Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat

Abstract

Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through high-performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. Although DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect.

Figure 1

Behavioral effects of unilateral 6-OHDA lesion and chronic L-DOPA treatment on motor activity and anxiety-like behaviors measured in the locomotor chambers (n=11–17/group). Bars denote the effects of each group on (A) total distance, (B) entries to center, (C) vertical movements in center, and (D) time in center of the test field for 2 h. Main effects of lesion ( p<0.05) and treatment ( p<0.05) were determined via two-way ANOVA.

Figure 2

Behavioral effects of unilateral 6-OHDA lesion and chronic L-DOPA treatment on anxiety-like behaviors in the social interaction test. Bars denote the effects of each group (n=5/group) on (A) approaches, (B) anogenital sniffing, (C) other sniffing, and (D) following of the stimulus animal and (E) flights away from the stimulus animal. Main effects of lesion ( p<0.05) were determined via two-way ANOVA.

Figure 3

Behavioral effects of unilateral 6-OHDA lesion and chronic L-DOPA treatment on depression-like behaviors in the modified forced swim test. (A) Climbing, (B) swimming, and (C) immobility behaviors for the first 5 min of day 1 of exposure (white bars) and first 5 min of day 2 of exposure (black bars) are shown for Sham-VEH, Sham-LD, Lesion-VEH, and Lesion-LD groups (n=5/group). Two-way ANOVAs revealed significant main effects of day on climbing and immobility. A significant lesion by day interaction was also found for climbing (*p<0.05).

Figure 4

Schematic representation of coronal sections of the rat brain depicting the regions that were microdissected for analysis via HPLC-ED. The sections were taken from Paxinos and Watson (1998). Shaded portions denote microdissected areas of the (A) prefrontal cortex, (B) striatum, (C) hippocampus, and (D) amygdala. Relevant anatomical structures are: CC, corpus callosum; NA, nucleus accumbens.

Figure 5

Neurochemical effects of unilateral 6-OHDA lesion and chronic L-DOPA treatment as determined by HPLC-ED. Monoamine levels within the striatum (STR), prefrontal cortex (PFC), hippocampus (HPC), and amygdala (AMG) are shown for (A) DA, (B) DOPAC, (C) NE, (D) 5-HT, and (E) 5-HIAA. Interactions and main effects of lesion ( p<0.05) and treatment ( p<0.05) were determined via two-way ANOVA. LSD post-hoc comparisons demonstrated significant differences between Sham-VEH (* p<0.05), Sham-LD (+ p<0.05), and Lesion-VEH (# p<0.05).