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

Abstract

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 Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia

“…46 Moreover, while the maternal immune activation model also did not alter NIC self-administration, NIC self-administration did mitigate cognitive deficits observed in maternal immune activation animals, lending further support for a self-medication hypothesis. 21 Additionally, mice with a mutation commonly observed in human SCZ patients in CHRNA5, which codes for the α5 subunit of the nicotinic receptor, demonstrated cortical hypofunction that could be normalized with chronic NIC delivery. 47 This diversity of findings may reflect differences in the elements of SCZ pathophysiology captured by each particular model and their impact on the effects of NIC, as well as limitations in certain experimental designs.…”

“…However, maternal immune activation animals did not differ in self-administration from controls, except at a single dose with a high response requirement. 21 A study by Berg et al 22 using the neonatal ventral hippocampal lesion (NVHL) model of SCZ found that lesioned animals selfadminister more NIC than controls only at a moderate dose of NIC. These limited positive results are complicated by the inclusion of daily subcutaneous injections of saline or NIC during the adolescent period.…”

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…LPS treatment during gestation facilitates intravenous nicotine self-administration at higher reinforcement schedules (i.e. FR5, not FR1/FR2), but has no subsequent effects on dose-response responding or motivation for nicotine under a progressive ratio [100]. Similarly, in the MAM rat model of schizophrenia, Weeks and colleagues found no differences between MAM rats and controls in nicotine selfadministration [101].…”

“…Cognitive deficits in rats prenatally treated with LPS are ameliorated by chronic nicotine self-administration, compared to LPS rats which self-administer saline [100]. This may indicate a restoration of deficits in nicotinergic α7 and α4β2 receptor subtype function in LPS treated rats; however, this has not been assessed experimentally [100]. The effects of acute or chronic nicotine in neurodevelopmental models (e.g.…”

Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of schizophrenia-related alterations: effects of prenatal immune activation and peripubertal stress

“…Poly I:C (see Meyer 2014 for a review) and also with LPS exposure (Fortier et al, 2007;Romero et al, 2010;Simões et al, 2018;Swanepoel et al, 2018;Waterhouse et al, 2018;Wischhof et al, 2015) although some variables such as the species used (Imai et al, 2018), the prenatal period at which exposure occurs (Waterhouse et al, 2018) Figure 1, PUS seems to be counteracting LPS effects to some extent. Therefore, a stronger effect of LPS exposure might be needed to obtain a main effect of the maternal immune activation or an interaction between both factors.…”