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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 DOI on locomotor activity. (a) Dose response of DOI effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. *p<0.05, Dunnett’s test vs vehicle control. (b) The effects of high doses of DOI on locomotor activity were evaluated in a second dose response experiment. Data shown are the distance traveled (cm) during the first 10 min of testing. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control.
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Figure 1: Effects of DOI on locomotor activity. (a) Dose response of DOI effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. *p<0.05, Dunnett’s test vs vehicle control. (b) The effects of high doses of DOI on locomotor activity were evaluated in a second dose response experiment. Data shown are the distance traveled (cm) during the first 10 min of testing. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control.

Mentions: The effect of varying doses of DOI on distance traveled, a measure of locomotor activity, is shown in Figure 1a for successive 10-min intervals of the 1-h test session. DOI administration produced an inverted U-shaped dose-response function on distance traveled (F(5,57)=2.84, p<0.03). The 0.625, 1.25 mg/kg, and 5.0 mg/kg doses of DOI produced a delayed increase in distance traveled compared with vehicle, with post hoc analysis indicating these dosage groups had significantly higher locomotor activity during the last 40 min of the test session (p<0.05, Dunnett’s test). Conversely, compared with vehicle, there was a nonsignificant trend for the highest dose of DOI tested (10 mg/kg) to reduce distance traveled during the initial 10 min of testing (mean ± S.E.M.: vehicle = 4405.9 ± 215.2 cm, 10 mg/kg = 3829.3 ± 238.3 cm, F(1,19)=3.24, p<0.09).


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 DOI on locomotor activity. (a) Dose response of DOI effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. *p<0.05, Dunnett’s test vs vehicle control. (b) The effects of high doses of DOI on locomotor activity were evaluated in a second dose response experiment. Data shown are the distance traveled (cm) during the first 10 min of testing. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697271&req=5

Figure 1: Effects of DOI on locomotor activity. (a) Dose response of DOI effects on distance traveled (in cm). Mice used were male C57BL/6J. Data are mean±SEM. *p<0.05, Dunnett’s test vs vehicle control. (b) The effects of high doses of DOI on locomotor activity were evaluated in a second dose response experiment. Data shown are the distance traveled (cm) during the first 10 min of testing. Data are mean±SEM. **p<0.01, Dunnett’s test vs vehicle control.
Mentions: The effect of varying doses of DOI on distance traveled, a measure of locomotor activity, is shown in Figure 1a for successive 10-min intervals of the 1-h test session. DOI administration produced an inverted U-shaped dose-response function on distance traveled (F(5,57)=2.84, p<0.03). The 0.625, 1.25 mg/kg, and 5.0 mg/kg doses of DOI produced a delayed increase in distance traveled compared with vehicle, with post hoc analysis indicating these dosage groups had significantly higher locomotor activity during the last 40 min of the test session (p<0.05, Dunnett’s test). Conversely, compared with vehicle, there was a nonsignificant trend for the highest dose of DOI tested (10 mg/kg) to reduce distance traveled during the initial 10 min of testing (mean ± S.E.M.: vehicle = 4405.9 ± 215.2 cm, 10 mg/kg = 3829.3 ± 238.3 cm, F(1,19)=3.24, p<0.09).

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