Scopolamine-physostigmine combination does not substitute for nicotine.

1. Male Sprague-Dawley rats were trained to discriminate 0.4 mg/kg nicotine subcutaneously administered from its saline vehicle in a food-motivated operant discrimination task. Once trained, the discriminative performance was observed to be dose-responsive with an ED50 = 0.11 mg/kg. 2. The co-administration of 0.1 or 0.2 mg/kg physostigmine with either 0.1, 0.15 or 0.2 mg/kg scopolamine produced intermediate discriminative effects, i.e., neither nicotine- nor saline-like responding. However, the physostigmine-scopolamine combination neither substituted for nor increased the discriminative effects of co-administered nicotine. 3. The theoretical/mechanistic possibility that a combination of a cholinesterase inhibitor to increase available acetylcholine plus a specific anti-muscarinic to allow that increased acetylcholine to stimulate nicotinic receptors was investigated. Results indicate that the combination does not produce nicotine-like discriminative effects and evidence the possibility that nicotine discrimination may involve non-cholinergic mechanisms.