Abstract: Objective To investigate the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) of normal and 6-OHDA-lesioned rats and the responses of the neurons to 5-hydroxytryptamine-7 (5-HT7) receptor stimulation. Methods The changes in spontaneous firing of the pyramidal neurons in the mPFC in response to 5-HT7 receptor stimulation were observed by extracellular recording in normal and 6-OHDA-lesioned rats. Results Both systemic and local administration of 5-HT7 receptor agonist AS 19 resulted in 3 response patterns (excitation, inhibition and no change) of the pyramidal neurons in the mPFC of normal and 6-OHDA-lesioned rats. In normal rats, the predominant response of the pyramidal neurons to AS 19 stimulation was excitatory, and the inhibitory effect of systemically administered AS 19 was reversed by GABAA receptor antagonist picrotoxinin. In the lesioned rats, systemic administration of AS 19 also increased the mean firing rate of the pyramidal neurons, but the cumulative dose for producing excitation was higher than that in normal rats. Systemic administration of AS 19 produced an inhibitory effect in the lesioned rats, which was partially reversed by picrotoxinin. Local administration of AS 19 at the same dose did not change the firing rate of the neurons in the lesioned rats. Conclusion The activity of mPFC pyramidal neurons is directly or indirectly regulated by 5-HT7 receptor, and degeneration of the nigrostriatal pathway leads to decreased response of these neurons to AS 19.