Acetylcholine/cholinergic system nicotine

Cholinergic Transmission is the process of synaptic transmission which uses mainly acetylcholine as a transmitter. Cholinergic transmission is found widely in the peripheral and central nervous system, where acetylcholine acts on nicotinic and muscarinic receptors. 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

Dani JA, Bertrand D. 2007. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47 699-729. 

Nicotiana tabacum, and lobeline, present in the dried leaves and tops of the herb, Lobelia inflata (13). Both nicotine and lobeline act as agonists on a specific type of acetylcholine receptor, the nicotinic cholinergic receptor. In mammals, nicotinic cholinergic receptors mediate cholinergic neurotransmission in skeletal muscles, autonomic ganglia, and the central nervous system. At these sites nicotine s action has two phases, excitation and depression. Insect central nervous tissues are rich in nicotinic cholinergic receptors (cf. 14), but their role in behavior is not well understood. 

The nicotinic acetylcholine receptors of the neural excitatory cholinergic system are the targets for both nicotine and neonicotinoids in mammals and insects. 

Some toxic consequences of neonicotinoids for nontarget beneficial aquatic and terrestrial arthropods such as bees can be expected since these creatures have nicotinic acetylcholine receptors as functional components of the cholinergic system similar to those of insect pests. Surprisingly, neonicotinoid toxicity to numerous nontarget insect species and wildlife marker vertebrates, for example, rainbow trout, is lower than expected. In general, the environmental safety of neonicotinoids surpasses that of other insecticides. 

The muscarinic cholinergic system has quite a different mode of operation in that the receptor is connected to the final action by a chain of events. Thus its response is slower than the nicotinic, where the receptor and ion channel are closely connected. Five distinct muscarinic receptors have been identified in mammals, based on anatomical location, genetic analysis, function, and amino acid sequence. All of them have seven transmembrane domains [166, 167, 168, 169]. The N- terminal domain outside the cell binds acetylcholine or other ligands at a site that includes an aspartate residue, while the C-terminal domain inside the cell is coupled to a so-called G-protein , which is initially bound to guanosine diphosphate (GDP), but exchanges it for guanosine triphosphate (GTP) when activated by its transmitter. The activated G-protein then activates phospholipase C, which hydrolyzes phosphoinositides to release 1,4,5-inositol triphosphate [170]. The final action depends on which type of cell is involved so that in some types ion channels are opened just as with the nicotinic receptor, but in other cases other processes are affected, for example the release of dopamine [171]. Since there are these differences... 

Acetylcholine Approximately 5% of brain neurons have receptors for ACh. Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best-characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer s disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). 

The cholinergic system in insects is the main target of insecticides. One class of molecules, the neonicotinoids, induces direct activation of the neuronal nicotinic acetylcholine receptors (nAChRs). In the honey bee these receptors are mainly distributed in the olfactory pathways that link sensory neurons to antennal lobes and mushroom bodies. These structures seem to play an important role in olfactory conditioning. We have previously shown that cholinergic antagonists injected in different parts of the brain impaired the formation and retrieval of olfactory memory. We then advanced the hypothesis that, through the activation of the nAChR, the neonicotinoid imidacloprid (IMI) would lead to facilitation of the memory trace. 

Nicotine is the main psychoactive ingredient of tobacco and is responsible for the stimulant effects and abuse/ addiction that may result form tobacco use. Cigarette smoking rapidly (in about 3 sec ) delivers pulses of nicotine into the bloodstream. Its initial effects are caused by its activation of nicotinic acetylcholine (nACh) receptors. nACh receptors are ligand-gated ion-channels and pre- and postsynaptically located. Reinforcement depends on an intact mesolimbic dopamine system (VTA). nACh receptors on VTA dopamine neurons are normally activated by cholinergic innervation from the laterodorsal tegmental nucleus or the pedunculopontine nucleus. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Acetylcholine receptors have been classified into sub-types based on early studies of pharmacologic selectivity. Long before structures were known, two crude alkaloid fractions, containing nicotine and muscarine (Fig. 11-2), were used to subclassify receptors in the cholinergic nervous system (Fig. 11-3). The greatly different... 

There is considerable diversity among nicotinic acetylcholine receptors, and at least one source of this diversity is the multiplicity of acetylcholine receptor genes. Cholinergic-nicotinic receptors in skeletal muscle are different from those in autonomic ganglia and the central nervous system. 

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