Chronic L‐dopa Induced 5‐HT Neuron Loss and Behavioral Impairments in the Rat

Abstract

L-dopa is used to treat the dopamine deficits and motor impairments in Parkinson's disease but chronic administration results in loss of drug efficacy over time and side effects such as dyskinesia and mood disorders. Serotonin (5-HT) neurons have been implicated in some of these effects as they are capable of decarboxylating L-dopa to dopamine. Further, the accumulation and degradation of dopamine within 5-HT cells results in oxidative stress and apoptosis in-vitro. To examine in-vivo if L-dopa decreases 5-HT neurons and tissue content in rat brain through pro-oxidant mechanisms with a corresponding impairment of 5HT-dependent behaviors, rats were treated chronically with L-dopa (6 mg/kg; twice daily) with or without ascorbate for 10 days. Tryptophan hydroxylase-positive (TPH+) neurons in the dorsal raphe nucleus (DRN) as well as monoamine tissue content were examined. Cognitive and affective behaviors including performance in the Barnes maze, forced swim test, elevated plus and conditioned fear test were also assessed. Chronic L-dopa significantly decreased (↓28%) TPH+ neurons in the caudal extent of the dorsal DRN (t=2.618, p<0.05). Further, 5-HT tissue content was significantly decreased in the dorsal DRN (↓23%) (q=4.8, p<0.05) and prefrontal cortex (↓28%) (q=3.42, p<0.05). Behaviorally, chronic L-dopa potentiated freezing behavior in the conditioned fear test (q=4.44, p<0.05) and increased latency time in finding the goal box during the Barnes maze (q=-2.23, p<0.05). Furthermore, the TPH+ neuron and 5-HT content decreases as well as increased freezing behaviors were all prevented by ascorbate co-treatment. Overall, these findings suggest that chronic L-dopa produces both 5-HT deficits and behavioral impairments in a pro-oxidant manner.