Heroin discriminative stimulus effects of methadone, LAAM and other isomers of acetylmethadol in rats

Abstract

Rationale. LAAM (α-l-acetylmethadol) is a derivative of the synthetic mu-opiate agonist methadone and is one of the four isomers of acetylmethadol. Methadone and LAAM have similar pharmacological properties and both are approved medications for the treatment of heroin dependency disorders. Few studies have reported on the pharmacology of acetylmethadol's other isomers and most of these have focused on their potential analgesic activity.

Objectives. The purpose of the present investigation was to examine the discriminative stimulus effects of LAAM, the other isomers of acetylmethadol, and methadone in rats trained to discriminate heroin from water, and to compare the duration of the discriminative stimulus effects of heroin, methadone, and LAAM.

Methods. Long-Evans rats were trained to discriminate 0.3 mg/kg heroin from water under a fixed ratio 10 (FR10) schedule of food reinforcement. Dose-response functions for heroin, methadone, LAAM, three other isomers of acetylmethadol: α-d-acetylmethadol, β-d-acetylmethadol, β-l-acetylmethadol, and its precursor, β-l-methadol were examined. Additionally, the time course effects for heroin, methadone, and LAAM were examined.

Results. LAAM and methadone dose-dependently occasioned heroin-like discriminative stimulus effects. Two of acetylmethadol's isomers, α-d-acetylmethadol and β-d-acetylmethadol, were more potent than LAAM in producing heroin-like effects. The β-l-methadol precursor and β-l-acetylmethadol did not fully substitute for heroin's discriminative stimulus. LAAM elicited heroin-like discriminative stimulus effects for at least 6 h and generated partial generalization up to 36 h following administration.

Conclusions. Methadone, LAAM, β-d-acetylmethadol and α-d-acetylmethadol, but not β-l-acetylmethadol and β-l-methadol evoke heroin-like discriminative stimulus effects.