Abstract
In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague–Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague–Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the α1 adrenergic receptor antagonist prazosin. Furthermore, the α1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the α1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague–Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. [Neuropsychopharmacology 20:311–321, 1999]
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Acknowledgements
The authors thank Janssen, Hoechst Marion Roussel, Inc., and Novartis (formerly Sandoz) for their generous gifts of risperidone, M100907, and SDZ SER 082, respectively. We also thank Jon Yarris, Darlene Giracello, and Barbara Carasso for their excellent assistance with these studies. This work was supported by grants R02-DA02925 from the National Institute on Drug Abuse (NIDA), and R37-MH42228 from the National Institute of Mental Health (NIHM). Vaishali Bakshi was supported by grant F31-MH11636 from NIMH. Mark Geyer has an equity interest in San Diego Instruments, Inc., and was supported by a Research Scientist Award K05-MH01228 from NIMH.
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Varty, G., Bakshi, V., Geyer, M. et al. M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats. Neuropsychopharmacol 20, 311–321 (1999). https://doi.org/10.1016/S0893-133X(98)00072-4
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DOI: https://doi.org/10.1016/S0893-133X(98)00072-4
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