A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice.
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.
Heisler
L K
LK
Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California, San Francisco, San Francisco, California 94143-0984, USA.
Tecott
L H
LH
D000818:Animals; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009154:Mutation; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090701:GR 127935; C094868:SB 206553; C015068:1-(3-chlorophenyl)piperazine