Bristol Myers-Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Psychopharmacology (Berl). 2011 Apr;214(4):829-41. doi: 10.1007/s00213-010-2092-4. Epub 2010 Nov 18.
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.
最近的一些研究表明，脑组胺水平和 H（3）受体的信号转导在调节啮齿动物的酒精刺激和奖赏中起着重要作用。
本研究描述了一种新型、选择性和脑穿透性 H（3）受体拮抗剂（JNJ-39220675）对大鼠酒精强化作用的影响。
使用标准的双瓶选择法，在选择性繁殖的酒精偏好（P）大鼠中评估 JNJ-39220675对酒精摄入和酒精复发样行为的影响。还在非依赖大鼠中进行了操作性酒精自我给药和酒精诱导的旋转棒试验，测试了该化合物。此外，还在自由活动的大鼠中测试了酒精诱导的伏隔核多巴胺释放。
皮下给予选择性 H（3）受体拮抗剂可剂量依赖性地减少酒精偏好大鼠的酒精摄入量和偏好。JNJ-39220675 还可减少在 3 天酒精剥夺后相同品系大鼠的酒精偏好。该化合物可显著降低酒精自我给药，而不改变酒精非依赖性大鼠的蔗糖自我给药。此外，该化合物不改变酒精引起的共济失调作用、酒精消除率，也不改变伏隔核中的多巴胺释放。
这些结果表明，阻断 H（3）受体可能被认为是治疗酒精中毒的一种新的有吸引力的机制。
