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J Neurophysiol (November 20, 2002). doi:10.1152/jn.01004.2002
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Submitted on November 4, 2002
Accepted on November 11, 2002

Pharmacological Characterization of an Adenylyl Cyclase-Coupled Serotonin Receptor in Aplysia; Comparison with Mammalian Serotonin Receptors

Jonathan E. Cohen1, Chiadi U. Onyike2, Virginia L. McElroy1, Allison H. Lin1, and Thomas W. Abrams3*

1 Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
2 Neuropsychiatry, Johns Hopkins University, Baltimore, MD, USA; Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
3 Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA; Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: tabrams{at}umaryland.edu.

We attempted to identify compounds that are effective in blocking the serotonin (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in Aplysia central nervous system (CNS). We call this class of receptor 5-HTapAC. Eight of the 14 antagonists tested were effective against 5-HTapAC in CNS membranes, with the following rank order of potency: methiothepin > metergoline ~ fluphenazine > clozapine > cyproheptadine ~ risperidone ~ ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070 and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of AC with a Kb of 18 nM. Comparison of the pharmacological profile of the 5-HTapAC receptor with those of mammalian 5-HT receptor subtypes suggested it most closely resembles the 5-HT6 receptor. AC stimulation in Aplysia sensory neuron (SN) membranes was also blocked by methiothepin. Methiothepin substantially inhibited two effects of 5-HT on SN firing properties that are mediated by a cAMP-dependent reduction in S-K+ current: spike broadening in tetraethylammonium/nifedipine and increased excitability. Consistent with cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5-HT-induced increase in SN excitability. Methiothepin was less effective in blocking AC-mediated modulatory effects of 5-HT in electrophysiological experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This reduction in potency appears to be due to effects of the high ionic strength of physiological saline on the binding of this antagonist to the receptor. Methiothepin also antagonized AC-coupled dopamine receptors, but not AC-coupled small cardioactive peptide (SCP) receptors. In conjunction with other pharmacological probes, this antagonist should be useful in analyzing the role of 5-HT in various forms of neuromodulation in Aplysia




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