Knocking Down the DRD2 by shRNA Expressing Plasmids in the Nucleus Accumbens Prevented the Disrupting Effect of Apomorphine on Prepulse Inhibition in Rat

Prepulse Inhibition (PPI), the objective measure of sensorimotor gating disturbance has being widely used in animal models of schizophrenia. Dopaminergic direct and indirect agonists impair PPI. However, the profile of dopaminergic receptors involved in PPI impairment by dopamine agonists is not clear. By injecting shRNA expressing plasmids against dopamine D2 receptor genes (DRD2) in the nucleus accumbens, here, we studied the effect of apomorphine on PPI in D2 down-regulated rats. Seventy two adult Wistar rats assigned randomly in nine groups, each received coding (250 and 500 ng/µl) or noncoding shRNA expressing plasmids against DRD2 in the nucleus accumbens, with or without apomorphine (0.5 mg/kg, S.C., 72 hours after treatment with plasmids). Auditory startle response and PPI were measured after apomorphine injection. Real time RT-PCR was used to measure DRD2 expression. Results showed that apomorphine significantly decreased PPI in noncoding plasmid treated rats; While, PPI did not impaired in rats pretreated with 250 and 500 ng/µl shRNA expressing plasmids. Accordingly, the expression of DRD2 mRNA in the nucleus accumbens showed 72-78% decrease in expressing plasmid treated rats. Additionally, treatment with expressing plasmids had no effect on basal PPI and/or auditory startle response. Taken together, our results demonstrated that DRD2 silencing in the nucleus accumbens can prevent PPI impairment by apomorphine. These observations suggest application of molecular techniques such as the use of shRNA against DRD2s in studies of schizophrenia pathophysiology and development of new treatments in schizophrenia.