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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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Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to DOI 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 vs vehicle-vehicle control.
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Figure 3: Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to DOI 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 vs vehicle-vehicle control.

Mentions: As expected, treatment with 1.0 mg/kg DOI produced an increase in distance traveled (F(1,36)=18.04, p=0.0001), but there was no interaction between SER-082 pretreatment and 1.0 mg/kg DOI treatment. Treatment with a higher dose of DOI (10 mg/kg) reduced distance traveled during the initial blocks of testing, resulting in an interaction between drug and time (F(5,180)=8.44, p<0.0001). Pretreatment with the 5-HT2C/2B antagonist SER-082 attenuated the reduction of locomotor activity induced by 10 mg/kg DOI, resulting in an interaction between SER-082 pretreatment and 10 mg/kg DOI treatment during the first 10 min of testing (F(1,36)=4.63, p<0.04). Post-hoc analysis indicated that there was a trend toward blockade of the DOI-induced decrease in locomotor activity (Figure 3; p<0.1, Tukey’s test). There was an interaction of SER-082 pretreatment with time (F(5,270)=6.16, p<0.0001), but post hoc analysis failed to confirm the effect of SER-082 for any specific time block.


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)

Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to DOI 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 vs vehicle-vehicle control.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Effect of pretreatment with SER-082 on the locomotor response (measured as distance traveled) to DOI 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 vs vehicle-vehicle control.
Mentions: As expected, treatment with 1.0 mg/kg DOI produced an increase in distance traveled (F(1,36)=18.04, p=0.0001), but there was no interaction between SER-082 pretreatment and 1.0 mg/kg DOI treatment. Treatment with a higher dose of DOI (10 mg/kg) reduced distance traveled during the initial blocks of testing, resulting in an interaction between drug and time (F(5,180)=8.44, p<0.0001). Pretreatment with the 5-HT2C/2B antagonist SER-082 attenuated the reduction of locomotor activity induced by 10 mg/kg DOI, resulting in an interaction between SER-082 pretreatment and 10 mg/kg DOI treatment during the first 10 min of testing (F(1,36)=4.63, p<0.04). Post-hoc analysis indicated that there was a trend toward blockade of the DOI-induced decrease in locomotor activity (Figure 3; p<0.1, Tukey’s test). There was an interaction of SER-082 pretreatment with time (F(5,270)=6.16, p<0.0001), but post hoc analysis failed to confirm the effect of SER-082 for any specific time block.

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