JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats

Abstract

A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents. The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats. The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats. Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens. These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.