Discriminative stimulus effects of (-)-ephedrine in rats: Analysis with catecholamine transporter and receptor ligands

A drug discrimination procedure was used to examine the neuropharmacology of (-)-ephedrine (5 mg/kg), a sympathomimetic amine found in a variety of dietary supplements. (-)-Ephedrine has caused concern because of its use as a precursor in the manufacture of street drugs (e.g. methamphetamine) and its potential for abuse and toxicity. In the present study, the catecholamine reuptake inhibitors mazindol and nomifensine, the norepinephrine (NE) reuptake inhibitor desipramine, and the dopamine D₂-like (e.g. D₂, D₃ and D₄) agonist quinpirole substituted for (-)-ephedrine (≥80% (-)-ephedrine-lever responding). The NE reuptake inhibitor nisoxetine, the D₁-like (e.g. D₁ and D₅) agonists (±)-SKF 38393 and SKF 82958, and the mixed D₁-/D₂-like agonist apomorphine occasioned intermediate levels of responding (50-79% (-)-ephedrine-lever responding). The (-)-ephedrine cue was antagonized by the D₁-like antagonist SCH 23390 and the α₁-adrenoceptor antagonist prazosin as well as the D₂-like antagonists (-)-eticlopride and haloperidol, although only at doses that disrupted responding in some rats. The discriminative stimulus effects of a small dose of (-)-ephedrine (1.25 mg/kg) were enhanced by the α₂-adrenoceptor antagonist idazoxan and to a lesser extent by the β-adrenoceptor antagonist (-)-propranolol. However, the α₂-adrenoceptor agonist clonidine (0.04 mg/kg) did not attenuate the (-)-ephedrine stimulus. These results suggest that D₁-, D₂-like, and α₁-adrenergic receptors mediate the discriminative stimulus effects of (-)-ephedrine. Substitution of desipramine for (-)-ephedrine and not for some other stimulants suggests that NE transmission is a prominent feature of the (-)-ephedrine discriminative stimulus, and that NE underlies therapeutic and abuse-related effects of (-)-ephedrine that diverge from those of other stimulants.