The aim of this study was to assess the 5-HT_1A receptor reactivity after neonatal noradrenergic neurons' lesion. DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), 50 mg/kg, was administered 30 min after a selective serotonin reuptake inhibitor (SSRI) — zimelidine (10 mg/kg) on the 1st and 3rd day of life. Zimelidine was used to prevent serotonin (5-HT) depletion. 5-HT_1A autoreceptor is involved in the regulation of 5-HT release as well as the pathogenesis of depression. During a microdialysis study of anaesthetized rats, the 5-HT_1A receptor agonist, R-(+)-8-OH-DPAT (0.1 mg/kg), decreased 5-HT release in the medial prefrontal cortex of control rats but this effect was significantly attenuated in DSP-4-treated animals (10–12 weeks old). To further determine which type of receptor, either pre or postsynaptically located, is involved in the attenuated response to the 5-HT_1A receptor agonist in lesioned rats, behavioral tests were conducted. In the forced swimming test, DSP-4 treated rats after saline injection, displayed shorter immobility time in comparison to control rats. R-(+)-8-OH-DPAT (0.5 mg/kg) evoked an antidepressant-like effect in control and DSP-4 treated rats in a learned helplessness paradigm as well as the forced swimming test. The results of this study provided further support for the exclusive desensitization of 5-HT_1A autoreceptor in adult rats with neonatal lesion of the central noradrenergic system.