Nicotine antagonists

Slemmer JE, Martin BR, Damaj MI Bupropion is a nicotinic antagonist. J Pharmacol Exp Therap 295 321-327, 2000... 

In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood-brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drug that is blocking the excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). 

A combination of the nicotine antagonist mecamylamine and bupropion (Quitpack )... 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Markou, A., Paterson, N.E. The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob. Res. 3 361, 2001. 

Cognitive effects Animais Cognitive effects of nicotine have been observed in several species, including humans. Experimental studies have focused primarily on the effects on attention and memory. Cognitive benefits are seen after both acute and chronic administration (Levin et al. 1992). In experimental animals, nicotine improves learning and memory on a variety of tasks. Conversely, the nicotinic antagonist mecamylamine... 

MaUn DH, Lake JR, Carter VA, Cunningham JS, Wilson OB (1993) Naloxone precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 112(2-3) 339-342 MaUn DH, Lake JR, Carter VA, Cunningham JS, Hebert JS, Conrad DL, Wilson OB (1994) The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome. Psychopharmacology 115 339-342... 

Studies with Nicotinic Antagonists and Partial Agonists. 312... 

F%. 1 (a) Dose-response curve from rats trained to discriminate between 0.2 mg kg of nicotine and saline. Data are from 13 rats, each tested at least three times at each dose, (b) Block of nicotine (0.2 mg kg ) discrimination by the centrally active nicotinic antagonist mecamylamine (0.25 mg kg ) but not by chlorisondamine at a 0.025 mg kg dose that blocks peripheral nicotinic choUnoceptors but does not penetrate into the CNS (Sal, Saline Nic, Nicotine Csd, Chlorisondamine Mec, Mecamylamine). Chlorisondamine blocks nicotine discrimination when injected intra-cerebroventricularly (Kumar et al. 1987, data not shown). Data shown are for the number of sessions that began with selection of the nicotine-appropriate lever expressed as a percentage of the total number of sessions. Redrawn with permission from Tables 1 and 2 in Morrison CF, Stephenson JA. Nicotine injections as the conditioned stimulus in discrimination learning (1969), Copyright Springer... 

Garcha HS, Stolerman IP (1993) Discriminative stimulus effects of the nicotine antagonist mecamylamine in rats. J Psychopharmacol 7 43-51 Garcha HS, Stolerman IP (1989) Discrimination of a drug mixture in rats role of training dose, and specificity. Behav Pharmacol 1 25-31... 

Abstract Behavioral discrimination procedures clearly demonstrate that nicotine elicits interoceptive stimulus effects in humans that are malleable by various pharmacological manipulations as well as by some behavioral manipulations. The parameters of nicotine discrimination and both chronic and acute factors that may alter discrimination behavior are addressed in this chapter, which emphasizes research by the author involving nicotine delivered by nasal spray. Human discrimination of nicotine is centrally mediated, as the central and peripheral nicotine antagonist mecamylamine blocks discrimination but the peripheral antagonist trimethaphan does not. The threshold dose for discrimination of nicotine via spray appears to be very low in smokers as well as nonsmokers. Because smoked tobacco delivers nicotine more rapidly than spray, the threshold dose of nicotine via smoking is probably even lower. In terms of individual differences, smokers may become tolerant to the discriminative stimulus effects of higher nicotine doses but not of low doses. 

Stolerman IP, Goldfarb T, Fink R, Jarvik ME (1973) Influencing cigarette smoking with nicotine antagonists. Psychopharmacology 28 217-259... 

Naloxone precipitation, nnlike nicotine-antagonist challenge, fails to decrease DA-activity, yet still precipitates somatic signs (Carboni et al. 2000). Thus the aversiveness of nicotine withdrawal can be dissociated in part from those effects on the mesolimbic-DA reinforcement pathway that have sometimes been proposed to account for the affective aspects of withdrawal (Balfour 2004 Paterson et al. 2007). 

---