Brain histamine H3 receptors in rats with portacaval anastomosis: in vitro and in vivo studies

Abstract

The long-term effects of portacaval anastomosis (PCA) on histamine H3 receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [3H]-R-alpha-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [3H]-R-alpha-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K+-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [3HI-R-alpha-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [3H]-R-alpha-methylhistamine binding density, particularly in striatum and cortex, where H3 receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H3 receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H3 receptors located at histaminergic neurons is preserved after long-term PCA.

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

“…4 In addition, there is a moderate increase in the release of histamine from the anterior hypothalamus of PCA rats. 5 Finally, significantly increased levels of histamine have been found in the cerebrospinal fluid of patients with HE. 3 Taken together, these findings point to an increased availability of histamine in the brain of rats with PCA and patients with HE.…”

“…Among the least exploited consequences of HE are the marked changes in the brain histaminergic system, which have been previously documented both in patients with HE 3 and in rats with portacaval anastomosis (PCA), a well-established animal model of the disease. [4][5][6][7][8] There is substantial evidence that histamine acts as a neurotransmitter in mammalian brain. 9 Histaminergic neurons are located exclusively in the tuberomammillary nucleus of the posterior hypothalamus and send their varicose fibers to almost every region of the brain.…”

Effects of the histamine H1receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis

“…12,17 Furthermore, the spontaneous, as well as the depolarizationinduced and pharmacologically induced histamine release from anterior hypothalamus are significantly increased in these rats. 17 Histamine, through the activation of postsynaptic H 1 receptors, is involved in the regulation of the mechanisms of arousal, 19,20 locomotor activity, 21-24 feeding behavior, and energy balance, 25,26 and circadian rhythmicity (for reviews, see Tuomisto 27 and Nowak 28 ). We have previously suggested that histaminergic synaptic imbalance may have contributed to the sleep disturbances in rats with PCA.…”

“…We have previously suggested that histaminergic synaptic imbalance may have contributed to the sleep disturbances in rats with PCA. 18 We have now examined the effects of histamine H 1 receptor blockade on feeding, locomotor activity, and circadian rhythmicity in rats with long-term PCA to find out whether the modified histaminergic neurotransmission in the brain of rats with portacaval anastomosis 6 months after surgery 12,[16][17][18] has also participated in the generation and maintenance of the disturbances in the circadian rhythmicity of feeding and locomotor activity. Pyrilamine (mepyramine), a selective and high-affinity H 1 receptor antagonist, 29 was used to block histamine H 1 receptors in the CNS.…”

“…PSE has been described as a disorder of multiple neurotransmitter systems. 13 Specifically, the histaminergic synaptic imbalance, which becomes apparent shortly 14,15 and persists for at least 8 months after surgery, 12,[16][17][18] is among the most interesting consequences of portacaval shunting in the rat.…”