Neuroscience Center and Institute of Biomedicine/Anatomy, POB 63, FI-00014, University of Helsinki, Helsinki, Finland.
J Pharmacol Exp Ther. 2011 Jan;336(1):9-16. doi: 10.1124/jpet.110.170928. Epub 2010 Sep 23.
Data from rat models for alcohol preference and histidine decarboxylase knockout (HDC KO) mice suggest that brain histamine regulates alcohol-related behaviors. Histamine levels are higher in alcohol-preferring than in alcohol-nonpreferring rat brains, and expression of histamine H(3) receptor (H(3)R) is different in key areas for addictive behavior. H(3)R inverse agonists decrease alcohol responding in one alcohol-preferring rat line. Conditioned place preference induced by alcohol is stronger in HDC KO mice than in control mice. The HDC KO mice display a weaker stimulatory response to acute alcohol than the wild-type (WT) mice. In male inbred C57BL/6 mice the H(3)R antagonist ciproxifan inhibits ethanol-evoked stimulation of locomotor activity. Ciproxifan also potentiates the ethanol reward, but does not alone result in the development of place preference. At least in one rat model developed to study alcohol sensitivity high histamine levels are characteristic of the alcohol-insensitive rat line, and lowering brain histamine with a HDC inhibitor increases alcohol sensitivity in the tilting plane test. However, the motor skills of HDC KO mice do not seem to differ from those of the WT mice. Current evidence suggests that the histaminergic system is involved in the regulation of place preference behavior triggered by alcohol, possibly through an interaction with the mesolimbic dopamine system. Histamine may also interact with dopamine in the regulation of the cortico-striato-pallido-thalamo-cortical motor pathway and cerebellar mechanisms, which may be important in different motor behaviors beyond alcohol-induced motor disturbances. H(3)R ligands may have significant effects on alcohol addiction.
来自酒精偏好大鼠模型和组氨酸脱羧酶敲除（HDC KO）小鼠的数据表明，脑组胺调节与酒精相关的行为。与非酒精偏好大鼠相比，酒精偏好大鼠的大脑组胺水平更高，并且与成瘾行为关键区域的组胺 H3 受体（H3R）表达不同。H3R 反向激动剂可减少一种酒精偏好大鼠品系的酒精反应。与对照小鼠相比，HDC KO 小鼠对酒精诱导的条件性位置偏好的反应更强。与野生型（WT）小鼠相比，HDC KO 小鼠对急性酒精的刺激反应较弱。在雄性近交 C57BL/6 小鼠中，H3R 拮抗剂西普西芬抑制乙醇诱发的运动活性刺激。西普西芬还增强了乙醇的奖赏作用，但单独使用并不会导致位置偏好的发展。至少在一种用于研究酒精敏感性的大鼠模型中，高组胺水平是酒精不敏感大鼠系的特征，用 HDC 抑制剂降低脑组胺可增加倾斜平面试验中酒精的敏感性。然而，HDC KO 小鼠的运动技能似乎与 WT 小鼠没有区别。目前的证据表明，组胺能系统参与了酒精引发的位置偏好行为的调节，可能通过与中脑边缘多巴胺系统的相互作用。组胺还可能与多巴胺在调节皮质-纹状体-苍白球-丘脑-皮质运动通路和小脑机制中的作用相互作用，这在酒精引起的运动障碍以外的不同运动行为中可能很重要。H3R 配体可能对酒精成瘾有显著影响。
