Schizophrenia and Nicotine Addiction: Analysis of genetic mouse models
Final Report Abstract
The incidence of smoking and addiction to nicotine is higher in patients suffering from schizophrenia compared to healthy controls. The reasons for this are not entirely clear, but two possible hypotheses have been put forward: Smoking may be a form of self-medication and/or genetic risk factors for schizophrenia may also affect the rewarding and addictive effects of smoking. These hypotheses are not mutually exclusive. We have generated a genetic mouse model of schizophrenia by expressing the primate-specific gene LG72, which has been identified as a candidate susceptibility gene for schizophrenia, in transgenic mice. These animals show a number of behavioural phenotypes that have been associated with schizophrenia symptoms, such as impaired PPI, cognitive, olfactory and motor deficits. The schizophrenia pathology probably involves and increased mitochondrial production of reactive oxidant species through binding of LG72 to the respiratory chain complex I. This resulted in increased levels of oxidized lipids and proteins, with a concomitant up-regulation of antioxidant mechanisms such that the antioxidant compound glutathione was exhausted in transgenic animals. An increase in glutathione through administration of the rate-limiting amino acid cysteine rescued most of the behavioural effects of the LG72 expression. Nicotine treatment of transgenic animals also ameliorated many, but not all, of the cognitive deficits including working memory, social memory and operant learning. Spatial learning and memory, as assessed in the Morris water maze test, however, was not improved by nicotine treatment. The G72- expression also affected nicotine-induced changes in the expression of nicotinic acetylcholine receptors (nAChR) in specific brain regions. Thus, nicotine induced up-regulation of α4β2 nAChR in many brain regions. This effect was less pronounced in transgenic mice. In contrast, G72 expression facilitated an increase in α7 nAChR density, most notably in the dentate gyrus and CA1-region of the hippocampus. Our findings demonstrate that a genetic risk factor for schizophrenia alters the molecular and behavioural consequences of chronic nicotine exposure. As nicotine also ameliorates some of the impairments associated with the genetic condition, they are also compatible with the hypothesis that the intense smoking behaviour observed in many schizophrenic patients may represent a form of selfmedication.
Publications
- (2011). N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 36: 2233–2243
Otte D-M, Sommersberg B, Kudin A, Guerrero C, Albayram O, Filiou MD, et al.
(See online at https://doi.org/10.1038/npp.2011.109) - (2012). Involvement of the primate specific gene G72 in schizophrenia: From genetic studies to pathomechanisms. Neurosci Biobehav Rev
Drews E, Otte D-M, Zimmer A
(See online at https://doi.org/10.1016/j.neubiorev.2012.10.009) - (2013). Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety- Related Behavior. PLoS ONE 8: e67131
Otte D-M, Barcena de Arellano ML, Bilkei-Gorzó A, Albayram O, Imbeault S, Jeung H, et al.
(See online at https://doi.org/10.1371/journal.pone.0067131) - (2014). Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia. Br J Pharmacol 171: 1758–1771
Hambsch B, Keyworth H, Lind J, Otte DM, Racz I, Kitchen I, et al.
(See online at https://doi.org/10.1111/bph.12578) - (2014). Dynorphins regulate the strength of social memory. Neuropharmacology. 77:406-413
Bilkei-Gorzo A, Mauer D, Michel K, Zimmer A
(See online at https://doi.org/10.1016/j.neuropharm.2013.10.023) - (2014). Lipidomics reveals dysfunctional glycosynapses in schizophrenia and the G72/G30 transgenic mouse. Schizophr Res 159: 365–369
Wood PL, Filiou MD, Otte DM, Zimmer A, Turck CW
(See online at https://doi.org/10.1016/j.schres.2014.08.029)
