Discriminative stimulus effects of cholinergic agonists and the actions of their antagonists

Both muscarinic- and nicotinic-cholinergic agonists have been used for discrimination training, but only nicotine has been studied extensively. The limited information available suggests that the discriminative stimulus effects of drugs classified as muscarinic-cholinergic agonists are blocked competitively by atropine but not by ganglion-blockers. The discriminative effects of nicotine are blocked non-competitively by ganglion-blocking drugs that penetrate into the CNS (e.g. mecamylamine), but they are not blocked by atropine. The specificity of the block is shown by the failure of mecamylamine to block several non-nicotinic drugs. The ganglion-blocking drug chlorisondamine penetrates poorly into the CNS when injected systemically; when injected intraventricularly, it is a potent and specific nicotine antagonist with a 4-week duration of effect. Haloperidol attenuates discriminative effects of nicotine but this is not a specific block; there are marked reductions in response rate, the morphine stimulus is also attenuated, and other neuroleptics have much weaker effects. The results support the view that the discriminative effect of nicotine involves predominantly cholinoceptive sites, and they suggest that it is not mediated primarily by the dopamine system. The transduction mechanisms for the nicotine stimulus may include the receptor sites that mediate many of its other CNS effects, but more information is needed about possible subtypes of nicotinic receptors before definitive conclusions are possible.