Cholinergic activators

Acetylcholine receptors in the plasma membrane were initially identified by immunoelectronmicros-copy using anti-acetylcholine receptor antibodies (Klymkowsky and Stroud 1979). Transversing the lipid bilayer is a central channel measured by structural analysis as about 0.7 nm diameter (Kistler et al. 1982), close to the maximum diameter derived from electrophysiological measurements of conductivity of organic cations of various size (Furukawa and Furukawa 1959, Maeno et al. 1977, Huang et al. 1978, Dwyer et al. 1980). Acetylcholine receptors are sevenfold membrane-spanning receptors (Kubo et al. 1986, Hesch 1991). 

Five distinct muscarinic receptors have been identified (Mi-Mj) by molecular cloning, and there is evidence to suggest that at least four of them (M,-M4) are of functional importance within the airways (Barnes 1993). Mj, M3, and M5 receptors stimulate polyphosphoinositide hydrolysis, leading to an increase in inositol monophosphate. This occurs predominantly through the stimulation of pertussis 

Autoradiographs of lungs from adult male Sprague-Dawley rats injected with the muscarinic binding probe H-quinuclidinyl benzilate showed little labelling despite a 6 month exposure time (Smith and Sidhu 1984). 

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Precursor loading using choline (qv) or lecithin (qv) (13) failed to have a significant effect on AD symptoms (98,105—107). These negative results may, in part, be related to the observation that lecithin does not alter central cholinergic activity in AD (108). 

Dementia with Lewy bodies (DLB) is considered the second most common cause of dementia after AD. The disorder is characterized by progressive fluctuating cognitive impairment, visual hallucinations and motor features of Parkinsonism. Neocoitical cholinergic activity is more severely depleted in DLB than in AD, and DLB also affects the caudate nucleus, the thalamus and the brain stem. Tolerability of ChEI in DLB appears similar to AD, with some gastrointestinal effects and muscle cramps. 

Greene, R. W., Gerber, U. McCarley, R. W. (1989). Cholinergic activation of medial pontine reticular formation neurons in vitro. Brain Res. 476, 154-9. 

Revell, 1988). These studies were interpreted as showing that nicotine was a cognitive enhancer, boosting alertness through an increase in cholinergic activity (Parrott and Winder, 1989 Revell, 1988 Wesnes and Warburton, 1983 Wesnes and Parrott, 1992). 

Reduced activation of dopamine-1 and dopamine-2 receptors results in greater inhibition of the thalamus. Clinical improvement may be more tied to restoring activity at the dopamine-2 receptor than at the dopamine-1 receptor. Loss of presynaptic nigrostriatal dopamine neurons results in inhibition of thalamic activity and activity in the motor cortex. Degeneration of nigrostriatal dopamine neurons results in a relative increase of striatal cholinergic activity, which contributes to the tremor of PD. 

While there is a variety of neurotransmitter deficits, loss of cholinergic activity is most prominent and correlates with AD severity. 

Agents that increase acetylcholine activity can decrease manic symptoms (e.g, use of cholinesterase inhibitors or augmentation of muscarinic cholinergic activity). 

Reverses age-related decline in choline acetyltransferase Reverses an age-related decline in muscarinic receptors Stimulates learning-related cholinergic activity Monoamine Facilitates release of norepinephrine (through o2)... 

Day J, Damsma G, Fibiger HC. 1991. Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity an in vivo microdialysis study. Pharmacol Biochem Behav 38(4) 723-729. 

Durkin T. 1992. GABAergic mediation of indirect transsynap-tic control over basal and spatial memory testing-induced activation of septo-hippocampal cholinergic activity in mice. Behavioral Brain Research 50(1-2) 155-165. 

There is also evidence that the density of muscarinic receptors is increased in limbic regions of depressed patients who have committed suicide. If it is assumed that such a change reflects an increased activity of the cholinergic system, it could help to explain the reduced noradrenergic function as there is both clinical and experimental evidence to suggest that increased central cholinergic activity can precipitate depression and reduce noradrenergic activity. 

The tropane alkaloids, especially hyoscine (scopolamine) (18), have been used to treat PD since they increase DA activity by antagonizing cholinergic activity at the muscarinic receptors in the striatum. The naturally occurring alkaloids, foimd in various genera of the Solanaceae, are not... 

Perry N, Court G, Bidet N, European herbs with cholinergic activities, potential in dementia therapy, Int J Geriatr Psychiatry 11 1063—1069, 1996. 

It disrupts neuronal reuptake of monoamines in the CNS and possesses moderate tranquilizing and cholinergic activity. It improves mood significantly and relieves feelings of fear. Maprotiline is used in various forms of depression accompanied by a feeling of fear and irritability. Ludiomil is a synonym of maprotiline. 

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