Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Abstract

Rationale Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct, dopamine D1 receptor-expressing and indirect, D2 receptor-expressing striatal output pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. Objectives To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Results Our results indicate that in rats: 1) PDE10A inhibition (TP-10, 0.32-10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; 2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg). Conclusions These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.

Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile

“…In the striatum, PDE10A is largely distributed in medium spiny neurons, which are the striatal projection units and 95% of striatal neurons. This vast distribution pattern indicates that PDE10A inhibitors influence both striatal output pathways and globally the BG circuitry (Gresack et al, 2014; Megens et al, 2014; Strick et al, 2010), which is consistent with their predicted antipsychotic efficacy (Carlsson, 2001; Goff and Coyle, 2001; O’Donnell and Grace, 1998). Moreover, the analysis of single circuit activation has recently demonstrated that both direct and indirect striatal output pathways act in coordinated motion, highlighting the notion that these two information streams function cooperatively rather than competitively (Cui et al, 2013).…”

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

“…In line with these findings, Sotty et al (2009) proposed that PDE10A inhibition may favor D2 MSNs at basal dopaminergic conditions and prefer D1 MSNs under an elevated dopaminergic state (Sotty et al, 2009). Furthermore, Gresack et al (2014) demonstrated with a rodent model of sensorimotor gating that the relative dopaminergic tone at D1 and D2 receptors impacts the level to which PDE10A inhibitors can activate the direct pathway (Gresack et al, 2014).…”

Combined treatment with a selective PDE10A inhibitor TAK‐063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic‐like effects without affecting plasma prolactin levels and cataleptic responses in rodents

“…Both direct and indirect pathways have competing effects on antipsychotic‐like activities and motor functions in rodents . Compared to other PDE10A inhibitors, the balanced activation of the direct and indirect pathway MSNs by TAK‐063 may represent a novel therapeutic approach to treat patients with schizophrenia, either alone or in combination with other D 2 antagonist antipsychotics.…”

“…Compared with other PDE10A inhibitors such as MP‐10 and compound 1 [1‐[cyclopropylmethyl]‐4‐fluoro‐5‐[5‐methoxy‐4‐oxo‐3‐(1‐phenyl‐1H‐pyrazol‐5‐yl)pyridazin‐1(4H)‐yl]‐3,3‐dimethyl‐1,3‐dihydro‐2H‐indol‐2‐one] (previously synthesized by Takeda Pharmaceutical Limited, TAK‐063 showed comparable activation of indirect pathway MSNs while producing partial activation of direct pathway MSNs by its fast dissociation property in the rat striatum . These MSN pathways have competing effects on antipsychotic‐like activities and motor functions in rodents . TAK‐063 with this unique activation pattern of MSN pathways produces antipsychotic‐like effects in the multiple paradigms of rodent models .…”

“…15 These MSN pathways have competing effects on antipsychotic-like activities and motor functions in rodents. [15][16][17] TAK-063 with this unique activation pattern of MSN pathways produces antipsychotic-like effects in the multiple paradigms of rodent models. 15 TAK-063 also has a lower risk of inducing a cataleptic response than haloperidol, olanzapine, and aripiprazole in rats.…”