In order to study the impact of serotonin depletion on gene expression of the serotonin transporter (5-HT t ) we measured 5-HT t mRNA levels by Northern blot in rats treated withp-chlorophenylalanine methyl ester (PCPA) for 10 days. Six rats received PCPA i.p. only, and another 6 rats receiving 0.9% NaCl served as controls. An additional group of 6 rats received both PCPA i.p. and imipramine, 5 mg/kg/day by osmotic minipumps. 5-HT t mRNA levels decreased to 81.1% (P = 0.05) and 76.0% (P = 0.05) of the control level for PCPA treated animals without and with concomitant imipramine treatment, respectively. The average level of the PCPA treated groups was 78.6% (P = 0.03). The isolated effect of 21 days of imipramine treatment was a 5-HT t mRNA level of 89.4%, which was not significantly different from the control level. In conclusion, 5_HT t gene expression is suppressed in the serotonin depleted state. A decreased synaptic reuptake of 5-HT may be interpreted as a compensatory mechanism aiming at preserving adequate synaptic 5-HT levels in a generally deficient state.