Vol. 297, Issue 1, 403-409, April 2001

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

Esther M. Chapin and Rodrigo Andrade

Departments of Psychiatry and Behavioral Neurosciences and Pharmacology and the Cellular and Clinical Neurobiology Training Program, Wayne State University School of Medicine, Detroit, Michigan

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-HT₇ receptor-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-HT₇ receptor 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-HT₇ receptor-mediated depolarization, we used the selective I_h blocker 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.