Tremors oxotremorine-induced

Both the M2 and M4 receptors are, as indicated above, coupled to Gj pathways and appear to mediate similar responses. The M2 receptor is widely expressed in the CNS but also present in heart and smooth muscle, while M4 is preferentially expressed in the CNS, especially in forebrain. Ablation of the M2 receptor leads to complete loss of muscarinic-agonist-stimulated bradycardia [55]. In the CNS, deletion of the M2 receptor abolishes oxotremorine induced akinesia and tremors [56]. Memory and learning tasks including passive avoidance and working memory are impaired in M2-receptor knockout mice, and there is decreased LTP in hippocampal slices [12],... 

Racemic (191) (226), as well as its pure enantiomers (227), blocks oxotremorine-induced tremors. In other regions of the brain (e.g., those involved in analgesia and hypothermia), (191) acts as a muscarinic agonist (228). Replacement of the acetamido group of (191) with an oximino moiety and homologation of the chain (192) resulted in a fivefold greater selectivity for receptors (229). 

The potencies of the drugs in blocking oxotremorine-induced salivation and tremors are also given in Table I. These results are taken from Brimblecombe and Green (1968). 

The peripheral and central anticholinergic activities of the 8 drugs were also measured in terms of their potencies in antagonising oxotremorine-induced salivation and tremors respectively in mice. 

All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of Mx through M3 have been analyzed by means of experiments in knockout mice. The Mx subtype is richly expressed in brain areas involved in cognition. Knockout of Mx receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in Mx mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass. 

The possible modes of action of amantadine and other drugs in parkinsonism are summarized in Table 1. Amantadine does not act like the centrally-acting anticholinergics In three animal preparations amantadine failed to cause anticholinergic effects (guinea pig ileum, acetylcholine-induced depressor effects in dogs, oxotremorine tremor in mice) ... 

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