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

Abstract

To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portalsystemic encephalopathy, we examined the effects of histamine H 1 receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H 1 receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H 1 receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [ 3 H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H 1 receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H 1 receptors in both sham-and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H 1 receptor-mediated mechanism. (HEPATOL-OGY 2000;31:336-344.)Animal models of human disease provide the means of studying the pathological condition in a way that is not always possible in human patients. The rat with an end-toside portacaval anastomosis (PCA) represents an attractive model of portal-systemic encephalopathy (PSE) 1,2 because many of the behavioral abnormalities that occur in this model correspond to the subclinical forms of PSE. Among these abnormalities are the significantly reduced spontaneous locomotor activity and exploration, 3 as well as the reduced or completely abolished differences between day time and night time activity, suggesting a disruption of their circadian rhythmicity. 4-10 These rats also have disturbances in their food intake 11 and show marked growth retardation. 12 Although much research has been performed to elucidate the pathophysiological background of PSE, the exact mechanisms that underlie this condition are still largely unclear. 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, 12,16-18 is among the most interesting consequences of portacaval shunting in the rat.We have previously shown that rats with PCA have profound disturbances in their brain histaminergi...

Olanzapine Reduces Physical Activity in Rats Exposed to Activity-Based Anorexia: Possible Implications for Treatment of Anorexia Nervosa?

“…Regarding conflicting data on serotonergic control of RWA, the possible involvement of other neurotransmitters should not be ignored. For instance, the antagonizing effects of olanzapine on the histamine 1 (H 1 ) receptor might also lead to reduced physical activity and increased food intake (Fukagawa et al 1989;Lozeva et al 2000). In addition, possible antagonism of the dopamine (DA) system causing decreased motor activity should not be disregarded, although it is generally stated that olanzapine has only limited extrapyramidal side effects.…”

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

“…Studies in rats with chronic PCA show a significant improvement in their circadian rhythmicity and feeding following treatment with the histamine H 1 receptor antagonist, pyrilamine (mepyramine). 8 Antihistamines have been used in patients with cirrhosis without apparent side effects. 47 Given that the most-commonly prescribed sleeping-aid drugs, the benzodiazepines, are not recommended for cirrhotic patients because they may precipitate overt encephalopathy, and in view of the fact that there are no clinical studies on the effects of melatonin in patients with cirrhosis, these findings suggest that centrally acting antihistamines may be beneficial in the treatment of the early symptoms of HE, particularly the altered sleep patterns.…”

“…Consistent with these possibilities, we have previously shown that blockade of central histamine H 1 receptors with the specific antagonist, pyrilamine (mepyramine), restores the altered circadian rhythmicity of feeding and locomotor activity. 8 Together, these findings suggest an involvement of histamine H 1 receptors in the pathophysiology of HE.Abbreviations: HE, hepatic encephalopathy; PCA, portacaval anastomosis; AP, anteroposterior.From the …”

“…[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 voluntary movement, and increased plasma prolactin levels in patients with HE and in the hormonal changes, growth retardation, and the altered vigilance, locomotor activity, and circadian rhythmicity in rats with PCA. Consistent with these possibilities, we have previously shown that blockade of central histamine H 1 receptors with the specific antagonist, pyrilamine (mepyramine), restores the altered circadian rhythmicity of feeding and locomotor activity.…”

“…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.…”