Abstract
Previous studies have shown that 5-hydroxytryptamine (5-HT) can modulate the hyperpolarization-activated nonselective cation current (Ih) 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 Ih 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 Ih in the ADn. We found that 5-HT induced a shift in the voltage dependence of Ih 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 Ih. 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 Ih. These results suggest that 5-HT regulates Ih in the ADn through a cAMP-dependent but protein kinase A (PKA)-independent mechanism. To determine the contribution of Ih to the 5-HT7receptor-mediated depolarization, we used the selective Ihblocker 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 Ih through a cAMP-dependent, PKA-independent mechanism.
Footnotes
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Send reprint requests to: Dr. Rodrigo Andrade, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2309 Scott Hall, Detroit, MI 48201. E-mail:randrade{at}med.wayne.edu
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This work was supported in part by a research grant (Joe Young, Sr.) from the State of Michigan and by Grant MH43985 from the National Institute of Mental Health.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine
- ADn
- anterior dorsal nucleus of the thalamus
- Ih
- hyperpolarization-activated nonselective cation current
- 5-CT
- 5-carboxamidotryptamine
- 8-OHDPAT
- 8-hydroxydipropylaminotetralin
- PKA
- protein kinase A
- Received September 14, 2000.
- Accepted December 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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