Cholinergic manipulations modulate the discriminative stimulus effects of methamphetamine in C57BL/6J mice

Abstract

Cholinergic transmission modulates several aspects of stimulant abuse, including initial exposure, transition to dependence, and relapse risk. The goals of the current work were to 1) establish methamphetamine (MA) as a discriminative stimulus (SD) in mice, 2) assess the ability of M1‐ or M1/M4‐active compounds to generalize from or block the SD effects of MA, and 3) evaluate the nACh receptor subtypes underlying the MA‐like SD effects of nicotine. Sixteen male C57BL/6J mice were trained to discriminate 1 mg/kg MA (i.p.) from saline on a FR‐12 schedule. Following acquisition (41 ± 3 sessions), substitution testing revealed that the M1/M4‐preferrring agonist xanomeline and the M1‐preferring agonist n‐desmethylclozapine were perceived as saline‐like whereas the non‐selective antagonist scopolamine and the M1‐preferring antagonists trihexyphenidyl and dicyclomine exhibited low partial substitution for MA. Pretreatments were administered 10‐min prior to MA during blocking tests, and it was observed that dicyclomine producing a leftward shift in the MA dose‐response curve whereas xanomeline resulted in a non‐significant rightward shift. Nicotine partially generalized (50%) from MA in mice, and pretreatment with the nACh antagonists mecamylamine and DHβE as well as the partial agonist varenicline completely blocked the MA‐like SD effects of nicotine. Supported by DA018165, AA016849 and OD011092.