Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: reversal by the mGLU2/3 receptor agonist LY379268

Abstract

Converging evidence implicates glutamate neurotransmission in attention and inhibitory response control. To investigate how the background genotype contributes to glutamate's effects on attention and response control, we examined how phencyclidine (PCP) affected the performance of a five-choice serial reaction time (5-CSRT) task in two inbred mouse strains, C57BL/6N and DBA/2N. We also tested a potent mGlu(2/3) receptor agonist, LY379268, against PCP's effects. Mice were trained on a 5-CSRT task, which measures visual attention and response control until they reached asymptotic performance. Both strains of mice were then injected intraperitoneally with 0.5, 1.5 or 3.0 mg/kg PCP. Doses of 1.0 and 3.0 mg/kg of LY379268 were injected subcutaneously to vehicle or PCP-treated mice. At asymptotic performance DBA/2N mice were less accurate and made more anticipatory responses than C57BL/6N. PCP impaired accuracy (% correct) and increased perseverative responses of DBA/2N mice at 1.5 mg/kg. However, at doses up to 3.0 mg/kg it had no effect on these measures in C57BL/6N. In DBA/2N mice 1.5 mg/kg PCP increased anticipatory responses far more than 3.0 mg/kg in C57BL/6N mice. No dose of LY379268 prevented the PCP-induced accuracy deficit of DBA/2N mice. The PCP-induced anticipatory and perseverative responding of DBA/2N mice was reduced by 3.0 mg/kg LY379268, while 1.0 and 3.0 mg/kg reduced anticipatory responding in C57BL/6N. The background genotype may determine the effects of PCP on attentional performance and the results confirm the importance of glutamate transmission in some aspects of this performance.