| First Author | Heisler LK | Year | 2000 |
| Journal | J Neurosci | Volume | 20 |
| Issue | 8 | Pages | RC71 |
| PubMed ID | 10751458 | Mgi Jnum | J:121198 |
| Mgi Id | MGI:3709515 | Doi | 10.1523/JNEUROSCI.20-08-j0003.2000 |
| Citation | Heisler LK, et al. (2000) A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice. J Neurosci 20(8):RC71 |
| abstractText | Paradoxical behavioral responses to nonselective neuropsychiatric drugs are frequently encountered and poorly understood. We report that a single receptor gene mutation produces a paradoxical response to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compound normally suppresses locomotion, it produces hyperactivity in mice bearing a targeted mutation of the 5-HT(2C) receptor gene. This effect was blocked by pretreatment with a 5-HT(1B) receptor antagonist, indicating that the behavioral consequences of mCPP-induced 5-HT(1B) receptor stimulation are unmasked in animals devoid of 5-HT(2C) receptor function. Furthermore, this paradoxical response to mCPP was reproduced in wild-type C57BL/6 mice by previous pharmacological blockade of 5-HT(2C) receptors, indicating that the mutant phenotype does not result from perturbations of brain development. These effects of 5-HT1B and 5-HT(2C) receptor antagonists likely reflected blockade of pharmacological actions of mCPP, because these compounds did not alter locomotor activity levels when administered alone. Thus, mCPP interacts with distinct 5-HT receptor targets that produce opposing effects on locomotor activity levels. A paradoxical behavioral response is produced by the genetic inactivation of the target that produces the prevailing effect of the drug in the wild-type animal. This genetically based paradoxical drug effect provides a model for considering the effects of genetic load on neurobehavioral responses to drugs. |
