and Maric 8 have postulated that an increase in floating times of cholestatic rats during the test is an index of fatigue. In a previous study by the same authors, 12 decreased entry of in-It has been recognized for centuries that there is a relationner squares of an open-field apparatus by cholestatic rats ship between the functional status of the liver and that of was also regarded as an index of fatigue. Interpretation of the brain. 1 The one component of this relationship that is swim test data would be facilitated by a comprehensive unwell recognized is that hepatocellular failure may be compliderstanding of the interrelationships between stress (includcated by the behavioral syndrome of hepatic encephalopathy.
ing stress attributable to underlying disease), anxiety, de-Although the mechanisms that contribute to hepatic encephpression, fatigue, and decreased motor activity in the test. In alopathy are not completely understood, it is becoming inpatients with primary biliary cirrhosis, a relationship becreasingly apparent that altered neurotransmission in the tween fatigue and depression has recently been reported. 13 brain can account for at least some of the manifestations of However, it has not been determined whether the administhis syndrome. 2,3 Whether altered neurotransmission is also tration of antidepressant drugs to patients with primary bilia component of other behavioral complications of liver disease ary cirrhosis and manifestations of depression would improve is less certain. This possibility, however, has recently been associated fatigue. raised by evidence that suggests that scratching activity, In this study, 8 a manifestation of an abnormal behavioral caused by pruritus complicating cholestasis, may be, at least state, which was detected in cholestatic rats but not rats with in part, the consequence of a central mechanism, specifically acute hepatitis, was reversed by the administration of a 5increased opioidergic neurotransmission. 4,5 Fatigue, like he-HT 1A receptor agonist. This finding was interpreted as sugpatic encephalopathy and scratching, is another abnormal gesting that the abnormal behavioral state was attributable behavioral state 6 that may complicate liver disease. 7 Accordto altered transmission in neural pathways on which 5-HT 1A ingly, it seems pertinent to ask whether fatigue in patients receptors are located, and that it could be corrected by enwith liver diseases, such as primary biliary cirrhosis, 7 is also hancing neurotransmission in these pathways. 8 However, it associated with altered neurotransmission. This possibility is necessary to be cautious in interpreting the results of a has been tentatively suggested before, 6 but it has not been behavioral study of this type. 5-HT 1A receptors are located rigorously tested in either animal models or patients.
presynaptically as well as postsynaptically. 14 In different re-In this issue of HEPATOLOGY, Swain and Maric 8 report a gions of the brain, effects mediated by either presynaptic or highly original study, which has potential relevance to the postsynaptic receptors may dominate. Stimulation of presynissue of whether fatigue associated with cholestasis is attribaptic 5-HT 1A receptors may inhibit the release of serotonin utable to altered serotoninergic neurotransmission in the into the synaptic cleft and may consequently decrease neurobrain. The performance of four groups of rats fitted with a transmission. Furthermore, stimulation of presynaptic 5-HT 1A flotation device was assessed in a defined forced swim test. 9 receptors may also influence the release of other neurotrans-The four groups were rats with carbon tetrachloride-induced mitters into the synaptic cleft, with the result that neuroacute hepatocellular necrosis, vehicle-treated controls, rats transmission in non-5-HT pathways may be affected. In this with acute cholestasis caused by bile duct resection, and experimental paradigm, 8 evaluation of the effects of selective sham-resected controls. In this study, fatigue was defined as 5-HT 1A receptor antagonists (e.g., WAY-100635) 15 may clarify ''a complex interplay between motivation, endurance, dewhether the abnormal behavioral state and/or the effects of spair, and cognition as reflected by the time spent by rats LY293284 in this study are indeed mediated by pathways struggling, floating, and swimming'' during the swim test. 8 involving 5-HT 1A receptors. Hence, in this study, 8 it is not In the swim test, the duration of struggling and floating possible to infer with confidence the status of neurotransmisamong the rats with acute hepatitis and the duration of strugsion in the cholestatic rats before LY293284 was adminisgling among cholestatic rats were not obviously abnormal.
tered. Another issue that may influence the interpretation The mean time that cholestatic rats spent floating in the of the results 8 is the behavioral syndrome induced by the swim test, however, was significantly longer than the correactivation of central 5-HT 1A receptors. The administration of sponding mean for sham-resected controls. The administraa 5-HT 1A receptor agonist to normal rats has been reported tion of LY293284, a 5-hydroxytryptamine 1A (5-HT 1A ) receptor to induce ''flat body posture, reciprocal forepaw treading and agonist, 10 did not significantly affect floating times in shamhead weaving.'' 14 The existence of this behavioral syndrome resected controls, but corrected the prolonged floating times raises the possibility that the increase in motor activity dein cholestatic rats. The dose dependency of this phenomenon tected in cholestatic rats after the administration of was not reported.
LY293284 might be attributable to an effect of the drug that The precise relevance to fatigue of prolonged floating times and unchanged struggling times of cholestatic rats in the is independent of any action that would specifically reverse swim test is uncertain. The swim test in rats, which clearly a behavioral complication of cholestasis. It seems likely that involves monitoring responses to a stressful situation, was nonspecific motor hyperactivity related to the 5-HT 1A behavoriginally devised to assess antidepressive treatments, 11 and, ioral syndrome would be detected quantitatively more readily in rats with a preexisting motor deficit than in control rats. 16 In this context, it is noteworthy that the administration of LY293284 was associated with decreased floating times and Abbreviation: 5-HT, 5-hydroxytryptamine (serotonin).