Translating laboratory discovery to the clinic: from nicotine and mecamylamine to Tourette's, depression, and beyond

The early development of novel nicotinic drugs for Tourette's and depression was a very long journey in discovery, which began with basic behavioral neuroscience studies aimed at understanding how cholinergic and dopaminergic systems interact in the basal ganglia to control goal directed movement. These early rodent studies with nicotine and dopamine antagonists formed the basis for investigating a potentially improved treatment for children suffering from Tourette's syndrome (TS). Clinically, the research trajectory first focused on studies employing the use of nicotine gum to potentiate the therapeutic effect of the dopamine receptor antagonist, haloperidol, in patients with TS. These projects led to the discovery of a new use for a decades-old blood pressure medication, mecamylamine, a nicotine antagonist, which also appeared to provide symptomatic relief in some TS patients when used clinically and was found to reduce symptoms of mood instability and depression. This unexpected discovery led to a new hypothesis regarding the mechanism of action of antidepressants as well as a series of successful independent trials employing mecamylamine, and its active enantiomer, TC5214, as an augmenting agent in the treatment of major depression. This article is a chronological mini review of these basic and clinical translational studies on nicotinic therapeutics for Tourette's syndrome and depression over the past 25 years.