Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT 1 as well as 5-HT 2C receptors in mice

Abstract

1-( meta-chloro)phenylpiperazine ( m-CPP) is a 5-HT receptor agonist which has been purported to be relatively selective for the 5-HT 2C receptor. In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT 2C receptors. m-CPP binds with high affinity to 5-HT 1 as well as 5-HT 2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT 1 as well as 5-HT 2 receptors. The present study investigated the effects of m-CPP alone and in the presence of the 5-HT 2 receptor antagonist 6-methyl-1-(1-methyethyl)-ergoline-8 β-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT 1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]- ethyl}- N-(2pyridinyl)cyclohexanecarboxamide 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-corboxylic 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-HT 1A 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-HT 2 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-HT 1A 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-HT 1 receptors. Taken together the data indicate that m-CPP affects locomotor activity by the physiologic summation of agonist activity at the 5-HT 2C receptor as well as the 5-HT 1 receptor family.