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Pharmacological effects of carcinine on histaminergic neurons in the brain.

ABSTRACT: 1 Carcinine (beta-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. 2 Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (microM)=0.2939+/-0.2188 vs 3621.2+/-583.9 or 365.3+/-232.8 microM, respectively). 3 Carcinine at a dose of 20 mg kg(-1) slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186+/-0.069 to 0.227+/-0.009 pmol mg protein(-1) min(-1)). In addition, carcinine (10, 20, and 50 mg kg(-1)) significantly decreased histamine levels in mice brain. 4 Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 microM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. 5 Carcinine (20 mg kg(-1)) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completely reversed by (R)-alpha-methylhistamine, a representative H3 receptor agonist, and alpha-fluromethylhistidine, a selective HDC inhibitor. 6 Carcinine (20 mg kg(-1)) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-alpha-methylhistamine as evaluated by the passive avoidance test in mice. 7 Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. 8 The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.

SUBMITTER: Chen Z

PROVIDER: S-EPMC1575432 | biostudies-other | 2004 Nov

REPOSITORIES: biostudies-other

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Proton- and ammonium-sensing by histaminergic neurons controlling wakefulness.

Project description:The histaminergic neurons in the tuberomamillary nucleus (TMN) of the posterior hypothalamus are involved in the control of arousal. These neurons are sensitive to hypercapnia as has been shown in experiments examining c-Fos expression, a marker for increased neuronal activity. We investigated the mechanisms through which TMN neurons respond to changes in extracellular levels of acid/CO(2). Recordings in rat brain slices revealed that acidification within the physiological range (pH from 7.4 to 7.0), as well as ammonium chloride (5 mM), excite histaminergic neurons. This excitation is significantly reduced by antagonists of type I metabotropic glutamate receptors and abolished by benzamil, an antagonist of acid-sensing ion channels (ASICs) and Na(+)/Ca(2+) exchanger, or by ouabain which blocks Na(+)/K(+) ATPase. We detected variable combinations of 4 known types of ASICs in single TMN neurons, and observed activation of ASICs in single dissociated TMN neurons only at pH lower than 7.0. Thus, glutamate, which is known to be released by glial cells and orexinergic neurons, amplifies the acid/CO(2)-induced activation of TMN neurons. This amplification demands the coordinated function of metabotropic glutamate receptors, Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase. We also developed a novel HDC-Cre transgenic reporter mouse line in which histaminergic TMN neurons can be visualized. In contrast to the rat, the mouse histaminergic neurons lacked the pH 7.0-induced excitation and displayed only a minimal response to the mGluR I agonist DHPG (0.5 ?M). On the other hand, ammonium-induced excitation was similar in mouse and rat. These results are relevant for the understanding of the neuronal mechanisms controlling acid/CO(2)-induced arousal in hepatic encephalopathy and obstructive sleep apnoea. Moreover, the new HDC-Cre mouse model will be a useful tool for studying the physiological and pathophysiological roles of the histaminergic system.

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