Acta Pharmacologica Sinica 2007 January; 28 (1): 10-18; doi 10.1111/j.1745-7254.2007.00470.x

Aim: The conditioned place preference (CPP) paradigm was used to investigatethe effects of endogenous histamine on the processes leading to morphine- induced reward-seeking behavior in Sprague-Dawley rats.

Methods: The model of CPP was used to assess the rewarding effect of morphine. The levels of histamine, glutamate, g-aminobutyric acid (GABA), dopamine (DA) and 3, 4-dihydroxyphenyl-acetic acid (DOPAC) in rat brains were measured with high-performance liquid chromatography. Immunohistochemistry technique was used to observe the morphological changes of neurons.

Results: Intraperitoneal injection of morphine (2, 5 or 10 mg/kg) induced the development of CPP in a dose-dependent manner. In addition, morphine administrations (10 mg/kg) decreased the histamine content and reduced the number and size of histaminergic neurons in the tuberomammillary nucleus (TM), as well as markedly increasing the DOPAC/DA ratios in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Intra-peritoneal injection of histidine (50, 100 or 200 mg/kg) dose-dependently inhibited the development of morphine-induced CPP. Bilateral lesions of the TM, which decreased the histamine levels in the VTA and NAc, potentiated the development of CPP induced by morphine (1 mg/kg, a dose that produced no appreciable effectwhen given alone) and increased the DOPAC/DA ratios in the VTA and NAc, but did not change the glutamate or GABA levels in these nuclei. Histidine reversed the effects of the TM lesions.

Conclusion: These results indicate that endogenous histamine plays a role in inhibiting the development of morphine-induced reward-seeking behavior, and the inhibition may involve the modulation of dopa-minergic activity.

Keywords: conditioned place preference; histamine; morphine; rat; tuberomammillary nucleus