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Chronic salsolinol administration prevents the behavioral and neurochemical effects of L-DOPA in rats.

Wąsik A, Romańska I, Michaluk J, Antkiewicz-Michaluk L - Neurotox Res (2015)

Bottom Line: Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment.These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration.In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland, wasik@if-pan.krakow.pl.

ABSTRACT
1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is a well-known endogenous compound that has been proposed as a factor involved in the pathogenesis of Parkinson's disease. In the present study, we investigated the impact of acute and chronic salsolinol (100 mg.kg i.p.) administration on L-DOPA-induced locomotor hyperactivity and neurochemical changes (the dopamine level and its metabolism in rat brain structures). Moreover, using the in vivo microdialysis technique, we measured the effect of acute and chronic salsolinol injection on L-DOPA-induced dopamine release in the rat striatum. The behavioral data demonstrated that both acute and chronic salsolinol administration antagonized L-DOPA-mediated hyperactivity. An ex vivo neurochemical experiment indicated that chronic but not acute salsolinol administration partially inhibited the L-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment. Acute injection of salsolinol enhanced the L-DOPA-induced elevation of dopamine release (by ~1200 %; P < 0.01), whereas chronic administration of salsolinol completely blocked the L-DOPA-induced elevation of dopamine release in the rat striatum. These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration. In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy.

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The influence of acute (a) and chronic (b) administration of salsolinol on l-DOPA-induced changes in the locomotor activity of rats. The rats were placed in actometers and, after 40 min of adaptation, received the specified drugs. Salsolinol was administered at a dose of 100 mg/kg i.p acutely (a) or chronically for 14 consecutive days (b). In the combined treatment group, l-DOPA (100 mg/kg i.p.) was administered once 15 min after final salsolinol administration. The control rats received a single injection of saline. Next, the measurement was recorded for 30 min. The data are expressed as the means  ±  SEM (n = 6). The data were analyzed via two-way ANOVA followed by Duncan’s post hoc test when appropriate. Statistical significance: *P < 0.05, **P < 0.01 versus the control group; +P < 0.05 versus the l-DOPA-treated group
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Fig1: The influence of acute (a) and chronic (b) administration of salsolinol on l-DOPA-induced changes in the locomotor activity of rats. The rats were placed in actometers and, after 40 min of adaptation, received the specified drugs. Salsolinol was administered at a dose of 100 mg/kg i.p acutely (a) or chronically for 14 consecutive days (b). In the combined treatment group, l-DOPA (100 mg/kg i.p.) was administered once 15 min after final salsolinol administration. The control rats received a single injection of saline. Next, the measurement was recorded for 30 min. The data are expressed as the means  ±  SEM (n = 6). The data were analyzed via two-way ANOVA followed by Duncan’s post hoc test when appropriate. Statistical significance: *P < 0.05, **P < 0.01 versus the control group; +P < 0.05 versus the l-DOPA-treated group

Mentions: Duncan’s post hoc test showed that acute administration of l-DOPA (100 mg/kg i.p.) induced a significant elevation of horizontal locomotor activity by the rats (P < 0.01). However, salsolinol administered alone at a dose of 100 mg/kg i.p. did not change their locomotor activity (Fig. 1a). Similarly, in the combined treatment group, salsolinol did not influence on l-DOPA-induced hyperactivity (Fig. 1a).Fig. 1


Chronic salsolinol administration prevents the behavioral and neurochemical effects of L-DOPA in rats.

Wąsik A, Romańska I, Michaluk J, Antkiewicz-Michaluk L - Neurotox Res (2015)

The influence of acute (a) and chronic (b) administration of salsolinol on l-DOPA-induced changes in the locomotor activity of rats. The rats were placed in actometers and, after 40 min of adaptation, received the specified drugs. Salsolinol was administered at a dose of 100 mg/kg i.p acutely (a) or chronically for 14 consecutive days (b). In the combined treatment group, l-DOPA (100 mg/kg i.p.) was administered once 15 min after final salsolinol administration. The control rats received a single injection of saline. Next, the measurement was recorded for 30 min. The data are expressed as the means  ±  SEM (n = 6). The data were analyzed via two-way ANOVA followed by Duncan’s post hoc test when appropriate. Statistical significance: *P < 0.05, **P < 0.01 versus the control group; +P < 0.05 versus the l-DOPA-treated group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383836&req=5

Fig1: The influence of acute (a) and chronic (b) administration of salsolinol on l-DOPA-induced changes in the locomotor activity of rats. The rats were placed in actometers and, after 40 min of adaptation, received the specified drugs. Salsolinol was administered at a dose of 100 mg/kg i.p acutely (a) or chronically for 14 consecutive days (b). In the combined treatment group, l-DOPA (100 mg/kg i.p.) was administered once 15 min after final salsolinol administration. The control rats received a single injection of saline. Next, the measurement was recorded for 30 min. The data are expressed as the means  ±  SEM (n = 6). The data were analyzed via two-way ANOVA followed by Duncan’s post hoc test when appropriate. Statistical significance: *P < 0.05, **P < 0.01 versus the control group; +P < 0.05 versus the l-DOPA-treated group
Mentions: Duncan’s post hoc test showed that acute administration of l-DOPA (100 mg/kg i.p.) induced a significant elevation of horizontal locomotor activity by the rats (P < 0.01). However, salsolinol administered alone at a dose of 100 mg/kg i.p. did not change their locomotor activity (Fig. 1a). Similarly, in the combined treatment group, salsolinol did not influence on l-DOPA-induced hyperactivity (Fig. 1a).Fig. 1

Bottom Line: Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment.These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration.In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland, wasik@if-pan.krakow.pl.

ABSTRACT
1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is a well-known endogenous compound that has been proposed as a factor involved in the pathogenesis of Parkinson's disease. In the present study, we investigated the impact of acute and chronic salsolinol (100 mg.kg i.p.) administration on L-DOPA-induced locomotor hyperactivity and neurochemical changes (the dopamine level and its metabolism in rat brain structures). Moreover, using the in vivo microdialysis technique, we measured the effect of acute and chronic salsolinol injection on L-DOPA-induced dopamine release in the rat striatum. The behavioral data demonstrated that both acute and chronic salsolinol administration antagonized L-DOPA-mediated hyperactivity. An ex vivo neurochemical experiment indicated that chronic but not acute salsolinol administration partially inhibited the L-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment. Acute injection of salsolinol enhanced the L-DOPA-induced elevation of dopamine release (by ~1200 %; P < 0.01), whereas chronic administration of salsolinol completely blocked the L-DOPA-induced elevation of dopamine release in the rat striatum. These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration. In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy.

Show MeSH
Related in: MedlinePlus