5-HT1B receptor knockout mice show a compensatory reduction in 5-HT2C receptor function.
Although null mutant ('knockout') mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition. These effects are not mimicked by pretreatment of wildtype (WT) mice with a 5-HT1B receptor antagonist showing that they result from a longer term adaptation to the loss of 5-HT1B receptor function and not from a short-term interaction between 5-HT1B- and 5-HT2C-mediated functions. In addition, we show that 5-HT1B receptor KO mice have a lowered hypothalamic c-fos response to the administration of 5-HT2C receptor agonists. These results demonstrate that compensatory adaptations to the constitutive loss of 5-HT1B receptors may be an important determinant of the altered response of 5-HT1B KO mice to a variety of pharmacological challenges.
Clifton
Peter G
PG
Experimental Psychology, University of Sussex, Brighton BN1 9QG, UK. pete@biols.susx.ac.uk
Lee
Michelle D
MD
Somerville
Elizabeth M
EM
Kennett
Guy A
GA
Dourish
Colin T
CT
D000818:Animals; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004435:Eating / Q000187:drug effects; D005021:Ethylamines / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000172:deficiency* / Q000378:metabolism* / Q000502:physiology; D018490:Serotonin Agents / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
D005021:Ethylamines; D007211:Indoles; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; C015068:1-(3-chlorophenyl)piperazine