Mecamylamine nicotinic receptor antagonist

Brain activity changes (measnred with fMRl) during cigarette withdrawal were recently reported for nicotine-dependent rats (Shoaib et al. 2004). In this study, subcutaneous mecamylamine (1 mg kg ), a nicotine receptor antagonist, was administered to precipitate withdrawal dnring scanning, and this state was compared to a control state after subcntaneons saline administration. After subcutaneous mecamylamine, nicotine-dependent rats had bilateral increases in NAc activity compared to the control state. 

Mecamylamine (a nicotinic receptor antagonist) Mecamylamine decreased intravenous nicotine self-administration under various procedures in rats and monkeys... 

The dependence indnced by nicotine infnsion can be prevented by coinfusion with the nicotinic receptor antagonist mecamylamine (Malin 2001). 

Most of the anticholinergic drugs which cause delirium have prominently antimuscarinic actions. However, nicotinic receptors are also present in the brain. Mecamylamine, a nicotinic receptor antagonist which penetrates the brain to some extent, has produced delirium (Paykel et al., 1982). Furthermore, general (inhalational) anaesthetics, which by definition decrease arousal, target nicotinic receptors among others (Chapter 9). Conversely, nicotine itself increases arousal and selective attention (Ashton, 1992b). 

Chlorpyrifos at 1.5-50 pg/ml (noncytotoxic les els) arrests DNA synthesis in undifferentiated cells, having less effect on RNA synthesis and liuLe on protein synthesis effect on DNA maximal at 1 hr these effects are not blocked by atropine or mecamylamine (moscarinic and nicotinic receptor antagonists, respectively) nicotinic (cholinergic) stimulation of undifferentiated cells does not mimic chlorpyrifos chlorpyrifos (50 pg/ml for I hr) inhibits residual DNA synthesis in differentiating cultures and robustly inhibits RN.A synthesis during early differentiation. 

The precise molecular mechanism by which chronic nicotine treatment prevents the effects of stress on memory and synaptic plasticity is not clearly understood. It is known that stress and/or stress hormones downregulate nAChRs [252—254] and that this effect is prevented by treatment with chronic nicotine [254]. This suggests that nicotine is, perhaps, acting through nACliRs to prevent stress-induced impairment of memory. Support for this proposal comes from the finding that the effects of nicotine on memory are prevented by mecamylamine, a nonselective nicotinic receptor antagonist [see 255 for review]. 

Figure 8 Integrated antidromic neural activity in the carotid sinus nerve (CSN) and lingual nerve (LN) branches of the glossopharyngeal nerve (IXth n.). Nerve preparation was superfused in vitro. Superimposed traces show that application of a 100-pg bolus (arrows) of ACh to the petrosal ganglion evokes a substantial increase in the CSN and LN nerve discharge, which is inhibited in the presence of 100 pM mecamylamine, a nicotinic receptor antagonist.

An abstinence syndrome can be promptly precipitated in nicotine-infused rats by blocking nicotinic receptors with the competitive antagonist DHpE (Epping-Jordan et al. 1998 Malin et al. 1998a), or by inactivating them with noncompetitive antagonists mecamylamine (Malin et al. 1994), hexamethonium (Malin et al. 1997), or chlorisondamine (Hildebrand et al. 1997). 

Suzuki T, Ise Y, Tsuda M, Maeda J, Misawa M (1996) Mecamylamine-precipitated nicotine-withdrawal aversion in rats, Eur J Pharmacol 314 281-284 Suzuki T, Ise Y, Mori T, Misawa M (1997) Attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by the 5-HT3 receptor antagonist ondansetron. Life Sci 6LPL249-254 Tzavara ET, Monory K, Hanoune J, Nomikos GG (2002) Nicotine withdrawal syndrome behavioural distress and selective up-regulation of the cyclic AMP pathway in the amygdala. Eur J Neurosci 16 149-153... 

The extraordinary antinociceptive potency of the unknown compound was determined in a mouse model of acute nociception, the hot plate test. Despite the Straub-tail effect observed earlier, the antinociceptive effect of the compound could not be not antagonized with the p-opioid receptor antagonist naloxone but with the nAChR antagonist mecamylamine, so the unknown compound was deduced to be a potent nicotinic analgesic (Spande et al., 1992 Qian et al., 1993 Badio and Daly, 1994 Sullivan and Bannon, 1996). 

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a form of partial epilepsy which is characterized by frontal-lobe motor seizures occurring during sleep (Philips et al., 1998). This disorder has been linked to a mutation in the channel-lining domain (M2) of the a 4 nicotinic receptor subunit with use-dependent potentiation of the electrophysiological response to nicotinic agonists (Lena and Changeux, 1998). If the symptoms of ADNFLE are secondary to overactivity of this receptor or unusual potentiation, then nicotinic antagonists such as mecamylamine may be helpful. 

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