Nicotine animal model

Evidence for the Genomic Basis of Nicotine Addiction from Animal Models... 

Likelihood of developing dependence to nicotine will involve specific functional changes in the brain. Examining the detailed genetic basis for these functional changes is difficult in humans, so animal models are needed. Three approaches have been taken to examining genetic influences of the effects of nicotine in rodents namely inbred lines, selectively bred lines and knockout mice. 

Biallelic or Multiallelic Markers for Linkage Studies 451 Genome Scans in the Future 452 Evidence for the Genomic Basis of Nicotine Addiction from Animal Models 452... 

An acute dose of lobeline impairs attention in one animal model, but not as much as mecamylamine (Turchi et al. 1995). Lobeline improves memory when administered after a passive avoidance paradigm (Decker et al. 1993). Pretreatment with lobeline improves performance in rats with septal lesions on a spatial discrimination water maze. Lobeline is about one-tenth as potent as nicotine in the passive avoidance memory task, but equivalent to nicotine in the water maze. 

Mouse CYP2A5 is a comparable isoform to human CYP2A6 (Raunio et al. 1988), because these isozymes are responsible for the majority of nicotine s C-oxidation (Raunio et al. 2008), cotinine s subsequent oxidation to 3 -hydroxycotinine (Sin and Tyndale 2007), and coumarin 7-hydroxylation (Kaipainen et al. 1984). Taken together, these findings suggest that mice may be a cost-effective animal model of human CYP2A6-mediated nicotine C-oxidation. 

Tourette s syndrome (TS) is a chronic neurological disorder characterized by motor tics, involuntary verbalizations, and obsessive-compulsive behaviors. The current treatment lends itself to the use of antipsychotic agents. However, these treatments are only effective in about 70% of the treated population.84-85 Nicotine potentiates the behavioral effects of antipsychotics in a number of animal models.86 Clinical trials are under way involving patients receiving both nicotine and antipsychotic agents and appear to be promising.87 To date, there have been no studies mentioning the use of lobeline in TS. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

The properties of ABT-594, the most advanced compound derived from the discovery of epibatidine, are well documented in the literature (Decker et al., 1998 Thatte, 2000). Its antinociceptive potential has been proven in various animal models, but according to Boyce et al. (2001) the side-effect profile of ABT-594 does not represent a significant improvement compared to other potential nicotinic analgesics. 

Bartek MJ, LaBudde JA (1975) Percutaneous absorption in vitro. In Maibach HI (ed) Animal Models in Dermatology. Churchill Livingstone, New York, pp 103-120 Bronaugh R, Maibach HI (1999) Percutaneous Absorption. 3rd edn. Marcel Dekker, New York and 4thedn in press Guy RH, Wester RC, Tur E, Maibach HI (1983) Noninvasive assessments of the percutaneous absorption of methyl nicoti-nate in humans. J Pharm Sci 72(9) 1077-1079 Guy RH, Tur E, Bugatto B et al. (1984) Pharmaco-dynamic measurements of methyl nicotinate percutaneous absorption. Pharm Res 1 76-81... 

The aim of this study was to determine, as a proof of concept, if DMXB-A significantly improves neurocognition and to assess, by effects on P50 inhibition, whether its actions are consistent with activation of oc7-nicotinic receptors. Because the proposed effect is agonism at a ligand-gated ion channel, biological effects were expected immediately, consistent with the results from animal models (Stevens et al., 1998). Twelve persons with schizophrenia consented to the study. They were concurrently treated with neuroleptic medications. Subjects who had not used nicotine or tobacco within the last month were selected to avoid possible interaction with chronic nicotine exposure. DMXB-A was administered orally (150 or 75 mg) followed 2 h later by a half dose (75 or 37.5 mg). The half dose, administered at the predicted half-life of the... 

Stevens KE, Wear KD. 1997. Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol Biochem Behav... 

Fiedler JL, Epstein CJ, Rapoport SI, Caviedes R, Caviedes P (1994) Regional alteration of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome). Brain Res 658 27-32 Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41 31-37 Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38 22-33... 

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