The natural alkaloids nicotine and muscarine (Fig. 1) were the key pharmacologic tools that uncovered the two families of acetylcholine (ACh) receptors in the CNS. These families were defined by the action of these alkaloids to mimic the multiplicity of effects of ACh as a mediator of synaptic transmission (TAYLOR 1996). This was accomplished well before the recognition that nicotinic ACh receptors (nAChR) are ligand-gated ion channels (LGICs), and muscarinic ACh receptor (mAChR) families are seven transmembrane domain (7TM) coupled metabotropic receptors. In the past, the prevailing dogma of these receptors tended to view mAChRs as the primary (if not sole) mechanism required to understand the central neuropsychopharmacolgical effects of ACh (WATSON et al. 1987), while nAChRs were examined primarily for their role in mediating neuromuscular transmission and in mediating ganglionic transmission in the parasympathetic and sympathetic nervous systems (TAYLOR 1996). Indeed, clinically useful therapeutics have for some time been identified targeting the interruption of autonomic and neuroskeletal muscle transmission (TAYLOR 1996). Focus away from the CNS stemmed largely from two impressions. First, the low abundance of brain nAChRs (i.e., ten-fold lower than mAChRs) suggested to many that they are less likely to be physiologically important. Second, the difficulty in demonstrating nicotinically mediated synaptic transmission in the brain gave little impetus for others to further pursue the pharmacologie relevance of these receptors (CLARK et al. 1999). Also contributing to the lack of medicinal chemistry efforts and drug discovery focus for neuronal nAChRs has been a continuing negative association between nicotine and tobacco consumption (COHEN 1996; WILLIAMS and ARNERIC 1996). More recently, this trend has changed with recent studies at both the preclinical and clinical levels indicating that neuronal nAChRs may have a substantial role in enhancing the release of transmitters involved in facilitating cognitive performance, modulating affect, and in potently controlling nociceptive processes (DECKER et al. 1995; LINDSTROM 1997; DECKER and ARNERIC 1999).