Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD)

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After decades of social stigma, hallucinogens have reappeared in the clinical literature demonstrating unique benefits in medicine. The precise behavioral pharmacology of these compounds remains unclear, however.


Two commonly studied hallucinogens, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD), were investigated both in vivo and in vitro to determine the pharmacology of their behavioral effects in an animal model.


Rabbits were administered DOI or LSD and observed for head bob behavior after chronic drug treatment or after pretreatment with antagonist ligands. The receptor binding characteristics of DOI and LSD were studied in vitro in frontocortical homogenates from naïve rabbits or ex vivo in animals receiving an acute drug injection.


Both DOI- and LSD-elicited head bobs required serotonin2A (5-HT2A) and dopamine1 (D1) receptor activation. Serotonin2B/2C receptors were not implicated in these behaviors. In vitro studies demonstrated that LSD and the 5-HT2A/2C receptor antagonist, ritanserin, bound frontocortical 5-HT2A receptors in a pseudo-irreversible manner. In contrast, DOI and the 5-HT2A/2C receptor antagonist, ketanserin, bound reversibly. These binding properties were reflected in ex vivo binding studies. The two hallucinogens also differed in that LSD showed modest D1 receptor binding affinity whereas DOI had negligible binding affinity at this receptor.


Although DOI and LSD differed in their receptor binding properties, activation of 5-HT2A and D1 receptors was a common mechanism for eliciting head bob behavior. These findings implicate these two receptors in the mechanism of action of hallucinogens.


▸ The pharmacology of DOI and LSD were compared in vivo and in vitro using rabbits. ▸ Both DOI and LSD elicited head bobs through activation of 5-HT2A and D1 receptors. ▸ Both DOI and LSD bound 5-HT2A receptors, but only LSD bound D1 receptors. ▸ LSD and ritanserin pseudo-irreversibly bound frontocortical 5-HT2A receptors. ▸ DOI and ketanserin reversibly bound frontocortical 5-HT2A receptors.

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