Increased brain histamine in an alcohol-preferring rat line and modulation of ethanol consumption by H(3) receptor mechanisms.

The histaminergic system is thought to regulate brain reward, but the exact mechanisms are poorly understood. This study aims to reveal the pathophysiological differences in the brain histaminergic system between selectively outbred alcohol-preferring AA and alcohol-avoiding ANA rats by using a combination of biochemical, immunohistochemical, and molecular biological methods. We also want to test the functional significance of the system by using operant ethanol self-administration method. We show that alcohol-preferring AA rats, when compared with alcohol-avoiding ANA rats, display higher levels of brain histamine and its first metabolite as measured by HPLC and mass spectrometry, a higher density of histamineimmunoreactive nerve fibers, and lower H1 receptor mRNA expression and H1 and H3 receptor binding as studied by using in situ hybridization and autoradiography. Two H3 receptor antagonists, thioperamide and clobenpropit, reduced and an agonist, R-α-methylhistamine, increased operant responding for ethanol by the alcohol-preferring rats, whereas an H1 receptor ligand, mepyramine, was inefficient. The results indicate that high alcohol preference is correlated with enhanced histaminergic mechanisms, most likely via H3 receptor-mediated processes. Central histaminergic mechanisms may thus participate also in other addictive behaviors.