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The 5-HT(2A) Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate.

Ansah TA, Ferguson MC, Nayyar T - Front Syst Neurosci (2011)

Bottom Line: 5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD).We hypothesized that 5-HT(2A) receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum.In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College Nashville, TN, USA.

ABSTRACT
5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT(2) receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT(2A) receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT(2A) receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT(2A) receptors may represent a novel therapeutic target for the motor symptoms of PD.

No MeSH data available.


Related in: MedlinePlus

M100907 decreased glutamate levels in the dorsal striatum in saline and MPTP-treated mice. Data are expressed as percentages of values in saline-injected control mice. Dialysis was carried out 3 weeks after MPTP or saline treatment and 7 days after the cannula implantation. (A) Five baseline samples were first collected and then a challenge dose of M100907 (100 nM) and an additional seven samples were collected. (B) The effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. ***p < 0.001 compared with saline-injected control mice; ###p < 0.001 when compared with MPTP-treated mice. The line segment on time course graphs indicate duration of drug administration.
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Figure 3: M100907 decreased glutamate levels in the dorsal striatum in saline and MPTP-treated mice. Data are expressed as percentages of values in saline-injected control mice. Dialysis was carried out 3 weeks after MPTP or saline treatment and 7 days after the cannula implantation. (A) Five baseline samples were first collected and then a challenge dose of M100907 (100 nM) and an additional seven samples were collected. (B) The effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. ***p < 0.001 compared with saline-injected control mice; ###p < 0.001 when compared with MPTP-treated mice. The line segment on time course graphs indicate duration of drug administration.

Mentions: We hypothesized that 5-HT2A receptor antagonists may restore motor function by normalizing the overactive glutamatergic drive resulting from DA depletion. We have used in vivo microdialysis to determine whether extracellular striatal glutamate is increased in mice treated with MPTP and whether local administration of the 5-HT2A receptor antagonist M100907 will decrease striatal glutamate. The mean basal striatal extracellular glutamate levels in the dialysates obtained from saline-treated mice used in these studies were 3.41 ± .24 pmol/μL (mean ± SEM; n =  11; Figure 3). Local application of 1 μM tetrodotoxin resulted in a dramatic fall in basal glutamate output reaching 25% of baseline (data not shown). This suggests that a significant fraction of the resting level of striatal glutamate is of neuronal origin. Figure 3A depicts the time course of the effects of M100907 on basal glutamate levels (expressed as percentage of values of saline-injected controls) of saline and MPTP-treated mice. MPTP-treated mice exhibited increased basal extracellular glutamate levels compared to the saline-treated mice (Figure 3A). Local perfusion of 100 nM M100907 into the dorsal striatum decreased basal glutamate levels in saline- and MPTP-treated mice. Two-way ANOVA of the time course data revealed significant main effects for treatment [F(1,28) = 230.7; p < 0.0001, drug effect, F(1,28) = 305, p < 0.0001, and treatment × drug interaction F(1,28) = 65.67; p < 0.0001; Figure 3A]. The significant treatment x drug interaction suggests that despite elevated basal glutamate levels in the MPTP-treated mice, M100907 was capable of significantly suppressing glutamate output. Figure 3B compares the effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. The baseline data were obtained from the average of five time points and data for drug treatment were obtained from average of seven time points from Figure 3A. One-way ANOVA revealed significant main effects [F(3,28) = 49.20; p < 0.0001; Figure 3B]. Post hoc analysis using the Tukey's multiple comparison test revealed a significant increase (p < 0.001) in basal extracellular glutamate values in MPTP-treated mice (Figure 3B). Local perfusion of 100 nM M100907 into the dorsal striatum significantly decreased basal glutamate levels in saline (p < 0.001) and MPTP (p < 0.001)-treated mice (Figure 3B).


The 5-HT(2A) Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate.

Ansah TA, Ferguson MC, Nayyar T - Front Syst Neurosci (2011)

M100907 decreased glutamate levels in the dorsal striatum in saline and MPTP-treated mice. Data are expressed as percentages of values in saline-injected control mice. Dialysis was carried out 3 weeks after MPTP or saline treatment and 7 days after the cannula implantation. (A) Five baseline samples were first collected and then a challenge dose of M100907 (100 nM) and an additional seven samples were collected. (B) The effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. ***p < 0.001 compared with saline-injected control mice; ###p < 0.001 when compared with MPTP-treated mice. The line segment on time course graphs indicate duration of drug administration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117200&req=5

Figure 3: M100907 decreased glutamate levels in the dorsal striatum in saline and MPTP-treated mice. Data are expressed as percentages of values in saline-injected control mice. Dialysis was carried out 3 weeks after MPTP or saline treatment and 7 days after the cannula implantation. (A) Five baseline samples were first collected and then a challenge dose of M100907 (100 nM) and an additional seven samples were collected. (B) The effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. ***p < 0.001 compared with saline-injected control mice; ###p < 0.001 when compared with MPTP-treated mice. The line segment on time course graphs indicate duration of drug administration.
Mentions: We hypothesized that 5-HT2A receptor antagonists may restore motor function by normalizing the overactive glutamatergic drive resulting from DA depletion. We have used in vivo microdialysis to determine whether extracellular striatal glutamate is increased in mice treated with MPTP and whether local administration of the 5-HT2A receptor antagonist M100907 will decrease striatal glutamate. The mean basal striatal extracellular glutamate levels in the dialysates obtained from saline-treated mice used in these studies were 3.41 ± .24 pmol/μL (mean ± SEM; n =  11; Figure 3). Local application of 1 μM tetrodotoxin resulted in a dramatic fall in basal glutamate output reaching 25% of baseline (data not shown). This suggests that a significant fraction of the resting level of striatal glutamate is of neuronal origin. Figure 3A depicts the time course of the effects of M100907 on basal glutamate levels (expressed as percentage of values of saline-injected controls) of saline and MPTP-treated mice. MPTP-treated mice exhibited increased basal extracellular glutamate levels compared to the saline-treated mice (Figure 3A). Local perfusion of 100 nM M100907 into the dorsal striatum decreased basal glutamate levels in saline- and MPTP-treated mice. Two-way ANOVA of the time course data revealed significant main effects for treatment [F(1,28) = 230.7; p < 0.0001, drug effect, F(1,28) = 305, p < 0.0001, and treatment × drug interaction F(1,28) = 65.67; p < 0.0001; Figure 3A]. The significant treatment x drug interaction suggests that despite elevated basal glutamate levels in the MPTP-treated mice, M100907 was capable of significantly suppressing glutamate output. Figure 3B compares the effects of M100907 on extracellular glutamate values of saline and MPTP-treated mice. The baseline data were obtained from the average of five time points and data for drug treatment were obtained from average of seven time points from Figure 3A. One-way ANOVA revealed significant main effects [F(3,28) = 49.20; p < 0.0001; Figure 3B]. Post hoc analysis using the Tukey's multiple comparison test revealed a significant increase (p < 0.001) in basal extracellular glutamate values in MPTP-treated mice (Figure 3B). Local perfusion of 100 nM M100907 into the dorsal striatum significantly decreased basal glutamate levels in saline (p < 0.001) and MPTP (p < 0.001)-treated mice (Figure 3B).

Bottom Line: 5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD).We hypothesized that 5-HT(2A) receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum.In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College Nashville, TN, USA.

ABSTRACT
5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT(2) receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT(2A) receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT(2A) receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT(2A) receptors may represent a novel therapeutic target for the motor symptoms of PD.

No MeSH data available.


Related in: MedlinePlus