title: Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists.
abstract: Serotonergic transmission has been suggested to modulate the effects of cocaine. However, the specific receptors underlying this phenomenon have not been identified. To evaluate the role of the 5-HT1B receptor in mediating the actions of cocaine, we used two model systems: knockout (KO) mice lacking the 5-HT1B receptor and an acute treatment with the 5-HT1B/1D antagonist GR127935. GR127935 attenuated the ability of cocaine to stimulate locomotion and induce c-fos expression in the striatum. However, GR127935 had no apparent effect on the rewarding or sensitizing effects of cocaine. In contrast, as demonstrated previously, the 5-HT1B receptor KO mice showed a heightened locomotor response to cocaine, as well as an increased propensity to self-administer cocaine. Thus, an acute pharmacological blockade of the 5-HT1B receptor decreases some effects of cocaine, while a constitutive genetic KO of the same receptor has opposite effects. These results suggest that compensatory changes have taken place during the development of the 5-HT1B KO mice, which may have rendered these mice more vulnerable to cocaine. The 5-HT1B KO mice should therefore be considered as a genetic model of vulnerability to drug abuse rather than a classic pharmacological tool.
authors.affiliation: Institut Francois Magendie, INSERM U394, rue Camille Saint Saens, 33077 Cedex, Bordeaux, France.
authors.forename: N
authors.initials: N
authors.lastname: Castanon
authors.forename: K
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: J J
authors.initials: JJ
authors.lastname: Lucas
authors.forename: B
authors.initials: B
authors.lastname: Rocha
authors.forename: R
authors.initials: R
authors.lastname: Hen
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D010069:Oxadiazoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C090701:GR 127935; D003042:Cocaine