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Discriminative stimulus effects of 5‐HT2C neutral antagonist methysergide in pigeons

Blockade of serotonin2C (5‐HT2C) receptors is a therapeutic target in a number of central nervous system disorders. In vitro, these compounds can be further classified into antagonists and inverse agonists. Proposed antagonist, methysergide, was trained as a discriminative stimulus in pigeons (n=6) to examine the role of 5‐HT2C receptor blockade in vivo. Pigeons were trained to discriminate 0.1 mg/kg methysergide from saline, i.m., under an FR20 schedule of grain delivery. 5‐HT2C compounds were tested for substitution and antagonism using a single‐trial test procedure. Methysergide dose‐dependently substituted at some dose in all pigeons. Bromo‐lysergic acid and metergoline, proposed antagonists, substituted for methysergide along with proposed inverse agonists SB206553, mianserin and cyproheptadine. Agonists such as MK212 failed to produce significant methysergide responding when administered alone and differentially affected the potency of methysergide to produce methysergide responding when administered in combination with methysergide. These data suggest that the discriminative stimulus effects of methysergide are mediated predominantly through the blockade of 5‐HT2C receptors. Furthermore, methysergide fails to differentiate between neutral antagonists or proposed inverse agonists under these training conditions.