Effects of medial prefrontal cortex 5-HT₇ receptor knockdown on cognitive control after acute heroin administration

Heroin abuse is linked to a deleterious effect on cognitive functioning in the individual. Recent evidences suggest that the serotonin₇ receptor (5-HT₇R) is engaged in the regulation of cognitive control and the drug use-associated behaviors. However, the role of 5-HT₇R in the cognitive control after acute heroin administration has not been studied. The present study aims to investigate whether the knockdown of the 5-HT₇R by virus-mediated gene silencing in the medial prefrontal cortex (mPFC) could ameliorate the acute heroin-induced cognitive impairments. The attentional function, impulsivity and compulsivity were assessed by the 5-choice serial reaction time task (5-CSRTT) in mice. The memory ability and locomotor activity were examined by the novel objects recognition (NOR), Y-maze and open-field test (OFT). Acute heroin administration at 5 mg/kg produced robust disruptions in attention, impulsivity and motivation in mice. 5-HT₇R knockdown in the mPFC did not affect the 5-CSRTT baseline performance, spatial working memory, visual episodic memory and locomotion. However, mPFC 5-HT₇R knockdown selectively ameliorated acute heroin-induced increase in omissions and premature responses under conditions of increased perceptual load. In addition, mPFC 5-HT₇R knockdown induced increases in perseverative responding observed across both saline and heroin-treated animals. Moreover, 5-HT₇R knockdown prevented the heroin-induced decrease in NR1/CaMKII phosphorylation in mPFC, thus suggesting that 5-HT₇R and N-methyl-d-aspartic acid (NMDA) receptor signaling may be involved in the cognitive outcomes of acute heroin administration. Altogether, these observations suggest modest and restricted effects of mPFC 5-HT7R knockdown on cognitive behaviors, both in the presence or absence of acute heroin treatment.