5-HT2A and 5-HT2C Receptors Exert Opposing Effects on Locomotor Activity in Mice

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 34; no. 8; pp. 1958 - 1967
• Main Authors: HALBERSTADT, Adam L, VAN DER HEIJDEN, Iris, RUDERMAN, Michael A, RISBROUGH, Victoria B, GINGRICH, Jay A, GEYER, Mark A, POWELL, Susan B
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 25.03.2009
• Subjects: Biological and medical sciences; Drug dosages; Hallucinogens; Hypothesis testing; LSD; Lysergic acid diethylamide; Medical sciences; Psychiatry; La Jolla California; United States > US; California; 5-HT2A serotonin receptor; knockout; Serotonin; Rodentia; mice; Locomotion; Vertebrata; Mammalia; Gene; Mouse; Animal; Hallucinogen; Neurotransmitter; Genetics; locomotor activity; Mutation; DOI
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2009.29

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.