Muscarinic Agonists

Activation of muscarinic receptors may exert antipsychotic-like activity in animals and humans. The first indication that activation of muscarinic receptors might have antipsychotic activity in humans arose from the use of cholinesterase inhibitors to treat behavioral disturbances in demented individuals, particularly those with dementia with Lewy bodies (DLBs) (see 6.08 Neurodegeneration).64 These patients exhibit visual hallucinations, delusions, apathy, agitation, dementia, and mild parkinsonism. Cholinergic deficits in this disorder are even more severe than in Alzheimer's disease (AD). Improvements in neuropsychiatric symptoms have been reported from small studies of DLB patients treated with the cholinesterase inhibitors tacrine 59, rivastigmine 60, donepezil 61, and galantamine 62. Because of the overwhelming peripheral cholinergic side effects of these drugs, it is unlikely that this class of agents will be used broadly but these studies have opened new avenues for future studies with safer drugs.

Because acetylcholinesterase inhibitors nonspecifically increase the release of ACh and lead to the activation of muscarinic and nicotinic receptors, it is difficult to ascribe the effects of these agents on psychotic behavior to either subtype. While selective muscarinic and nicotinic agonists have not been studied for antipsychotic activity in humans, xanomeline 63, a broadly acting muscarinic partial agonist with limited selectivity for the M1 and M4 receptor subtypes, has been shown to reduce behavioral disturbances in patients with AD. Reductions in hallucinations, agitation, delusions, vocal outbursts, and suspiciousness were seen in these patients with AD after xanomeline treatment.79 Xanomeline and other more selective muscarinic agonists have an antipsychotic-like profile in various animal models of psychosis. Muscarinic agonists have activity in these rodent models that is very similar to that seen with D2 antagonists, with the exception that muscarinic agonists do not cause catalepsy. These findings led to the suggestion that muscarinic agonists may have potential antipsychotic effects. A small study in patients with schizophrenia suggested xanomeline had antipsychotic activity in this population as well as AD. The utility of selective muscarinic agonists in patients with schizophrenia needs to be evaluated. An NCE that selectively activates the Mi muscarinic receptor would be of interest as long as it did stimulate the M3 and to a lesser extent the M2 muscarinic receptors causing unwanted peripheral cholinergic side effects.

"N' Tacrine 59

"N' Tacrine 59

Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

I leave absolutely nothing out! Everything that I learned about Alzheimer’s I share with you. This is the most comprehensive report on Alzheimer’s you will ever read. No stone is left unturned in this comprehensive report.

Get My Free Ebook


Post a comment