A paradoxical locomotor response in serotonin 5-HT2C receptor mutant mice

Paradoxical behavioral responses to nonselective neuropsychiatric drugs are frequently encountered and poorly understood. We report that a single rece ptor gene mutation produces a paradoxical response to the nonspecific serot onin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compou nd normally suppresses locomotion, it produces hyperactivity in mice bearin g a targeted mutation of the 5-HT2C receptor gene. This effect was blocked by pretreatment with a 5-HT1B receptor antagonist, indicating that the beha vioral consequences of mCPP-induced 5-HT1B receptor stimulation are unmaske d in animals devoid of 5-HT2C receptor function. Furthermore, this paradoxi cal response to mCPP was reproduced in wild-type C57BL/6 mice by previous p harmacological blockade of 5-HT2C receptors, indicating that the mutant phe notype does not result from perturbations of brain development. These effec ts of 5-HT1B and 5-HT2C receptor antagonists likely reflected blockade of p harmacological actions of mCPP, because these compounds did not alter locom otor activity levels when administered alone. Thus, mCPP interacts with dis tinct 5 HT receptor targets that produce opposing effects on locomotor acti vity levels. A paradoxical behavioral response is produced by the genetic i nactivation of the target that produces the prevailing effect of the drug i n the wild-type animal. This genetically based paradoxical drug effect prov ides a model for considering the effects of genetic load on neurobehavioral responses to drugs.