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

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.