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5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice.

Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB - Neuropsychopharmacology (2009)

Bottom Line: Although it is well established that hallucinogens act as 5-HT(2A) and 5-HT(2C) receptor agonists, little is known about the relative contributions of 5-HT(2A) and 5-HT(2C) receptors to the acute behavioral effects of these drugs.Studies were also conducted to assess the contributions of 5-HT(2A) and 5-HT(2C) receptors to the behavioral effects of DOI.Furthermore, these data also suggest that 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0804, USA.

ABSTRACT
Although it is well established that hallucinogens act as 5-HT(2A) and 5-HT(2C) receptor agonists, little is known about the relative contributions of 5-HT(2A) and 5-HT(2C) receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT(2A) and 5-HT(2C) receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose-response function, with lower doses (0.625-5.0 mg/kg) increasing and higher doses (> or =10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT(2A) receptor KO mice, suggesting the involvement of 5-HT(2A) receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT(2A) KO mice and attenuated by pretreatment with the selective 5-HT(2C/2B) antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT(2C) receptors, an interpretation that is supported by the finding that the selective 5-HT(2C) agonist WAY 161,503 produces reductions in the locomotor activity that are potentiated in 5HT(2A) KO mice. These results show for the first time that 5-HT(2A) and 5-HT(2C) receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity.

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Effects of WAY-161,503 on locomotor activity. (a) Dose response of WAY 161,503 effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control. (b) Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to WAY 161,503 during the first 10 min of testing. Mice used were male C57BL/6J. Doses are in mg/kg. Data are mean±SEM. **p<0.01, Tukey’s test. (c) Effect of 5-HT2A gene deletion on the locomotor response to vehicle or 10 mg/kg WAY 161,503 in male and female 5-HT2A WT and KO mice. Data are mean±SEM. **p<0.01, Tukey’s test vs 5-HT2A WT vehicle.
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Figure 4: Effects of WAY-161,503 on locomotor activity. (a) Dose response of WAY 161,503 effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control. (b) Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to WAY 161,503 during the first 10 min of testing. Mice used were male C57BL/6J. Doses are in mg/kg. Data are mean±SEM. **p<0.01, Tukey’s test. (c) Effect of 5-HT2A gene deletion on the locomotor response to vehicle or 10 mg/kg WAY 161,503 in male and female 5-HT2A WT and KO mice. Data are mean±SEM. **p<0.01, Tukey’s test vs 5-HT2A WT vehicle.

Mentions: Treatment with the 5-HT2C-selective agonist WAY 161,503 had a significant effect on distance traveled (F(3,42)=26.22, p<0.0001), and there was a significant interaction of WAY 161,503 treatment with time (F(15,170)=10.92, p<0.0001). The high dose, 30 mg/kg, was the most effective, with post hoc analysis indicating this group had significantly lower distance traveled compared with vehicle in all time blocks, whereas the decrease induced by the 10 mg/kg dose reached significance only during the first 20 min of the session (Figure 4a; p<0.01, Dunnett’s test).


5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice.

Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB - Neuropsychopharmacology (2009)

Effects of WAY-161,503 on locomotor activity. (a) Dose response of WAY 161,503 effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control. (b) Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to WAY 161,503 during the first 10 min of testing. Mice used were male C57BL/6J. Doses are in mg/kg. Data are mean±SEM. **p<0.01, Tukey’s test. (c) Effect of 5-HT2A gene deletion on the locomotor response to vehicle or 10 mg/kg WAY 161,503 in male and female 5-HT2A WT and KO mice. Data are mean±SEM. **p<0.01, Tukey’s test vs 5-HT2A WT vehicle.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2697271&req=5

Figure 4: Effects of WAY-161,503 on locomotor activity. (a) Dose response of WAY 161,503 effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control. (b) Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to WAY 161,503 during the first 10 min of testing. Mice used were male C57BL/6J. Doses are in mg/kg. Data are mean±SEM. **p<0.01, Tukey’s test. (c) Effect of 5-HT2A gene deletion on the locomotor response to vehicle or 10 mg/kg WAY 161,503 in male and female 5-HT2A WT and KO mice. Data are mean±SEM. **p<0.01, Tukey’s test vs 5-HT2A WT vehicle.
Mentions: Treatment with the 5-HT2C-selective agonist WAY 161,503 had a significant effect on distance traveled (F(3,42)=26.22, p<0.0001), and there was a significant interaction of WAY 161,503 treatment with time (F(15,170)=10.92, p<0.0001). The high dose, 30 mg/kg, was the most effective, with post hoc analysis indicating this group had significantly lower distance traveled compared with vehicle in all time blocks, whereas the decrease induced by the 10 mg/kg dose reached significance only during the first 20 min of the session (Figure 4a; p<0.01, Dunnett’s test).

Bottom Line: Although it is well established that hallucinogens act as 5-HT(2A) and 5-HT(2C) receptor agonists, little is known about the relative contributions of 5-HT(2A) and 5-HT(2C) receptors to the acute behavioral effects of these drugs.Studies were also conducted to assess the contributions of 5-HT(2A) and 5-HT(2C) receptors to the behavioral effects of DOI.Furthermore, these data also suggest that 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0804, USA.

ABSTRACT
Although it is well established that hallucinogens act as 5-HT(2A) and 5-HT(2C) receptor agonists, little is known about the relative contributions of 5-HT(2A) and 5-HT(2C) receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT(2A) and 5-HT(2C) receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose-response function, with lower doses (0.625-5.0 mg/kg) increasing and higher doses (> or =10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT(2A) receptor KO mice, suggesting the involvement of 5-HT(2A) receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT(2A) KO mice and attenuated by pretreatment with the selective 5-HT(2C/2B) antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT(2C) receptors, an interpretation that is supported by the finding that the selective 5-HT(2C) agonist WAY 161,503 produces reductions in the locomotor activity that are potentiated in 5HT(2A) KO mice. These results show for the first time that 5-HT(2A) and 5-HT(2C) receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity.

Show MeSH
Related in: MedlinePlus