AbstractsBiology & Animal Science

Neuronal histamine and its H3 receptor (H3R) regulate several physiological functions and are involved in the pathophysiology of various central nervous system disorders such as Parkinson s disease, Alzheimer s disease, Tourette syndrome and narcolepsy. Studies conducted in experimental animals have also suggested a role for histamine and especially H3R in the effects of drugs of abuse. In this thesis, the main aim was to study how histamine and H3R regulate alcohol-related behaviors. Furthermore, our goal was to investigate the underlying mechanisms in the observed behaviors. By using both wild type mice in different background strains and genetically modified mice, we studied whether histamine and H3R regulate the behavioral responses to alcohol. Three different H3R antagonists (ciproxifan, JNJ-10181457 and JNJ-39220675) were used and it was found that both pharmacological antagonism and genetic knockout of H3R (H3R KO) lead to diminished alcohol consumption and reward. By using histamine deficient histidine decarboxylase knockout (HDC KO) mice, we found that the lack of histamine does not alter alcohol consumption or reward but histamine is indeed required for the H3R-mediated alcohol reward inhibition. We also found that JNJ-39220675 inhibited the acute stimulation of amphetamine, but failed to inhibit the rewarding properties of amphetamine. This indicates that although H3R antagonists inhibit alcohol reward, they may not possess the same ability on psychostimulants, such as amphetamine. The findings obtained from the behavioral experiments led us to hypothesize that H3R interacts with the dopaminergic system. This was further studied on a molecular level using both radioactive in situ hybridization and semi-quantitative Western blotting. We found that compared with control mice, H3R KO mice displayed lower levels of dopamine D1 receptor messenger RNA in the striatum, which is an area important in the regulation of e.g. reward. In addition, we found that activation of dopamine D1 and D2 receptors resulted in abnormal striatal cell signaling in the absence of H3Rs. Taken together, these findings demonstrate that H3R is an important regulator of alcohol-related behaviors. The mechanism by which H3R regulates these phenomena might involve the interaction between the striatal H3R and dopamine receptors. In addition, these results provide preclinical evidence that H3R antagonists may serve as a novel approach to treat alcohol dependence. Aivojen histamiini ja sen H3-reseptori säätelevät useita fysiologisia toimintoja, mutta ovat myös mukana erilaisten keskushermostohäiriöiden patofysiologiassa. Tällaisia ovat muun muassa Parkinsonin tauti, Alzheimerin tauti, Touretten syndrooma ja narkolepsia. Aikaisemmissa eläinkokeissa on lisäksi havaittu että histamiini sekä H3-reseptori ovat myös osallisina riippuvuuskäyttäytymisessä. Tämän väitöskirjan päätavoitteena oli selvittää, miten histamiini ja H3-reseptori säätelevät alkoholikäyttäytymistä. Lisäksi tavoitteena oli selvittää, mitkä molekyylitason mekanismit ovat…