The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-induced Cognitive Deficits in Monkeys

Stress exposure impairs the cognitive functioning of the prefrontal cortex (PFC). Previous research has examined the dopamine (DA) D1 receptor mechanisms underlying this response. The current study performed a preliminary examination of the role of D4 receptor mechanisms by determining whether the selective D4 receptor antagonist, PNU-101387G, could prevent stress-induced working memory deficits in monkeys. Animals were tested on the delayed response task following treatment with PNU-101387G (0 or 0.1-0.8 mg/kg, 60-min pretreatment), and the pharmacological stressor, FG7142 (0 or 0.2 mg/kg, 30-min pretreatment). FG7142 significantly impaired delayed response performance relative to vehicle; PNU-101387G pretreatment produced a dose-related reversal of the FG7142 response. PNU-101387G had no significant effects on its own, but there were trends toward improvement at low doses and impairment at higher doses. Further studies in a larger number of animals appear warranted. These preliminary findings suggest that D4 receptor mechanisms contribute to stress-induced cognitive dysfunction.