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Nicotinic Agonists and Antagonists. Fig. 4. Schematic overview of the predominant central nAChR subtypes that are targets for the treatment of the central nervous system (CNS) disorders discussed in this chapter. Examples of CNS areas that are modulated by nAChRs are cortex (CTX), prefrontal cortex (PFC), hippocampus (HIPP), thalamus (THAL), locus coeruleus (LC), ventral tegmental area (VTA), nucleus accumbens (NAcc), striatum (STR), and spinal cord. Medicinal chemistry efforts targeting CNS disorders attempt to minimize activity at peripheral nAChR subtypes such as a1 PSe (muscle) and a3P4 (ganglionic) that control a variety of critical physiological functions. Note that the figure is not inclusive of all nAChR subtypes expressed in the body; additional receptor subtypes not shown could represent therapeutic targets or mediate adverse events.

nonalcohol-dependent, heavy-drinking smokers. Additionally, one week of varenicline pretreatment significantly reduced alcohol consumption, attenuated alcohol craving, and increased the likelihood of remaining completely abstinent during an ad libitum self-administration period. Although these data came from a small study of short duration, they provide support for further clinical trials on the effects of a4p2 nAChR partial agonists on drinking behavior. Given the uncertainty over which nAChR subtypes mediate the effects of alcohol, studies on compounds with different nAChR subtype selectivity might provide clues for the potential of other nAChRs as targets for alcohol dependence treatments.

Depression

The cholinergic-adrenergic theory of ► depression states that overactivation of nAChRs by ACh contributes to the development and exacerbation of depressive symptoms. This hypothesis is supported by the well-established association between depression and nicotine and quitting smoking, the weak nAChR antagonist properties of most antidepressants, and the preclinical antidepressant-like activity of compounds that reduce nAChR activity. Clinical observations that the nonselective nAChR antagonist mecamylamine improves the antidepressant response in treatment-resistant depressed patients further strengthen the idea that reducing nAChR activity results in antide-pressant effects (Shytle et al. 2002).

Nicotinic Agonists and Antagonists. Fig. 5. Structures of nicotine and nAChR ligands discussed for nicotine and alcohol dependence.

While nonselective nAChR antagonists block all central nAChR subtypes, selectively reducing the activity of nAChRs thought to contribute to depressive symptoms could result in better antidepressant efficacy and/or improved side-effect profiles. Decreasing a4b2 and/or a7 nAChR signaling can be achieved via receptor blockade using selective antagonists, via receptor desensitization using selective partial agonists, or by the action of negative allosteric modulators. As discussed earlier, partial agonists can potently desensitize nAChRs and could thus have anti-depressant activity at low concentrations associated with desensitization (Picciotto et al. 2008).

Results from preclinical studies in animal behavioral models have demonstrated antidepressant-like activity for the antagonists mecamylamine (nonselective), methyllyca-conitine (MLA, a 7 selective), and dihydro-b-erythroidine (DHbE, a4b2), and the a4b2 selective partial agonists var-enicline, cytisine, and ispronicline (TC-1734, AZD-2389) (Fig. 6). In contrast, the full agonists nicotine (Fig. 5), RJR-2403 (a4b2 selective; Fig. 6), and PNU-282987 (a7 selective; Fig. 6), were devoid of antidepressant-like activity.

Combined with antidepressants, nAChR antagonists and partial agonists show synergistic effects in animal depression models. Mecamylamine potentiates the activity of both ► tricyclic antidepressants and selective serotonin reuptake inhibitors (► SSRI), co-administration of nicotine also enhances the effects of antidepressants, consistent with the potent desensitization activity of nicotine. Additionally, co-administration of a low dose of varenicline significantly enhances the effect of the SSRI ► sertraline.

The potential of nAChR antagonists and partial agonists as an antidepressant-augmentation strategy is supported by clinical data in treatment-resistant patients with major depressive disorders. Results from a small pilot study suggested that adding mecamylamine to antidepressants significantly decreases depressive symptoms, while a larger study found that co-administration of ► citalopram and mecamylamine improves depressed mood and irritability. Further clinical studies are now being conducted with the (+) enantiomer of mecamylamine, TC-5214, which showed robust effects as an augmentation therapy in treatment resistant patients in a large phase 2a study. Finally, in a small open label study, administration of the partial agonist varenicline to smokers on a stable antidepressant regimen significantly improved depression scores over eight weeks starting at week 2 of treatment.

While the available preclinical and clinical data support the notion that selective nAChR ligands may have antide-pressant effects via antagonism or desensitization of a4b2 and possibly a7 nAChRs, large blinded studies with selective nAChR ligands are needed to demonstrate the validity of this approach.

Cognitive Deficits

Nicotine improves aspects of attention and memory in both laboratory animals and humans. The high prevalence of smoking in individuals with mental disorders has led to the speculation that nicotine use may be a form

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