Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis.

The hallucinogens DOM and LSD act as partial agonists at serotonin 5-HT-2 receptors in rat cerebral cortex and at 5-HT-1c receptors in rat choroid plexus, stimulating phosphoinositide hydrolysis. In cortex, DOM and LSD produced maximum responses 76% and 25% of serotonin's maximum, respectively, with LSD 500 times more potent than DOM. LSD partially blocked serotonin's effect, consistent with partial agonism. In choroid plexus, DOM and LSD reached 67% and 34% of serotonin's maximum, with LSD 50 times more potent than DOM. These effects were blocked by specific serotonin antagonists, supporting the role of 5-HT-2 and 5-HT-1c receptors in mediating hallucinogenic actions.

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Abstract

Based on electrophysiological, radioligand binding, and behavioral studies in laboratory animals, it is generally believed that the psychotomimetic effects of the phenethylamine and indolealkylamine hallucinogens are mediated by central serotonin (5-HT) receptors, in particular the 5-HT-2 subtype. Agonist-stimulated phosphoinositide hydrolysis was utilized to determine the potency and efficacy of racemic 1-(2,5)-dimethoxy-4-methyl-phenyl)-2-aminopropane (DOM), and d-lysergic acid diethylamide (LSD) at the 5-HT-2 receptor in rat cerebral cortex and the 5-HT-1c receptor in rat choroid plexus. Both DOM and LSD stimulated phosphoinositide hydrolysis in cerebral cortex. These effects were blocked by the 5-HT-2 antagonists, ketanserin and spiperone, but not by antagonists of muscarinic, alpha-1 adrenergic or histaminergic receptors. The maximum responses of DOM and LSD, respectively, were 76% and 25% of the maximum response to 5-HT. However, LSD was 500 times more potent than was racemic DOM. Consistent with a partial agonist effect, LSD partially blocked the effect of 5-HT, with a maximal inhibition equivalent to the intrinsic activity of LSD alone. In choroid plexus, DOM and LSD stimulated phosphoinositide hydrolysis and both responses were blocked by mianserin and less effectively by spiperone. The maximum effect of DOM was 67% of that of 5-HT, whereas the maximum effect of LSD was only 34% of the maximum response of 5-HT. LSD was 50 times more potent than was racemic DOM. LSD partially antagonized the effect of 5-HT in the choroid plexus, consistent with a partial agonist effect at the 5-HT-1c receptor in this tissue.(ABSTRACT TRUNCATED AT 250 WORDS)