Histidine Decarboxylase Gene Knockout Mice Research Articles

Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice

Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice. WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus. Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 μg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice. These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse.

Morphine induces conditioned place preference behavior in histidine decarboxylase knockout mice

Pharmacological and lesion studies have shown that histamine exerts inhibitory effects on morphine-induced reward-seeking behavior. The present study was designed to further investigate the involvement of endogenous histamine in morphine-induced reward-seeking behavior using histidine decarboxylase gene knockout (HDC-KO) mice. Conditioned place preference (CPP) was present in both wild-type (WT) and HDC-KO mice treated with 5 or 10 mg/kg morphine. HDC-KO mice showed stronger morphine-induced CPP as compared with WT mice. Meanwhile, morphine significantly increased dopamine level in the VTA and NAc, especially in HDC-KO mice. However, the extinction of CPP is similar between WT and HDC-KO mice. Moreover, naloxone-precipitated withdrawal jumping was markedly decreased in HDC-KO mice. These results indicate that endogenous histamine inhibits the development, but not the extinction, of morphine-induced CPP and reduces morphine withdrawal sign, probably through modulating dopaminergic activity in the brain.

Histidine decarboxylase (HDC) knock out mouse immune cells have altered expression of ACTH, triiodothyronine and endorphin

In earlier experiments the immune cells of HDC gene knock-out (HDC-KO) mice contained significantly more serotonin, than those of the wild ones. It was supposed that serotonin, being another biogenic amine, replenishes histamine deficiency. Now we extended our earlier studies to the investigation of the levels of other hormones (adrenocorticotropic hormone [ACTH], beta-endorphin, triiodothyronine [T(3)]) in this knockout model. Peritoneal lavage fluid samples and thymuses were gained from HDC-KO and wild type mice. Their cells were prepared for flow cytometry and confocal microscopy by using specific antibodies to the three hormones (1st antibodies) and 2nd antibody to the 1st antibodies. The results of wild type and KO animals were compared. In KO animals the ACTH content in mast cells was significantly reduced and in thymic lymphocytes halved. Endorphin content was reduced both in peritoneal and thymic lymphocytes as well as in mast cells. T(3) content showed a two and a half-fold elevation in the monocyte-macrophage-granulocyte group. The confocal microscopic analysis showed the characteristic picture of HDC-KO mast cells, their cytoplasm being almost free of granules. Knock-out of the histidine decarboxylase gene causes a general endocrine imbalance in the hormones which are related to histamine, inside the immune cells. Levels of some hormones are elevated, others decreased.

Serotonin content is elevated in the immune cells of histidine decarboxylase gene knock-out (HDCKO) mice. Focus on mast cells

Biogenic amines, histamine and serotonin are present in the granules and nucleus of mast cells. We wanted to study the presence, amount and localization of serotonin in mast cells and other cells of the immune system, under conditions of histamine deficiency caused by knock out of histamine decarboxylase gene (HDCKO). Wild type and histamine deficient HDCKO mice were studied for serotonin content of the immune cells (lymphocytes as well as the monocyte-granulocyte-mast cell group) using flow cytometry and confocal microscopy. Groups of mice were kept either on complete rodent chow or on a histamine-free diet for a month before the experiments. The amount of serotonin was significantly higher in the KO animals, irrespective of the diet. Confocal microscopy demonstrated the presence of serotonin in the nucleus of mast cells in the wild type animals, while it was not present in the KO mice. Furthermore, in the cytoplasm (granules) of KO mast cells a bright fluorescence was observed in contrast to the pale fluorescence of wild animals. It seems likely that serotonin replaces the deficient histamine in the heparin-biogenic amine complex in the mast cell granules.

