyperactivity in the VTA of male MAM rats. The efficacy of THPP-1 in reversing MAM-induced impairments underscores its ability to target disease-specific circuitry without affecting normal regulated systems in control rats. Our findings highlight the therapeutic potential of THPP-1 for addressing cognitive deficits and DA dysregulation in SCZ.

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THPP-1 PDE10A 抑制剂可逆转精神分裂症神经发育模型中的认知缺陷和多巴胺能亢进状态。

精神分裂症（SCZ）是一种复杂的神经精神疾病，以阳性、阴性和认知症状为特征。神经发育性醋酸甲氧基甲醇（MAM）啮齿动物模型复制了精神分裂症的主要神经生物学特征，包括腹侧被盖区（VTA）的多巴胺能亢进状态和认知障碍。典型和非典型抗精神病药物主要能有效治疗 SCZ 的阳性症状，但往往无法解决认知障碍问题。通过抑制磷酸二酯酶10 A（PDE10A），一种有望治疗SCZ所有症状的治疗方法已经出现。我们的研究旨在调查急性和慢性 THPP-1（PDE10A 抑制剂）治疗对 MAM 大鼠的影响，重点是认知障碍和 VTA 多巴胺（DA）活性。在妊娠第 17 天用生理盐水或 MAM（20 毫克/千克）治疗怀孕大鼠的成年后代，在出生后第 70-80 天（PD）用 THPP-1 进行急性治疗（雄性/雌性大鼠；3 毫克/千克），或在出生后第 70-91 天用 THPP-1 进行慢性治疗（雄性大鼠；3 周；2-3 毫克/千克）。急性 THPP-1 治疗逆转了雄性和雌性 MAM 大鼠的认知障碍，并使 VTA 中活性 DA 神经元数量的增加恢复正常，但对对照组大鼠没有影响。此外，慢性 THPP-1 治疗可逆转雄性 MAM 大鼠的认知障碍，并使其 VTA 中 DA 活性亢进恢复正常。THPP-1在逆转MAM诱导的损伤方面的疗效凸显了其靶向疾病特异性回路的能力，而不会影响对照组大鼠的正常调节系统。我们的研究结果突显了 THPP-1 在解决 SCZ 认知缺陷和 DA 失调方面的治疗潜力。

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来源期刊

Schizophrenia Research 医学-精神病学

CiteScore

7.50

自引率

8.90%

发文量

429

审稿时长

10.2 weeks

期刊介绍： As official journal of the Schizophrenia International Research Society (SIRS) Schizophrenia Research is THE journal of choice for international researchers and clinicians to share their work with the global schizophrenia research community. More than 6000 institutes have online or print (or both) access to this journal - the largest specialist journal in the field, with the largest readership! Schizophrenia Research''s time to first decision is as fast as 6 weeks and its publishing speed is as fast as 4 weeks until online publication (corrected proof/Article in Press) after acceptance and 14 weeks from acceptance until publication in a printed issue. The journal publishes novel papers that really contribute to understanding the biology and treatment of schizophrenic disorders; Schizophrenia Research brings together biological, clinical and psychological research in order to stimulate the synthesis of findings from all disciplines involved in improving patient outcomes in schizophrenia.