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

Pharmacol Biochem Behav. 2000 Nov;67(3):559-66. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine Uptake Inhibitors / pharmacology*
  • Male
  • Mice
  • Mice, Knockout
  • 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*


  • Dopamine Uptake Inhibitors
  • Oxadiazoles
  • Piperazines
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin
  • Serotonin Antagonists
  • GR 127935
  • Cocaine