Muscarinic dysfunctions

In vitro studies (Tsakiris et al., 1998a,b, 2002), showed that preincubation of rat homogenates or pure eel, E. Electricus, with high Phe levels resulted in a decrease of acetylcholinesterase (AChE) activities, which reached about -18%. In addition, pure Na", K" -ATPase activity showed an increase by 20-30% after incubation with Phe (0.24-0.9 m ). A rat brain homogenate Na% K -ATPase activity increase by 60-65% appeared with 0.9-12.1 mM Phe incubation. These in vitro results may explain the observed muscarinic dysfunctions presented in untreated PKU patients. 

Clinical signs and symptoms of toxicity are related to the overstimulation of muscarinic, nicotinic, and central nervous system receptors in the nervous system. Muscarinic receptors are those activated by the alkaloid drug muscarine. These receptors are under the control of the parasympathetic nervous system, and their hyperactivity results in respiratory and gastrointestinal dysfunction, incontinence, salivation, bradycardia, miosis, and sweating. Nicotinic receptors are those activated by nicotine. Hyperactivity of these receptors results in muscle fasciculations even greater stimulation results in blockade and muscle paralysis (Lefkowitz et al. 1996 Tafliri and Roberts 1987). Hyperactivity of central nervous system receptors results in the frank neurological signs of confusion, ataxia, dizziness, incoordination, and slurred speech, which are manifestations of acute intoxication. Muscarine and nicotine are not... 

The following side effects apply to the irreversible, nonselective MAOI antidepressants (phenelzine and tranylcypromine). The most common side effects are orthostatic hypotension, headache, insomnia, weight gain, sexual dysfunction, peripheral edema, and afternoon somnolence. Although MAOIs do not have significant affinity for muscarinic receptors, anticholinergic-like side effects are present at the beginning of treatment. Dry mouth is common but not as marked as in TCA therapy. Fortunately, the more serious side effects, such as hypertensive crisis and serotonin syndrome, are not common. 

Altman JD, Trendelenburg AU, MacMillan L, Bernstein D, Limbird L, Starke K, Kobilka BK, Hein L (1999) Abnormal regulation of the sympathetic nervous system in 2a-adrenergic receptor knockout mice. Mol Pharmacol 56 154-61 Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, RahnamaNP, Nathanson NM, Silva A1 (2003) Selective cognitive dysfunction in acetylcholine Mi muscarinic receptor mutant mice. Nature Neurosd 6 51-8... 

The role of tau in synaptic dysfunction has not been as well documented as A. Tau has been reported to change intracellular calcium levels, probably via the interaction of extracellular tau with muscarinic receptors Ml and M3 (G6mez-Ramos et al., 2008). Also a spatially association of tau modifications with intraneuronal AP, in which both pathologies co-occur at synaspses has been reported (Takahashi et al., 2010). Finally, using two-photon calcium imaging in layer 2/3 of an AD mouse model cortical neurons, an increase in the frequency of spontaneous calcium transients in the vicinity of amyloid plaques was seen (Busche et al., 2008). 

Dahisch, P.A., Florsmon, M.S., Muse, W.T., Mioduszewski, R.J., Thomson, S.A. (2007h). Muscarinic receptor dysfunction induced by exposure to low levels of soman vapor. Toxicol. Sci. 100 281-9. 

Clozapine and olanzapine are the most likely of the atypical agents to cause anticholinergic (anti-muscarinic) effects. They are more likely than other atypicals to cause weight gain (glucose tolerance may be impaired and should be monitored in susceptible individuals) and are second only to quetiapine in their sedative effects. Sexual dysfunction and skin problems are rare with atypical antipsychotics. Risperidone and amisulpride are as likely as classical antipsychotics to raise prolactin concentrations and cause galactorrhoea. 

Bethanechol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but it is much more slowly deactivated. It has been used to treat clomipramine-induced orgasmic dysfunction (1). 

Drugs from several chemical families, most of which are capable of blocking DM receptors (formerly D2). To varying degrees, they also block muscarinic receptors (typical atropine-like effects) and alpha receptors (postural hypotension, sexual dysfunction) and are sedating. 

Answer C. Muscarinic receptor antagonists such as benztropine, trihexyphenidyl, and diphenhydramine are used to manage the reversible extrapyramidal dysfunction (e.g., pseu-do-Parkinsonism) that results from treatment with drugs that block DA receptors in the striatum. Drugs that activate DA receptors, although theoretically possible, require doses that are toxic and exacerbate psychoses. Because the actions of DA in the striatum lead to... 

Vilaro MT, Mengod G, and Palacios, JM (1993) Advances and limitations in the molecular anatomy of cholinergic receptors the example of multiple muscarinic receptors. In Cuello AC (Ed.), Cholinergic function and dysfunction. Progress in Brain Research, Vol. 98. Elsevier, Amsterdam, 77. 

Considerable evidence, particularly in the last five years, has spotlighted PC as a key seizurogenic site in the cerebral cortex and dysfunction of this area may play an important role in temporal lobe epilepsy. Systemic injection of muscarinic receptor agonists or acetylcholinesterase inhibitors produces robust, sustained seizure activity in PC. Several recent studies have demonstrated that PC is the first cortical or subcortical forebrain structure to exhibit increased c-fos expression, a marker for elevated neuronal activity, after convulsive doses of pilocarpine or the irreversible acetylcholinesterase... 

Davis, R et al., 1993. Subtype-selective muscarinic agonists potential therapeutic agents for Alzheimer s disease. In Cuello, C.A., (Ed.), Cholinergic Function and Dysfunction, Progress in Brain Research. Elsevier. Amsterdam, pp. 439-445. 

Bethanechol, like any muscarinic agent, has negative inotropic, chronotropic and dro-motropic effects. It may also cause systemic vasodilatation, decreased TPR, and dramatically lowered blood pressure. In a healthy person, sympathetic reflexes would compensate for these effects. However, such reflexes would worsen symptoms in a patient with cardiovascular dysfunction. Bethanechol s use is therefore contraindicated in patients with pronounced bradycardia, hypotension, coronary artery disease, or any type of cardiac disease. 

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