JNJ-39220675, a novel selective histamine H^sub 3^ receptor antagonist, reduces the abuse-related effects of alcohol in rats

• Published in: Psychopharmacology Vol. 214; no. 4; p. 829
• Main Authors: Galici, Ruggero, Rezvani, Amir H, Aluisio, Leah, Lord, Brian, Levin, Edward D, Fraser, Ian, Boggs, Jamin, Welty, Natalie, Shoblock, James R, Motley, S Timothy, Letavic, Michael A, Carruthers, Nicholas I, Dugovic, Christine, Lovenberg, Timothy W, Bonaventure, Pascal
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-04-2011
• Subjects: Alcoholism; Psychopharmacology; Rodents
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-2092-4

A few recent studies suggest that brain histamine levels and signaling via H^sub 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^sub 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^sub 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^sub 3^ receptor should be considered as a new attractive mechanism for the treatment of alcoholism.[PUBLICATION ABSTRACT]