Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice.
1-(Meta-chloro)phenylpiperazine (m-CPP) is a 5-HT receptor agonist which has been purported to be relatively selective for the 5-HT2C receptor. In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors. The present study investigated the effects of m-CPP alone and in the presence of the 5-HT2 receptor antagonist 6-methyl-1-(-methyethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2pyridinyl)c yclohexanecarboxamide trihydrochloride (WAY 100,635), and the 5-HT(1B/1D) receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-corbox ylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935) on locomotor activity. Administration of m-CPP alone (0.3-10 mg/kg) produced a dose-related decrease in locomotor activity. The 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) in combination with m-CPP produced a slight leftward shift of the dose-response curve of m-CPP. The 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg) in combination with m-CPP did not alter the m-CPP dose-response curve. The non-selective 5-HT2 receptor antagonist LY53857 (1.0 mg/kg) in combination with m-CPP unmasked a hyperlocomotion produced by m-CPP. Furthermore, the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg). The present results demonstrate that the hyperlocomotion seen with the combination of m-CPP and LY53857 is mediated by 5-HT1 receptors. Taken together the data indicate that m-CPP affects locomotor activity by the physiologic summation of agonist activity at the 5-HT2C receptor as well as the 5-HT1 receptor family.
Gleason
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SD
The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. gleason_scott_d@lilly.com
Shannon
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HE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D004873:Ergolines; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090701:GR 127935; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C032663:LY 53857; C015068:1-(3-chlorophenyl)piperazine