Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2000-11, Vol.67 (3), p.559-566
• Main Authors: Castanon, Nathalie, Scearce-Levie, Kimberly, Lucas, Jose J, Rocha, Beatriz, Hen, René
• Format: Article
• Language: English
• Subjects: 129/Sv mice; 5-HT1B receptors; Animals; Behavioral sensitization; Biological and medical sciences; c- fos induction; C57Bl/6J mice; Cell receptors; Cell structures and functions; Cocaine; Cocaine - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine Uptake Inhibitors - pharmacology; Drug addictions; Fundamental and applied biological sciences. Psychology; GR127935; Life Sciences; Locomotor activity; Male; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Motor Activity - drug effects; Motor Activity - physiology; Oxadiazoles - pharmacology; Piperazines - pharmacology; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin - drug effects; Receptors, Serotonin - genetics; Self Administration; Serotonin Antagonists - pharmacology; Toxicology
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(00)00389-0

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.