DIFFERENTIAL-EFFECTS OF N-ETHOXYCARBONYL-2-ETHOXY-1,2-DIHYDROQUINOLINE (EEDQ) ON VARIOUS 5-HT RECEPTOR-BINDING SITES IN THE RAT-BRAIN

The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an alkylating agent producing irreversible blockade of various membran e bound receptors in brain, were investigated on four different types of serotonin receptors, 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3, in various b rain regions in the rat. In addition, the fate of central benzodiazepi ne- and ''R''-zacopride-specific binding sites was also examined in ra ts treated with EEDQ. Membrane binding assays and/or quantitative auto radiography with appropriate radioligands indicated that EEDQ inactiva ted 5-HT1A, 5-HT1B and 5-HT2A sites, but was poorly active on 5-HT3, b enzodiazepine and ''R'' sites. Among the receptors affected by EEDQ, h ippocampal 5-HT1A sites were the most sensitive to the alkylating agen t (ID50 similar to 1 mg/kg i.p.), followed by the cortical 5-HT2A (ID5 0 similar to 3 mg/kg i.p.) and the striatal 5-HT1B (ID50 similar to 6 mg/kg i.p.) sites. Pretreatment by selective ligands partially protect ed hippocampal 5-HT1A sites from irreversible inactivation by EEDQ (10 mg/kg i.p.) with the following order of efficacy: WAY 100635 > spiper one > BMY 7378 > ipsapirone. Similarly, pretreatment by spiperone (5 m g/kg i.p.) also reduced the ability of EEDQ to inactivate cortical 5-H T2A receptors. Analyses of the time-course recovery of respective bind ing sites after EEDQ administration showed that the turnover rate of 5 -HT1A sites did not significantly differ in the dorsal raphe nucleus a nd in various forebrain areas (hippocampus, septum, cerebral cortex; h alf-life: similar to 4 days), but was lower than that of cortical 5-HT 2A sites (half-life: 2.9 days).