Acetylcholine and nicotine

Egan, T. M. North, R. A. (1986). Actions of acetylcholine and nicotine on rat locus coeruleus neurons in vitro. Neuroscience 19, 565-71. 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

Whitehouse PJ, Price DL, Clark AW, et al Alzheimer disease evidence for selective loss of cholinergic neurons in the nucleus basahs. Ann Neurol 10 122-126, 1981 Whitehouse PJ, Price DL, Struble RG, et al Alzheimer s disease and senile dementia—loss of neurons in the basal forebrain. Science 215 1237-1239, 1982 Whitehouse PJ, Hedreen JC, White CL, et al Basal forebrain neurons in dementia of Parkinson s disease. Ann Neurol 13 243-248, 1983 Whitehouse P, Martino A, Antuono P, et al Nicotinic acetylcholine binding sites in Alzheimer s disease. Brain Res 371 146-151, 1986 Whitehouse PJ, Martino AM, Marcus KA, et al Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 45 722-724, 1988 Whitton PS, Sama GS, O Connell MT The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal diasylates in vivo. Neuropharmacology 39 1-4, 1991 Whitworth P, Kendall DA Lithium selectively inhibits muscarinic receptor-stimulated inositol tetrakisphosphate accumulation in mouse cerebral cortex slices. J Neurochem 51 258-265, 1988... 

The nicotinic receptors on the neuromuscular end plate apparatus are similar but not identical to the receptors in the autonomic ganglia (Table 7-1). Both types respond to acetylcholine and nicotine. (However, as noted in Chapter 8, the receptors differ in their structural requirements for nicotinic blocking drugs.) When a nicotinic agonist is applied directly (by iontophoresis or by intra-arterial injection), an immediate depolarization of the end plate results, caused by an... 

Arenediazonium-containing reagents are used to photolabel acceptor sites, which bind cationic groups such as acetylcholine and nicotine in acetylcholine sterase and the nicotinic receptor, respectively.1110-112 ... 

The competition for nAChR binding by acetylcholine and nicotine illustrates the key role of selectivity in binding in supramolecular chemistry. Because nAChR is not fully selective, it is also able to bind the interfering nicotine. The fact that nicotine, like acetylcholine, possesses a quaternary ammonium moiety that is implicated in its binding mechanism highlights the dependence of biological processes on ostensibly weak supramolecular interactions. 

The modes of action of different alkaloids are diverse. For example, nicotine binds to and affects nicotinic acetylcholine receptors and shows toxicity. A recent molecular 3D model suggests that both acetylcholine and nicotine bind to the same pocket formed in a nicotinic acetylcholine receptor.15 Morphine binds to and activates opioid receptors, transmembrane-spanning G protein-coupled receptors, in the central nervous system of humans.16 Caffeine, which is structurally similar to adenine, inhibits cyclic AMP phosphodiesterase activity and inhibits the degradation of cAMP, thus exerting a toxic effect on insects 17 in human beings, binding of caffeine to the adenosine A2A receptor induces wakefulness.18 Atropine binds to muscarinic acetylcholine receptors, competing with acetylcholine, and blocks neurotransmission.1... 

Figure 7.24 Similarities between acetylcholine and nicotine binding to the acetylcholine receptor. (From Matsumura, F., Toxicology of Insecticides, 2nd ed., Plenum Press, New York, 1985. With permission.)...

The pharmacological actions of peganidine (189) and deoxypeganidine (190) were investigated. Both compounds potentiated the physiological eflfects of acetylcholine and nicotine and inhibited cholinesterase in vitro. 

Nicotinic Acetylcholine Receptors. Nicotinic acetylcholine receptors are ligandgated ion channels whose opening is controlled by acetylcholine and nicotine agonists (196,209,210). They are transmembrane protein structures. Each receptor consists of five subunits. The structure is inserted in the plasma membrane with an aqueous channel in... 

Figure 6.1 Chemical structures of acetylcholine and nicotinic cholinoceptor ligands used in this study.

Non-depolarising neuromuscular blockers (NMBs) in normal doses act by competitive inhibition of the interaction between acetylcholine and nicotinic receptors. In higher doses, they are thought to block the ion channel as well, which explains the decreased effectiveness of AChE inhibitors in treating non-depolarising neuromuscular blocker toxicity. 

Mode of Motion. Nicotine, anabasine, and imidocloprid affect the ganglia of the insect central nervous system, faciUtating transsynaptic conduction at low concentrations and blocking conduction at higher levels. The extent of ionisation of the nicotinoids plays an important role in both their penetration through the ionic barrier of the nerve sheath to the site of action and in their interaction with the site of action, which is befleved to be the acetylcholine receptor protein. There is a marked similarity in dimensions between acetylcholine and the nicotinium ion. 

Several cholinergic strategies, other than cholinesterase inhibition, have been employed with the intention of ameliora ting the symptoms of AD. These include precursor loading acetylcholine release enhancement, and direct activation of both muscarinic and nicotinic receptors. 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

Cholinergic receptors Receptors for acetylcholine are classified into muscarinic (muscarine is a selective agonist) and nicotinic (nicotine is a selective agonist). There are five muscarinic (mj to m5) and two nicotinic (neuronal, or ganglionic, and skeletal muscular) subtypes. 

Acetylcholine. Most of the acetylcholine in the basal ganglia is found in the striatum, as the neurotransmitter of the large spiny interneurons, which account for about 3% of all striatal neurons. Both muscarinic and nicotinic cholinergic receptors are found in the striatum. Postsynaptic muscarinic receptors may inhibit transmitter release from... 

Acetylcholine Binds to cholinergic receptor, which are of two types— muscarinic and nicotinic. 

Given the role of acetylcholine receptors in analgesic circuits, it is not surprising that a number of plants with cholinergic mechanisms have analgesic effects. The RVM has muscarinic and nicotinic receptors (Cortes and Palacios 1986 London et al. 1985). The PAG has nicotinic receptors as well (Segal et al. 1978). 

Chen DN, Patrick JW (1997) The a-bungarotoxin-binding nicotinic acetylcholine receptor from rat brain contains only the a7 subunit, J Biol Chem 272 24024-24029 Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain autoradiographic comparison of [ H]acetylcholine, [ H]nicotine, and [ I]-alpha-bungarotoxin, J Neurosci 5 1307-1315... 

Yates SL, Bencherif M, Fluhler EN, LippieUo PM (1995) Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or alpha 4 beta 2 receptors to nicotine, Biochem Pharmacol 50 2001-2008 Yeomans J, Baptista M (1997) Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brain-stimulation, Pharmacol Biochem Behav 57 915-921 Yoshida M, Yokoo H, Tanaka T, Mizoguchi K, Emoto H, Ishii H, Tanaka M (1993) Facilitatory modulation of mesolimbic dopamine neuronal-activity by a mu-opioid agonist and nicotine as examined with in-vivo microdialysis. Brain Res 624 277-280... 

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