Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

Abstract

L-Dopa (L-3,4-dihydroxyphenylalanine) is the precursor to dopamine and has become the mainstay therapeutic treatment for Parkinson's disease. Chronic L-dopa is administered to recover motor function in Parkinson's disease patients. However, drug efficacy decreases over time, and debilitating side effects occur, such as dyskinesia and mood disturbances. The therapeutic effect and some of the side effects of L-dopa have been credited to its effect on serotonin (5-HT) neurons. Given these findings, it was hypothesized that chronic L-dopa treatment decreases 5-HT neurons in the dorsal raphe nucleus (DRN) and the content of 5-HT in forebrain regions in a manner that is mediated by oxidative stress. Rats were treated chronically with L-dopa (6 mg/kg; twice daily) for 10 days. Results indicated that the number of 5-HT neurons was significantly decreased in the DRN after L-dopa treatment compared with vehicle. This effect was more pronounced in the caudal-extent of the dorsal DRN, a subregion found to have a significantly higher increase in the 3,4-dihydroxyphenylacetic acid/dopamine ratio in response to acute L-dopa treatment. Furthermore, pretreatment with ascorbic acid (400 mg/kg) or deprenyl (2 mg/kg) prevented the L-dopa-induced decreases in 5-HT neurons. In addition, 5-HT content was decreased significantly in the DRN and prefrontal cortex by L-dopa treatment, effects that were prevented by ascorbic acid pretreatment. Taken together, these data illustrate that chronic L-dopa causes a 5-HT neuron loss and the depletion of 5-HT content in a subregion of the DRN as well as in the frontal cortex through an oxidative-stress mechanism.

Behavioral impairments and serotonin reductions in rats after chronic L-dopa

“…Both the mPFC and hippocampus have been implicated in spatial learning and memory (Cano de la Cuerda, Vela et al 2010; Euston, Gruber et al 2012). Studies have demonstrated that remote memory recall requires activation of the mPFC (Tomita, Ohbayashi et al 1999; Blum, Hebert et al 2006; Margis, Donis et al 2010), an area that has been shown to contain deficits in 5-HT after chronic L-dopa (Navailles, Bioulac et al 2011; Eskow Jaunarajs, George et al 2012; Stansley and Yamamoto 2014). Further, 5-HT in the mPFC has been shown to play a role in control of memory retrieval, as blockade of 5-HT2A receptors within the mPFC reduces object recognition memory retrieval (Sethi, Factor et al 2010).…”

“…In the current study, the impairment in spatial memory caused by L-dopa was completely blocked by ascorbate co-treatment, suggesting that oxidative mechanisms underlie this behavioral impairment. Interestingly, L-dopa induced 5-HT tissue content deficits within the PFC has also been shown to be blocked by ascorbate co-treatment (Stansley and Yamamoto 2014). Therefore, it is likely that 5-HT related deficits in the PFC caused by L-dopa at least partially contribute to subsequent spatial memory impairments.…”

“…Briefly, rats were treated for 10 days with saline vehicle, L-dopa, ascorbate, or the combination of ascorbate plus L-dopa and then underwent the conditioned fear stress paradigm. Rats were killed 48 hours after testing, brains were dissected and concentrations of tissue monoamines were determined by high performance liquid chromatography with electrochemical detection (HPLC-EC) as described previously (Stansley and Yamamoto 2014). The DRN subregions (−7.3 to −8.3 mm from bregma) consisted of a rectangular dissection with boundaries of the cerebral aqueduct above and the decussation of the superior cerebellar peduncle below, and 1 mm to either side of the midline; the top half was considered dorsal DRN, and the bottom half was ventral DRN.…”

“…Indeed, L-dopa is toxic to 5-HT neurons in vitro by oxidative mechanisms that are dependent on dopamine production and degradation (Stansley and Yamamoto 2013). In vivo, chronic L-dopa has been shown to reduce the number of 5-HT neurons in the DRN by similar oxidative mechanisms (Stansley and Yamamoto 2014). In addition to decreases in the number of 5-HT cell soma, chronic L-dopa depletes 5-HT content in several brain regions including the DRN, striatum, hippocampus, amygdala and PFC (Borah and Mohanakumar 2007; Navailles, Bioulac et al 2011; Eskow Jaunarajs, George et al 2012; Stansley and Yamamoto 2014).…”

“…In vivo, chronic L-dopa has been shown to reduce the number of 5-HT neurons in the DRN by similar oxidative mechanisms (Stansley and Yamamoto 2014). In addition to decreases in the number of 5-HT cell soma, chronic L-dopa depletes 5-HT content in several brain regions including the DRN, striatum, hippocampus, amygdala and PFC (Borah and Mohanakumar 2007; Navailles, Bioulac et al 2011; Eskow Jaunarajs, George et al 2012; Stansley and Yamamoto 2014). Importantly, proper 5-HT function in these regions is crucial for normal behavioral physiology (Lowry, Johnson et al 2005; Maier and Watkins 2005; Berger, Gray et al 2009; Monti 2011) such that 5-HT deficits in these areas result in impaired memory consolidation, executive cognitive dysfunction, fear, depression and anxiety (Lowry, Hale et al 2008; Soh, McGinley et al 2011; Euston, Gruber et al 2012; Izumi, Ohmura et al 2012).…”