Nicotine self-administration reverses cognitive deficits in a rat model for schizophrenia.

High comorbidity between schizophrenia and tobacco addiction has been well established. Explanatory theories include nicotine as a cognitive enhancer ameliorating symptoms of schizophrenia and underlying shared substrates increasing susceptibility to addiction in these individuals. To test these non-mutually exclusive theories, the maternal immune activation (MIA) model was utilized. To this end, pregnant Sprague Dawley rats were subcutaneously injected with a bacterial endotoxin, lipopolysaccharide (0.5 mg/kg), on gestation days 10 and 11. Selective attention and working memory in adult male offspring were subsequently assessed using the latent inhibition and delayed non-matching to sample paradigms both before and after nicotine or saline self-administration. MIA led to deficits in both latent inhibition and delayed non-matching to sample in male offspring. Further, these animals showed a small but significantly increased responding for nicotine during self-administration acquisition, although there was no difference in dose-response effect or in progressive ratio testing. However, nicotine, but not saline self-administration, significantly ameliorated the cognitive deficits induced by MIA. While the male offspring of mothers prenatally exposed to lipopolysaccharide was only slightly more sensitive to the reinforcing effects of nicotine, after self-administration, the MIA-induced cognitive deficits significantly improved. These data lend support for the self-medication hypothesis of schizophrenia.

Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats.

Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).

Tobacco particulate matter self-administration in rats: differential effects of tobacco type.

Nicotine self-administration in rats is the most widely used animal model of tobacco dependence. There is increasing evidence, however, that non-nicotinic constituents in smoke contribute to addiction and that different tobacco products contain varying levels of these constituents. The present study firstly sought to compare self-administration of pure nicotine to tobacco particulate matter (TPM) to determine if there were differences in reward-efficacy attributable to the non-nicotine constituents. Secondly, cigarette and roll-your-own (RYO) TPM groups were included and compared to determine whether different formulations of non-nicotinic constituents could impact reward. Briefly, male Sprague Dawley rats were implanted with indwelling jugular catheters for self-administration (n = 76). The reinforcing efficacy of infusions of nicotine (0.0 or 30.0 µg/kg/infusion) versus cigarette/RYO TPM (with matched nicotine content) was determined using spontaneous acquisition of self-administration on a fixed ratio schedule. The progressive ratio schedule was then employed to determine the motivation to receive each drug and within-subject dose-response curves were also produced (7.5, 15.0, 30.0 and 60.0 µg/kg/infusion nicotine). The main finding was that the RYO TPM was more reinforcing and produced a different profile of reward-related behaviour compared with both the nicotine and the cigarette TPM groups. The conclusions were that non-nicotinic components have a role in tobacco dependence and that some tobacco products could have higher abuse liability, irrespective of nicotine levels.