Rationale: On the basis of electrophysiological evidence, it has been proposed that both antagonism of NMDA receptors by drugs such as PCP and stimulation of 5- HT(2A) receptors by drugs such as LSD result in the release of glutamate. Furthermore, it has been observed that antagonists and agonists at mGlu(2/3) receptors increase and decrease, respectively, the release of glutamate. Taken together, these observations predict behaviorally significant interactions between ligands at mGlu(2/3) receptors and hallucinogens such as LSD and PCP.
Objective: The present study sought to test in rats the glutamate hypothesis of hallucinogenesis using drug-induced stimulus control as the dependent variable and selected glutamatergic and serotonergic receptor ligands as independent variables.
Methods: Male F-344 rats were trained in a two-lever, fixed ratio 10, food-reinforced task with either phencyclidine (PCP; 3.0 mg/kg; i.p.; 30 min pretreatment) or lysergic acid diethylamide (LSD; 0.1 mg/kg; IP; 15 min pretreatment) as discriminative stimuli. The interactions of PCP and the mGlu(2/3) selective ligands, LY341495 and LY379268, with stimulus control by LSD were determined. The effects of these drugs were compared with those of serotonergic antagonists known to antagonize the stimulus effects of LSD, specifically, pirenperone and M100907.
Results: Stimulus control by LSD was potentiated by both PCP and the mGlu(2/3) antagonist, LY341495. In tests of antagonism, stimulus control by LSD was significantly but incompletely diminished by the mGlu(2/3) agonist, LY379268; this result was in contrast with the complete antagonism of LSD by both pirenperone and M100907. In PCP-trained rats, LY341495 was without effect on stimulus control by an intermediate dose of PCP. In contrast, the training dose of PCP was significantly but incompletely antagonized by LY379268.
Conclusions: These data, obtained using a stimulus control model of the hallucinogenic effects of PCP and LSD, provide support for the hypothesis that glutamate release is a factor in hallucinogenesis by both 5-HT(2) agonists and non-competitive NMDA antagonists.