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

被引：35

作者：

Galici, Ruggero ^{[3
]}

Rezvani, Amir H. ^{[2
]}

Aluisio, Leah ^{[1
]}

Lord, Brian ^{[1
]}

Levin, Edward D. ^{[2
]}

Fraser, Ian ^{[1
]}

Boggs, Jamin ^{[1
]}

Welty, Natalie ^{[1
]}

Shoblock, James R. ^{[1
]}

Motley, S. Timothy ^{[1
]}

Letavic, Michael A. ^{[1
]}

Carruthers, Nicholas I. ^{[1
]}

Dugovic, Christine ^{[1
]}

Lovenberg, Timothy W. ^{[1
]}

Bonaventure, Pascal ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Neurosci, San Diego, CA 92121 USA

[2] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA

[3] Bristol Myers Squibb Co, Wallingford, CT 06492 USA

来源：

PSYCHOPHARMACOLOGY | 2011年 / 214卷 / 04期

关键词：

Histamine; H-3; Alcoholism; Self administration; Microdialysis; Reward; Selectively bred alcohol-preferring rats; Dopamine; PREFERRING RATS; DOPAMINE RELEASE; NERVOUS-SYSTEM; NUCLEUS; BRAIN; DISORDERS; PHARMACOTHERAPY; TRANSMISSION; STIMULATION; DEPENDENCE;

D O I：

10.1007/s00213-010-2092-4

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：829 / 841

页数：13

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