The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward

Psychopharmacology (Berl). 2007 Feb;190(2):251-63. doi: 10.1007/s00213-006-0603-0. Epub 2006 Oct 28.


Rationale and objectives: Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in that reward inhibitory function, we assessed the stimulant and rewarding effects of cocaine in knockout mice lacking histidine decarboxylase (HDC KO mice), the histamine-synthesizing enzyme. If histamine actually plays an inhibitory role in reward, then it would be expected that mice lacking histamine would be more sensitive to the behavioral effects of cocaine.

Materials and methods: The first experiment characterized spontaneous locomotion and cocaine-induced hyperactivity (0, 8, and 16 mg/kg, i.p.) in wild-type and HDC KO mice. The rewarding effects of cocaine were investigated in a second experiment with the place-conditioning technique.

Results: The first experiment demonstrated that histidine decarboxylase mice showed reduced exploratory behaviors but normal habituation to the test chambers. After habituation to the test chambers, HDC KO mice were slightly, but significantly, less stimulated by cocaine than control mice. This finding was replicated in the second experiment, when cocaine-induced activity was monitored with the place-conditioning apparatus. Furthermore, a significant place preference was present in both genotypes for 8 and 16 mg/kg cocaine, but not for 2 and 4 mg/kg.

Conclusions: Our data confirm previous results demonstrating that HDC KO mice show reduced exploratory behaviors. However, contrary to the hypothesis that histamine plays an inhibitory role in reward, histamine-deficient mice were not more responsive to the psychostimulant effects of cocaine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arousal / drug effects
  • Arousal / genetics
  • Arousal / physiology
  • Association Learning / drug effects
  • Association Learning / physiology
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Genotype*
  • Histamine / physiology*
  • Histidine Decarboxylase / genetics*
  • Hypothalamic Area, Lateral / drug effects
  • Hypothalamic Area, Lateral / physiology*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Motivation*
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neural Inhibition / genetics
  • Neural Inhibition / physiology*
  • Reward*


  • Central Nervous System Stimulants
  • Histamine
  • Histidine Decarboxylase
  • Cocaine