Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor MT-3014 in rats
Introduction
Schizophrenia is a complex psychiatric disorder primarily characterized by positive symptoms, negative symptoms, and cognitive impairment (Owen et al., 2016). Typical antipsychotics with dopamine D2 receptor antagonism as a primary mechanism of action are highly effective against positive symptoms but less so against negative symptoms and cognitive impairment and are accompanied by side effects such as extrapyramidal symptoms (EPS) and hyperprolactinemia (De Hert et al., 2016; Kane, 2001). Atypical antipsychotics have partial effects on negative symptoms and cognitive impairment through a broader mechanism of actions, such as partial agonism of the dopamine D2 receptor, dual dopamine/serotonin blockage, and multiple receptor blockade. Atypical antipsychotics have achieved success in reducing side effects caused by typical antipsychotics but have been reported to cause other side effects such as weight gain and an increased risk of diabetes (Leucht et al., 2009; Serretti et al., 2004; Tschoner et al., 2007). New classes of drugs that show a greater effect against symptoms for which current antipsychotics lack potency, or that have better side effect profiles, are desired (Citrome, 2014; Forray and Buller, 2017; Krebs et al., 2006). Phosphodiesterase (PDE) 10A inhibitors are one of the candidates for novel antipsychotics (Kehler and Nielsen, 2011; Krogmann et al., 2019; Swierczek et al., 2019).
PDE10A is highly expressed in medium spiny neurons (MSNs) of the striatum (Fujishige et al., 1999; Seeger et al., 2003; Soderling et al., 1999) and hydrolyzes both cAMP and cGMP. The striatum is a region in which a large amount information is integrated, including glutamatergic input from the cortex and dopaminergic input from the ventral tegmental area or the substantia nigra (Graybiel, 1990, Graybiel, 2000). Outputs from the striatum are mainly divided into the direct pathway from D1-expressing neurons and the indirect pathway from D2-expressing neurons and then reintegrated (Surmeier et al., 2007). Inhibition of PDE10A activates both direct and indirect pathways via the upregulation of cAMP and cGMP in both types of neurons, indicating that PDE10A inhibitors could have a dual D1 agonist and D2 antagonist-like effect (Siuciak et al., 2006b). It is likely that PDE10A inhibitors may provide a new therapeutic approach for schizophrenia by rescuing the weakened cortical glutamatergic input, which seems to be associated with negative symptoms and cognitive symptoms in addition to the antipsychotic effect of D2 blockade (Siuciak et al., 2006a; Siuciak et al., 2006b; Snyder and Vanover, 2014, Snyder and Vanover, 2017). Moreover, PDE10A inhibitors may avoid side effects caused by current antipsychotics via excess activation of the indirect pathway, as well as activating the direct pathway. Indeed, several PDE10A inhibitors have been developed for the treatment of schizophrenia in the last decade (Arakawa et al., 2016; Geerts et al., 2017; Grauer et al., 2009; Kehler, 2013; Suzuki et al., 2015; Takakuwa et al., 2019; Zagorska et al., 2018).
In this study, we investigated the antipsychotic-like profiles of a novel PDE10A inhibitor, 1-({2-(7-fluoro-3-methylquinoxalin-2-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]pyrazolo[1,5-α]pyrimidin-7-yl}amino)-2-methylpropan-2-ol hydrochloride (MT-3014, Koizumi et al., 2019), in rats. Furthermore, we examined the receptor occupancy of PDE10A in the brain after intravenous injection of MT-3014 using positron emission tomography (PET) in rats.
Section snippets
Animals
Male Wistar rats (5–9 weeks old, Japan Charles River Inc., Yokohama, Japan) were used for the measurement of striatal cAMP and cGMP levels, measurement of cAMP response element-binding protein (CREB) phosphorylation levels and the conditioned avoidance response (CAR) test. Male Wistar rats (7–10 weeks old, Japan SLC, Inc., Hamamatsu, Japan) were used for the locomotor activity tests, prepulse inhibition (PPI) test, catalepsy test and measurement of plasma prolactin levels. Male Long-Evans rats
In vitro profiling of MT-3014
MT-3014 showed a potent inhibitory effect against PDE10A with an IC50 value (95% CI) of 0.357 (0.131–0.976) nmol/L (Table 1). MT-3014 showed good selectivity over other PDE families with IC50 values over 500-fold (Table 1) and over the other 52 primary target proteins (enzymes, ion channels, receptors and transporters related to central nervous systems) with IC50 values over 1000-fold (Supplemental Table 1).
Oral bioactivity of MT-3014 in rats
The oral bioactivity of MT-3014 was investigated. Oral administration of MT-3014
Discussion
Here, we demonstrated the antipsychotic-like effect of MT-3014 (Koizumi et al., 2019) in rats. MT-3014 showed a potent inhibitory effect against PDE10A with high selectivity over other PDE families and other primary off-targets. Oral administration of MT-3014 increased striatal cAMP, cGMP and CREB phosphorylation at doses of 1.0 mg/kg or higher doses, indicating good biological activity of MT-3014. For assessment of antipsychotic-like effects, MK-801-induced rat models have been widely used (
Acknowledgments
We sincerely thank Ms. Fumiko Eguchi, Ms. Itsuko Nakamura, Ms. Kumiko Hikida, Mr. Masayuki Suzuki, Mr. Youta Goto, Dr. Koji Teshima and MTPC colleagues for their support in conducting the experiments and writing the manuscript.
Declaration of competing interest
Dr. Hashimoto has received research support or consultant fees from Dainippon-Sumitomo, Otsuka, and Taisho. Other authors are employees of MTPC.
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