In this study, the relationship between the expression of 5-HT1A receptors and level of receptor mRNA in discrete regions of rat brain was examined by inactivation of 5-HT1A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; i.p., 10 mg/kg) and measurement of the time-course of receptor recovery and changes in receptor mRNA levels. Inactivation of 5-HT1A receptors ranged from 84% in the dorsal raphe to 97% in the cortex 12 h after administration of EEDQ. Receptor levels returned to 62-100% of control levels by day 7 and the rate of recovery was uniform across all regions examined. The rate of recovery of 5-HT1A receptors labeled by the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and by the putative antagonist [125I]4-(2'-methoxy)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamido] ethylpiperazine ([125I]p-MPPI) did not differ across regions, suggesting that the ratio of high versus low affinity states of the 5-HT1A receptor remains relatively constant during receptor recovery. However, there did appear to be a short lag in the recovery of sites labeled with the agonist. Significant increases in 5-HT1A receptor mRNA levels were observed as early as 12 h after treatment in all regions but the magnitude of these increases varied. The time-courses of recovery of 5-HT1A receptors and changes in mRNA levels were not parallel in individual regions. Moreover, inactivation of low (8-26%) to moderate (29-57%) levels of 5-HT1A receptors produced no change in mRNA levels, whereas inactivation of greater than 90% elicited a robust increase in mRNA levels. Thus, changes in 5-HT1A receptor expression are not mediated exclusively by changes in mRNA levels and extensive receptor inactivation is required to trigger transcriptional regulation.