Muscarinic receptors presynaptic

No overall reduction in cholinergic muscarinic receptors was found but recent studies with relatively specific ligands show a loss of presynaptic M2 receptors, in keeping with the loss of terminals, but no reduction in postsynaptic Mi receptors. Some acetylcholinesterase is found in plaques. 

The available data are consistent with the present thesis that cholinergic inputs to cerebral cortex mediate intradendritic events fundamental to conscious activity as a primary role, and that cholinergic modulation of electrophysiological activity may be secondary, even epiphenomenal. Transduction pathways exist whereby muscarinic receptors (and possibly nicotinic receptors acting presynaptically to inhibit acetylcholine release) may lead to actions on the cytoskeleton directly relevant to consciousness. The thesis presented here describes these pathways and also suggests a possible explanation for the diversity of neuromodulators and metabotropic receptors. Accordingly, qualitative aspects of our consciousness would be finely tuned by a number of neurochemicals, prominent among which is acetylcholine. 

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.

The TCA drugs have lost their place as first-line therapy for depression because of their bothersome side effects (Table 33.2) at therapeutic doses and lethal effects in toxic doses. In addition to their presynaptic effects on the neuronal uptake of norepinephrine and serotonin, they block several postsynaptic receptors. They are potent cholinergic muscarinic receptor antagonists, resulting in symptoms such as dry mouth, constipation, tachycardia, blurred vision and urinary retention. Blockade of histamine receptors (Hi) often results in sedation and weight gain. Antagonism of aj-adrenoceptors in the vasculature can cause orthostatic hypotension. 

Because of the multiple receptor sites that TCAs bind to, there are a variety of possible side effects that can be seen in treatment. The blockade of muscarinic receptors leads to increased anticholinergic tone and subsequent anti-cholinergic side effects, especially in the gastrointestinal system. These include delirium, dry mouth, tachycardia, constipation, and urinary retention in adults. In children, anticholinergic side effects are often not seen with treatment (Geller et ah, 1992). Tricyclic antidepressant blockade of the presynaptic a 2 receptors leads to increased autonomic tone throughout the body, causing elevations in heart rate and blood pressure. 

Abstract Presynaptic metabotropic receptors for acetylcholine and adrenaline/ noradrenaline were first described more than three decades ago. Molecular cloning has resulted in the identification of five G protein-coupled muscarinic receptors (Mi — M5) which mediate the biological effects of acetylcholine. Nine adrenoceptors (ociabd,oc2abc,Pi23) adrenafine/noradrenaline signals between cells. 

Fig. 1 Presynaptic signaling mechanisms of muscarinic receptor subtypes (M1-M5). Abbreviations otj/o, (S, y, subunits of G /0 heterotrimeric GTP-binding proteins DAG, diacylglycerol.

Trendelenburg AU, Gomeza J, Klebroff W, Zhou H, Wess J (2003a) Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter releases study with M2-and M4-receptor-deficient mice. Br J Pharmacol 138 469-80... 

In the peripheral (Wessler 1989) as well as central (Wonnacott 1997) nervous system, presynaptic nicotinic autoreceptors were reported to control the release of acetylcholine. In both locations, the consequence of presynaptic nAChR activation most commonly is an increase in both spontaneous and evoked acetylcholine release (MacDermott et al. 1999), whereas presynaptic muscarinic receptors mediate the opposite effect, an autoinhibition. Recent studies have focused on the composition of presynaptic nAChRs (Table 2). In the hippocampus, nicotinic autoreceptors were suggested to be a3/p4 receptors (Tani et al. 1998), but a role of p2 subunits has also been implicated (Lloyd et al. 1998). Likewise, in the neocortex, presynaptic nicotinic autoreceptors are likely to be 04/ p2 receptors (Marchi et al. 2002). In contrast, in the interpeduncular nucleus the autoreceptors were suggested to mainly contain a3 and p4 subunits (Grady et al. 2001). 

Raiteri M, Leardi R, Marchi M. 1984. Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain. J Pharmacol Exp Ther 228 209-214. 

Q6 In comparison with the sympathetic transmitter norepinephrine, the inactivation of acetylcholine by cholinesterases is rapid so that normally the activity of acetylcholine at the synapse is relatively short-lived. The choline component is taken up into the presynaptic terminal and acetylcholine is resynthesized and stored in the synaptic vesicles. Anticholinesterases function as cholinergic stimulants in the parasympathetic nervous system since they greatly prolong and so increase the actions of endogenous acetylcholine at muscarinic receptors on the effector tissue. 

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