Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat

Ligand binding studies have identified certain serotonin (5-HT) antagonists with selective affinity for 5-HT₂ receptors and other serotonin antagonists with affinity for both 5-HT₁ and 5-HT₂ receptors. This study compared the actions of ketanserin and pipamperone, selective 5-HT₂ receptor antagonists, with metergoline and methylsergide, nonselective 5-HT antagonists, on two behavioral response in rats that are produced by the activation of 5-HT receptors: 1) the head shake response and 2) the 5-HT syndrome. Both the selective and the nonselective 5-HT antagonists blocked the head shake response produced by 5-hydroxy-L-tryptophan. The order of relative potency was: metergoline > ketanserin > pipamperone > methysergide. All four antagonists also blocked the head shake response produced by the 5-HT agonist quipazine. In contrast, the symptoms of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine were blocked by pretreatment with the nonselective 5-HT receptor antagonists but not by the 5-HT₂ receptor antagonists. The differential actions of 5-HT antagonists on these behavioral responses suggest that different 5-HT receptors are involved in the head shake response and the 5-HT syndrome. That the order of relative potency for these drugs to block the head shake response was the same as their reported affinity for the 5-HT₂ receptor suggests that the 5-HT₂ receptor is involved in the head shake response. In contrast, the ability of 5-HT antagonists with affinity for the 5-HT₁ receptor to block the 5-HT syndrome and the inability of 5-HT₂ receptor antagonists to block the syndrome suggests that this behavioral response probably involves the activation of 5-HT₁ receptors.