M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawleyand Wistar rats

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antago nists ketanserin and risperidone reduced the disruptive effects of the nonc ompetitive N-methyl-D-aspartate (NMDA) antagonists 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 non competitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats foun d not effect with 5-HT2 antagonists. To test the hypothesis that strain dif ferences might explain the discrepancy in these findings, risperidone was t ested for its ability to reduce the PPI-disruptive effects of dizocilpine i n Wistar and Sprague-Dawley rats. Furthermore, to determine which serotoner gic receptor subtype may mediate this effect, the 5-HT2A receptor antagonis t M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonists SDZ SE R 082 were tested against dizocilpine. Recent studies have found that the P PI-disruptive effects of PCP are reduced by the alpha(1) adrenergic recepto r antagonist prazosin. Furthermore, the alpha(1) receptor agonist cirazolin e disrupts PPI. As risperidone and M100907 have affinity at the alpha(1) re ceptor, a final study examined whether M100907 would block the effects of c irazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller tha n previously reported. Consistent with previous studies, risperidone did no t alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly , M100907 pretreatment fully blocked the effect of dizocilpine in both stra ins; 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 c onfirm the suggestion that serotonin and glutamate interact in modulating P PI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. [Neurops ychopharmacology 20:311-321, 1999] (C) 1999 American College of Neuropsycho pharmacology. Published by Elsevier Science Inc.