Increased midbrain 5-MT1A receptor number and responsiveness in cholestatic rats

Midbrain somatodendritic 5-HT1A autoreceptors play a central inhibitor?; ro le in the regulation of serotonergic neurotransmission. Given that serotone rgic neurotransmission appears to be altered in experimental cholestatic li ver disease we examined alterations in midbrain 5-HT1A autoreceptor binding and physiological responses in rats with experimental cholestatic liver di sease in comparison to non-cholestatic controls. Using a standard receptor binding assay cholestatic rats exhibited an increase in midbrain 5-HT1A rec eptor number but no change in receptor affinity compared to controls. Midbr ain 5-HT1A receptor mRNA expression as determined by semiquantitative RT-PC R was similar in cholestatic and non-cholestatic animals. In addition, chol estatic rats exhibited enhanced 5-HT1A autoreceptor-mediated hypothermic an d hyperphagic responses compared to non-cholestatic controls after the admi nistration of the highly specific 5-HT1A receptor agonist LY293284. These f indings indicate that experimental cholestatic liver injury is associated w ith enhanced 5-HT1A autoreceptor-mediated physiological responsiveness in t he setting of increased midbrain 5-HT1A receptor number but not affinity. ( C) 2001 Elsevier Science B.V. All rights reserved.