**1. Introduction**

It is now 100 years since acetylcholine (ACh), described as "vagus stuff" by Otto Loewi has been recognized as the first discovered neurotransmitter. This discovery was based on an ingenious experiment where the exposure of a second heart to the media obtained from the electrical stimulation of the vagus nerve of the first heart, resulted in slowing of the second heart, similar to the effect observed by vagal stimulation of the first heart. ACh is now recognized as a critical neurotransmitter at various vital sites such as neuromuscular junction, autonomic ganglia and the brain or the central nervous system (CNS).

Without ACh no skeletal muscle contraction, no preganglionic sympathetic or parasympathetic activity can be obtained. This can result in dysregulation of cardiac, respiratory, gastrointestinal, and renal functions as well as disruption of secretion from various glands such as tears, salvia, digestive juices, sweat and milk. Moreover, since ACh is also the neurotransmitter at the adrenal medulla, its absence at this

site would prevent the release of adrenaline, an essential hormone in regulating the fight-fright response. Importantly, lack of ACh in the brain can have severe cognitive consequences.

Acetylcholine, as the name implies, is made up from two substances, an acetyl group (derived from glucose) and choline, a nutrient derived from foods such as egg yolks, soy and legumes. Choline is also synthesized by the liver. ACh synthesis is catalyzed by choline acetyltransferase (ChAT), the presence of which in a neuron implies that ACh is used as a neurotransmitter by that neuron. A distinguished feature of ACh in comparison with other neurotransmitters is that its action in the synapse is readily terminated by the enzyme acetylcholinesterase (AChE), in contrast to the reuptake mechanism prevalent with other neurotransmitters. Upon the action of AChE, ACh is broken down into acetate and choline, where the latter is taken up for re-use by the nerve. Inhibition of AChE by insecticides or nerve gases can result in accumulation of ACh. Excess ACh at the neuromuscular junction would cause depolarization of the post-synaptic cell and paralysis. Death from the nerve gas is primarily due to excess secretion and respiratory paralysis. On the other hand, some AChE inhibitors (AChEIs) can be used as therapeutic agents in diseases where ACh transmission is inadequate. This includes myasthenia gravis where AChEIs raise the level of ACh in the neuromuscular junction, and improve muscle activation, contraction, and strength, or in neurological disease such as Alzheimer's disease (AD).

The action of ACh is mediated by two distinct classes of receptors, namely the muscarinic (mAChRs) and nicotinic receptors (nAChRs). The focus of this chapter is on interaction of these 2 distinct receptor classes and its implication in health and disease. Thus, following a brief description of ACh actions and its central circuitry, an update on mAChRs and nAChRs and how their interaction may impact neuropsychiatric/neurodegenerative diseases will be provided. Moreover, potential novel therapeutic intervention based on these interactions will be touched upon.
