Alterations of tubulin function caused by chronic antidepressant treatmentin rat brain

1. Antidepressants have been used clinically for many years; however, the n eurochemical mechanism for their therapeutic effect has not been clarified yet. Recent reports indicate that chronic antidepressant treatment directly affects the postsynaptic membrane to increase the coupling between the sti mulatory GTP-binding (G) protein, G(s), and adenylyl cyclase. Tubulin, a cy toskeletal element, is involved in the stimulatory and inhibitory regulatio n of adenylyl cyclase in rat cerebral cortex via direct transfer of GTP to G proteins. In this study, we investigated whether the functional change of the adenylyl cyclase system caused by chronic antidepressant treatment inv olves an alteration of tubulin function in the regulation of adenylyl cycla se activity. 2. Male Sprague-Dawley rats were treated once daily with amitriptyline or s aline by intraperitoneal injection (10 mg/kg) for 21 days, and their cerebr al cortex membranes and GppNHp-liganded tubulin (tubulin-GppNHp) were prepa red for what. 3. GppNHp-stimulated adenylyl cyclase activity in cortex membranes from ami triptyline-treated rats was significantly higher than that in control membr anes. Furthermore, tubulin-GppNHp prepared from amitriptyline-treated rats was more potent than that from control rats in the stimulation of adenylyl cyclase activity in the cortex membranes of the controls. However, there wa s no significant difference in manganese-stimulated adenylyl cyclase activi ty between control and amitriptyline-treated rats. 4. The present results suggest that chronic antidepressant treatment enhanc es not only the coupling between G, and the catalytic subunit of adenylyl c yclase but also tubulin interaction with G, in the cerebral cortex of the r at.