INTRODUCTION: The hallmark symptoms of Parkinson’s disease (PD) are progressive motor impairments. Nevertheless, PD is also associated with altered executive function and other cognitive impairments. While treatments of PD provide at least temporary relief from the motor symptoms, the effects of L-DOPA on the cognitive impairments may provide mixed effects and require further investigation. AIM(S): Here we assess changes in gene expression in the prefrontal cortex (PFC) of rats with unilateral lesion of midbrain dopamine neurons. METHOD(S): Male Wistar Han rats were infused with 6‑hydroxydopamine (6‑OHDA, 8 µg/4 µl) into the left medial forebrain bundle. The experimental animals were treated i.p. with L‑DOPA (12.5 mg/kg) supplemented with benserazide hydrochloride (6.25 mg/kg) daily for 14 days. An hour after the last dose, the rats were killed, and the left and right PFC were isolated separately. Analysis of gene expression was performed by RNA‑seq (Illumina PE 150, 20M pair reads per sample). Reads were aligned to rn6 rat reference genome using hisat2 2.1.0. RESULTS: We identified 12,459 genes with FPKM > 1 after L‑DOPA treatment in both ipsi‑ and contralateral portions of the PFC of rats lesioned with 6‑OHDA. Two‑way ANOVA revealed 48 genes with differential expression profiles. The effect of treatment was the most pronounced, and included transcripts linked to activity-regulated expression in neurons and metabolism in the glia. Ontology analysis of the genes with altered expression indicated over-representation of terms associated with cytokine and glucocorticoid signalling. The involvement of altered glucocorticoid signalling induced by L-DOPA treatment was also confirmed by analysis of the promoter regions of the regulated genes. CONCLUSIONS: Unilateral lesions of dopamine neurons lead to enhanced sensitization of neurons in PFC to L‑DOPA action. We show that, to a large extent, these changes appear to bilaterally affect the molecular profile of PFC.