Neuropsychiatric Symptoms of Parkinson Disease: Role of Nigral Dopaminergic Lesion

Substantia nigra
Substantia nigra
Bilateral substantia nigra pars compacta lesion was linked to a memory deficit and to anxiety-like behavior.

Although the pathophysiology associated with neuropsychiatric manifestations of Parkinson disease (PD) remains elusive, a critical role for the substantia nigra pars compacta (SNc) in cognition has been clearly identified. A study was conducted in adult male Sprague-Dawley rats from Janvier Labs in Saint Berthevin, France, in which the laboratory animals were maintained in a controlled environment (lights on 07:00 to 19:00; ±22°C), with food and water readily available. Results of the analysis were published in Behavioural Brain Research.

The investigators sought to evaluate the role played by nigral dopaminergic (DA) cell loss, repeated exposure to DA medication, and the combination of the 2 in the development of neuropsychiatric symptoms observed among patients with PD. Anesthesia with isoflurane was administered while the rats were placed in a stereotaxic frame. A total of 52 rats received a cerebral injection of 6-hydroxydopamine (6-OHDA) or vehicle into the SNc. Levodopa chronic treatment was initiated 10 days after the stereotaxic surgery. Further, a subset of SNc-lesioned animals received a daily subcutaneous injection of levodopa methyl ester 20 mg/kg and benserazide 5 mg/kg for 12 consecutive days. All the behavioral procedures were begun 3 weeks after the cerebral injection of 6-OHDA.

Bilateral SNc lesion was linked to a memory deficit and to anxiety-like behavior, both of which were not enhanced by repeated exposure to levodopa. Moreover, the nigral lesion did not generate a deficit in social interaction or a heightened response to amphetamine-induced hyperlocomotion.

The rats that received a stereotaxic injection of 6-OHDA demonstrated a partial but significant decrease in the number tyrosine hydroxylase-positive cells within the SNc (48.23% cell loss vs sham rats; P <.0001). This partial SNc lesion was not associated with any impairment in general locomotor activity or any forelimb akinesia. In addition, lesioned rats exhibited a significant reduction in delta value (0.3 seconds) and recognition index (4.25%) compared with sham rats (10.3 seconds and 48.6%, respectively; P <.0001).

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Nonmotor symptoms of PD have been receiving increased attention in the scientific and medical communities during the last decade because of their negative effect on patients’ quality of life. The researchers concluded that the lack of effect of chronic levodopa exposure-examined behaviors demonstrated in this study, including anxiety, social interaction, and psychosis-like behavior, warrants further investigation.


Loiodice S, Wing Young H, Rion B, et al. Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease. Behav Brain Res. 2019;360:120-127. doi: 10.1016/j.bbr.2018.12.007.