NMDA receptor antagonists block development of tolerance to m-CPP-induced increases in ACTH concentrations in rats

We have recently demonstrated that a single administration of m-chlorophenylpiperazine (m-CPP, a preferential 5-HT2C receptor agonist) produces tolerance to its stimulatory effect on adrenocorticotropic hormone (ACTH) concentrations when challenged 24 h later with the same dose of m-CPP. In the present study, we studied the effects of pretreatment with various N-methyl-D-aspartate (NMDA) receptor antagonists on development of tolerance to m-CPP's stimulatory effect on ACTH concentrations. Pretreatment with various NMDA receptor antagonists such as 5.7-dichlorokynurenic acid (1.0 mg/kg), 3-amino-1-hydroxy 2-pyrrolidone (1.0 mg/kg), dizocilpine (0.1 mg/kg) and ifenprodil (1.0 mg/kg) injected 30 min before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 h later with the same dose (2.5 mg/kg) of m-CPP. These findings suggest that tolerance to postsynaptic 5-HT2C receptor-mediated response is initiated though stimulation of NMDA receptor complex and, furthermore, demonstrate a functional interaction between the 5-HT and glutamate systems.