A 5-HT₇ Receptor-Mediated Depolarization in the Anterodorsal Thalamus. II. Involvement of the Hyperpolarization-Activated Current I_h

Abstract

Previous studies have shown that 5-hydroxytryptamine (5-HT) can modulate the hyperpolarization-activated nonselective cation current (I_h) to elicit a membrane depolarization in neurons. However, the receptor subtype involved in this response remains controversial. In the accompanying study, we have identified a 5-HT₇ receptor-mediated depolarization in the anterodorsal nucleus of the thalamus (ADn). In the present study, we have examined the possible role of I_h in mediating this 5-HT₇receptor-mediated depolarization. We used the blind tight-seal patch clamp technique to examine the ability of 5-HT to modulate I_h in the ADn. We found that 5-HT induced a shift in the voltage dependence of I_h to more depolarized potentials. The pharmacology of the receptor mediating this effect was consistent with that of a 5-HT₇ receptor. Since the 5-HT₇receptor is coupled positively to adenylate cyclase, we examined the cAMP dependence of the 5-HT-induced modulation of I_h. Intracellular addition of cAMP mimicked and occluded the 5-HT response. Conversely, in the presence of the protein kinase inhibitors H-8 and staurosporine, ADn neurons still expressed a 5-HT-induced shift in the voltage dependence of I_h. These results suggest that 5-HT regulates I_h in the ADn through a cAMP-dependent but protein kinase A (PKA)-independent mechanism. To determine the contribution of I_h to the 5-HT₇receptor-mediated depolarization, we used the selective I_hblocker ZD7288. This compound greatly reduced the depolarizing response elicited by activation of 5-HT₇ receptors. We conclude that 5-HT₇ receptors depolarize ADn neurons primarily by increasing I_h through a cAMP-dependent, PKA-independent mechanism.