Intrathecally-administered histamine facilitates nociception through tachykinin NK 1 and histamine H 1 receptors: A study in histidine decarboxylase gene knockout mice

Intrathecal injection of histamine elicited behavioral responses consisting of scratching, biting and licking in conscious mice. To study the participation of histamine in pain perception, histidine decarboxylase knockout mice were examined for pain threshold by means of three different kinds of noxious stimuli: thermal nociception (hot-plate, tail-flick, and paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (formalin test and capsaicin test). Mutant mice lacking histidine decarboxylase showed significantly fewer nociceptive responses to the hot-plate, tail-flick, paw-withdrawal, tail-pressure, formalin and capsaicin tests. Sensitivity to noxious stimuli in the histidine decarboxylase knockout mice was significantly lower when compared to the wild-type mice. The intrathecally-administered histamine (400 pmol) significantly shortened the latency in the histidine decarboxylase knockout mice, but not in the wild-type mice in tail-flick tests. Pyrilamine, a histamine H 1 receptor antagonist, but not ranitidine, a histamine H 2 receptor antagonist, produced inhibition of the induced behavioral responses in the tail-flick test when co-administered with histamine. Sendide, a tachykinin NK 1 receptor antagonist, inhibited histamine-induced nociceptive behavior in the histidine decarboxylase knockout mice. In contrast, the treatment with d-(−)-2 amino-5-phosponovaleric acid ( d-APV), an N-methyl- d-aspartate (NMDA) receptor antagonist, did not prevent the induction of the behavioral responses by histamine. These studies substantiate the evidence that nociceptive behavior induced by intrathecal injection of histamine is largely mediated through tachykinin NK 1 and histamine H 1 receptors in the spinal cord.

Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout mice

A neuronal system dedicated to itch consists of primary afferent and spinothalamic projection neurons. Histamine is thought to be one of the main mediators for the transmission of itch sensation. However, there are little available information on the role of histamine in scratching behaviour and sensory transmission of atopic dermatitis and chronic eczema. In the present study, the role of histamine in scratching behaviour and neural conduction of sensation in the chronic eczema model was investigated by using l-histidine decarboxylase (HDC) gene knockout mice lacking histamine. The chronic contact dermatitis was induced with daily application of diphenylcyclopropenone (DCP) on a hind paw of HDC (+/+) and HDC (-/-) mice for 2 months. The observation of scratching behaviour and the hot-plate test were performed in both mice. Histological studies were performed in the skin and spinal cord tissues. Histological examination revealed that both HDC (+/+) and HDC (-/-) mice displayed the similar extent of inflammatory cell infiltration, hyperplastic epidermis and newly spreading of neuronal processes in the skin tissue. Scratching behaviour was exclusively induced in HDC (+/+) mice, whereas it was barely observed in HDC (-/-) mice. The expression of c-Fos was specifically upregulated in HDC (+/+) mice in lamina I of the spinal dorsal horn following repeated DCP application. Scratching behaviour in chronic contact dermatitis in mice was thought mainly mediated with histamine. The afferent pathway of sensation in chronic contact dermatitis model may connect with the central nervous system through lamina I of the spinal dorsal horn.

New functions of histamine found in histidine decarboxylase gene knockout mice

Gene targeting techniques have revolutionized the investigation of the effects of bioactive substances in pathological and physiological conditions. Histamine synthesis is uniquely catalyzed by l-histidine decarboxylase. The knockout mice of this gene express no histamine-producing activity and lack histamine. These mice have been used to examine the mechanisms of histamine in several known phenotypes, e.g., gastric acid secretion, contraction of smooth muscles, vascular permeability, and awakening, and have also been used to explore unreported effects of histamine in the whole body. First, we will review the former mechanisms and then move to the latter, new effects. Especially, in the latter mechanisms, we focus on several important roles of histamine in angiogenesis, neutrophil and eosinophil recruitment, bacterial infection, and systemic anaphylaxis in this review. Moreover, to our surprise, the morphology of mast cells in the knockout mice was severely affected by the absence of histamine in terms of their granules.

Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice.

We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O-phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.