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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 5-HT2A gene deletion on the locomotor response to DOI. Effect of vehicle or 1 mg/kg DOI (left panel) or vehicle or 10 mg/kg DOI (right panel) on distance traveled (in cm) in male and female 5-HT2A WT and KO mice. Data are mean±SEM. *p<0.025 compared to vehicle control
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Figure 2: Effect of 5-HT2A gene deletion on the locomotor response to DOI. Effect of vehicle or 1 mg/kg DOI (left panel) or vehicle or 10 mg/kg DOI (right panel) on distance traveled (in cm) in male and female 5-HT2A WT and KO mice. Data are mean±SEM. *p<0.025 compared to vehicle control

Mentions: Although there was a main effect of sex on distance traveled (F(1,41)=4.18, p<0.05), there was no interaction between sex and either gene or drug, or between sex, gene, and drug, so data were collapsed across sex. The effect of DOI treatment on distance traveled in 5-HT2A WT and KO mice is illustrated in Figure 2. Treatment with 1 mg/kg DOI had no effect on locomotor activity in 5-HT2A KO mice (Gene × Drug × Time: F(5,215)=2.45, p<0.04). Conversely, 1 mg/kg DOI increased distance traveled in WT mice (F(1,43)=6.65, p<0.02), an effect that occurred primarily during the last 40 min of the 1-h session (Drug × Time: F(5,215)=5.18, p<0.0001). As observed previously in C57BL/6J mice, administration of 10 mg/kg DOI to WT mice reduced distance traveled during the initial blocks of testing (Drug × Time: F(5,215)=20.22, p<0.0001). Interestingly, the duration of DOI-induced hypoactivity was significantly prolonged in 5-HT2A KO mice (Gene × Drug: F(1,43)=17.42, p=0.0001). Post-hoc ANOVAs confirmed that 10 mg/kg DOI significantly reduced distance traveled during the first 50 min of the 1-h session. At baseline, 5-HT2A KO mice display a hypoactive phenotype (F(1,43)=15.66, p=0.0003) relative to their WT littermates. However, post-hoc ANOVAs failed to reveal any 10-min time block during which the 5-HT2A KO mice significantly reduced distance traveled relative to WT mice.


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 5-HT2A gene deletion on the locomotor response to DOI. Effect of vehicle or 1 mg/kg DOI (left panel) or vehicle or 10 mg/kg DOI (right panel) on distance traveled (in cm) in male and female 5-HT2A WT and KO mice. Data are mean±SEM. *p<0.025 compared to vehicle control
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Effect of 5-HT2A gene deletion on the locomotor response to DOI. Effect of vehicle or 1 mg/kg DOI (left panel) or vehicle or 10 mg/kg DOI (right panel) on distance traveled (in cm) in male and female 5-HT2A WT and KO mice. Data are mean±SEM. *p<0.025 compared to vehicle control
Mentions: Although there was a main effect of sex on distance traveled (F(1,41)=4.18, p<0.05), there was no interaction between sex and either gene or drug, or between sex, gene, and drug, so data were collapsed across sex. The effect of DOI treatment on distance traveled in 5-HT2A WT and KO mice is illustrated in Figure 2. Treatment with 1 mg/kg DOI had no effect on locomotor activity in 5-HT2A KO mice (Gene × Drug × Time: F(5,215)=2.45, p<0.04). Conversely, 1 mg/kg DOI increased distance traveled in WT mice (F(1,43)=6.65, p<0.02), an effect that occurred primarily during the last 40 min of the 1-h session (Drug × Time: F(5,215)=5.18, p<0.0001). As observed previously in C57BL/6J mice, administration of 10 mg/kg DOI to WT mice reduced distance traveled during the initial blocks of testing (Drug × Time: F(5,215)=20.22, p<0.0001). Interestingly, the duration of DOI-induced hypoactivity was significantly prolonged in 5-HT2A KO mice (Gene × Drug: F(1,43)=17.42, p=0.0001). Post-hoc ANOVAs confirmed that 10 mg/kg DOI significantly reduced distance traveled during the first 50 min of the 1-h session. At baseline, 5-HT2A KO mice display a hypoactive phenotype (F(1,43)=15.66, p=0.0003) relative to their WT littermates. However, post-hoc ANOVAs failed to reveal any 10-min time block during which the 5-HT2A KO mice significantly reduced distance traveled relative to WT mice.

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