Increased midbrain 5-HT1A receptor number and responsiveness in cholestatic rats

Midbrain somatodendritic 5-HT_1A autoreceptors play a central inhibitory role in the regulation of serotonergic neurotransmission. Given that serotonergic neurotransmission appears to be altered in experimental cholestatic liver disease we examined alterations in midbrain 5-HT_1A autoreceptor binding and physiological responses in rats with experimental cholestatic liver disease in comparison to non-cholestatic controls. Using a standard receptor binding assay cholestatic rats exhibited an increase in midbrain 5-HT_1A receptor number but no change in receptor affinity compared to controls. Midbrain 5-HT_1A receptor mRNA expression as determined by semiquantitative RT–PCR was similar in cholestatic and non-cholestatic animals. In addition, cholestatic rats exhibited enhanced 5-HT_1A autoreceptor-mediated hypothermic and hyperphagic responses compared to non-cholestatic controls after the administration of the highly specific 5-HT_1A receptor agonist LY293284. These findings indicate that experimental cholestatic liver injury is associated with enhanced 5-HT_1A autoreceptor-mediated physiological responsiveness in the setting of increased midbrain 5-HT_1A receptor number but not affinity.