Tacrine is a centrally acting, reversible cholinesterase inhibitor that increases synaptic levels of acetylcholine (ACh) and can potentiate the actions of dopamine (DA). The present study was conducted to evaluate effects of tacrine on cocaine-reinforced responding in a rat line selectively bred for high levels of drug self-administration (the HS line). HS rats self-administered different doses of cocaine under a fixed-ratio-5 (FR-5) schedule. Over a four-day period, vehicle or tacrine (1.0, 3.2, or 10 mg/kg-day) was infused when animals were maintained in home cages (21 h per day). Tacrine dose-dependently decreased cocaine self-administration. Actions of tacrine differed for self-administration that was initiated within 20 min of pretreatment (described as early sessions), and for self-administration that occurred between one and three days after administration of tacrine was discontinued (late sessions). Tacrine's potency for attenuating self-administration during late sessions was greater for cocaine- relative to food-reinforcement in HS rats, and for HS relative to outbred rats. In a subset of tacrine-treated HS rats, cocaine self-administration was persistently attenuated by more than 80% from pretreatment baseline levels over a one-week period during which no further tacrine was administered. In summary, pretreatment with tacrine can produce a long-lasting attenuation of cocaine-reinforced responding.