Discriminative stimulus properties of α-ethyltryptamine (α-ET) in rats: α-ET-like effects of MDMA, MDA and aryl-monomethoxy substituted derivatives of α-ET

Rationale α-ET (α-ethyltryptamine), a homolog of the classical hallucinogen α-methyltryptamine, was once prescribed clinically as an antidepressant. Classical psychedelic drugs are currently of interest as potential pharmacotherapy for psychiatric disorders. Objectives Drug discrimination was used to (a) determine if α-ET-like stimulus effects could be engendered by the prototypical phenylalkylamines MDMA ("Ecstasy") or MDA ("Love Drug") and (b) evaluate the α-ET-like stimulus effects of four synthesized aryl-substituted monomethoxy analogs of α-ET (4-OMe-, 5-OMe-, 6-OMe- and 7-OMe-α-ET). Methods Rats were trained to discriminate α-ET (2.5 mg/kg) from saline using a two-lever operant task. Results The α-ET (ED₅₀ = 1.04 mg/kg) stimulus generalized to MDMA (ED₅₀ = 0.72 mg/kg) and MDA (ED₅₀ = 0.48 mg/kg). The four α-ET derivatives produced various results; 4-OMe α-ET yielded negligible (20% maximum) α-ET-like responding; 5-OMe α-ET occasioned a modest level (40% maximum) of α-ET-like substitution; 6-OMe α-ET (ED₅₀ = 6.26 mg/kg) generalized completely, but in a narrow dose range and in an inverted U-shaped manner; 7-OMe α-ET (ED₅₀ = 2.78 mg/kg) generalized completely. Conclusions α-ET stimulus effects are similar to those of MDMA, but appear more closely aligned to those of MDA and are produced by its stereoisomers which, when combined, exert MDA/MDMA-, hallucinogen- and some stimulant-like stimulus actions. Thus, α-ET exerts a complex (compound) stimulus and appears to be a tryptamine counterpart of these prototypic phenylalkylamines. The monomethoxy analogs of α-ET produced an assortment of α-ET-like outcomes such that future investigations of these agents will likely need to be performed on an individual basis; extrapolations of α-ET-like effects to these analogs should be done judiciously.