The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia. The Cholinergic HypothesisA variety of studies in humans indicate that basal forebrain and rostral forebrain cholinergic pathways including converging projections to the thalamus serve important functional roles in conscious awareness, attention, working memory, and a number of additional mnemonic processes (Perry et al., 1999).For more than 20 years, studies of the brains of those with advanced age and Alzheimer's disease (AD) have consistently found damage or abnormalities in these pathways (particularly basal forebrain projections) that appeared to correlate well with the level of cognitive decline. As a result, the so-called "cholinergic hypothesis" was developed, which essentially states that a loss of cholinergic function in the central nervous system contributes significantly to the cognitive decline associated with advanced age and AD (reviewed, Bartus, 2000). Extensive literature from animal experiments supports the human data described above. In fact, the importance of cholinergic function in the brain to learning and memory was first recognized more than 30 years ago after cholinergic antagonists (specifically antimuscarinic agents) were found to impair memory in rats (Deutsch, 1971). Considerable additional evidence now supports this early work, and antimuscarinic agents such as scopolamine and atropine have been shown to impair memory

1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M 3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M 2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M 3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M 3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.

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