Increased Density of Brain Histamine H1 Receptors in Rats With Portacaval Anastomosis and in Cirrhotic Patients With Chronic Hepatic Encephalopathy

Abstract

The binding properties and the regional densities of histamine H 1 receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [ 3 H]mepyramine. Histamine H 1 receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [ 3 H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Hepatic encephalopathy (HE) is a potential long-term complication of chronic liver disease. Despite extensive research and a succession of different hypotheses, the exact mechanisms underlying the development of the clinical symptoms of HE are not well understood. 1,2 Consequently, progress in the treatment of HE in cirrhotic patients has been limited. 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. 10 This widespread distribution of histaminergic neurons suggests that the brain histaminergic system is involved in the regulation of a wide range of neurobiologic functions. Histaminergic signaling is mediated by 3 types of receptors, histamine H 1 , H 2 , and H 3 receptors, distinguished by their pharmacologic properties, specific anatomic location, and by the intracellular responses they mediate. 11,12 Interest has focused on the histamine H 1 receptors, because histamine, through the activation of the postsynaptic histamine H 1 receptors, is involved in the regulation of the neuroendocrine system, 13,14 locomotor activity, 15-17 circadian rhythmicity, 18,19 and the sleep-wake cycle, 20 as well as in various behaviors, including feeding and drinking (for a review, see Schwartz, 9 Yamatodani et al., 21 and Sakata 22 ).We have previously shown that altered histaminergic neurotransmission is an important part of the neurophysiologic background responsible for the behavioral changes after PCA surgery in the rat, leading us to propose that it may contribute to the pathogenesis of HE in human subjects. [6][7][8] Relating the functions controlled by histamine to the clinical presentation of HE, it appears a priori that histamine could participate in the pathogenesis of the sleep disturbances, decreased spontaneous vo...

Changes in hippocampal histamine receptors across the hibernation cycle in ground squirrels

“…The method for histamine H 1 receptor binding using [ 3 H]mepyramine was based on previous publications (Palacios et al, 1981;Ruy et al, 1995;Lozeva et al, 2001 (Traiffort et al, 1992;Vizuete et al, 1997;Honrubia et al, 2000). [ 125 I]APT was synthesized as described before (Leurs et al, 1994).…”

Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients

“…In particular, selective alterations of glutamatergic and monoaminergic receptor sites have been reported in both experimental animal models of HE 1,2 and the brains of human cirrhotic patients. 3,4 Many of these receptors are functionally coupled to the nitric oxide (NO) cyclic guanosine monophosphate (cGMP) signal transduction pathway, which serves to amplify the postsynaptic response to receptor activation.…”

Histamine and H3Receptor in Alcohol-Related Behaviors

“…jpet.aspetjournals.org also increased, suggesting increased histamine turnover, whereas H 3 R radioligand binding is decreased (Lozeva et al, 2003). A concomitant increase in densities (B max ) of H 1 R in the frontal cortex has also been reported in patients with hepatic encephalopathy (Lozeva et al, 2001). Similar increases in brain histamine have been reported in portocavally shunted rats (Fogel et al, 2002).…”