Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus

Abstract

Rationale Limited access nicotine self-administration decreases hippocampal neurogenesis, providing a mechanism for the deleterious effects of nicotine on hippocampal neuronal plasticity. However, recent studies have shown that limited access nicotine self-administration does not exhibit key features of nicotine dependence such as motivational withdrawal and increased motivation for nicotine after deprivation. Objectives The present study used extended access nicotine self-administration (0.03 mg/kg/infusion, 21h/day (d), 4d) with intermittent periods of deprivation (3d) for 14 weeks, to test the hypothesis that this model enhances nicotine seeking and produces distinct responses in hippocampal neurogenesis when compared with limited access (1h/day, 4d) intake. Animals in the extended access group were either perfused prior to or following their final deprivation period, whereas animals in the limited access group were perfused after their last session. Results Limited access nicotine self-administration and extended access nicotine self-administration with periodic deprivation did not affect proliferation and differentiation of oligodendrocyte progenitors in the medial prefrontal cortex (mPFC). Conversely, extended access nicotine self-administration with periodic deprivation enhanced proliferation and differentiation of hippocampal neural progenitors. Furthermore, in the hippocampus, the number of differentiating NeuroD-labeled cells strongly and positively correlated with enhanced nicotine seeking in rats that experienced extended access nicotine self-administration. Conclusions These findings demonstrate that extended access versus limited access to nicotine self-administration differentially affects the generation of new oligodendroglia and new neurons during adulthood. The increases in the number of differentiating cells in extended access nicotine self-administering rats may consequently contribute to aberrant hippocampal neurogenesis and may contribute to maladaptive addiction-like behaviors dependent on the hippocampus.

Effects of addictive drugs on adult neural stem/progenitor cells

“…Similar effects were found after the animals were trained by the Morris water maze, after nicotine treatment [61]. Self-administration, a form of operant conditioning considered to be one of the most valid experimental models to investigate addiction-related behavior, may also induce detectable alterations in neurogenesis in response to various addictive drugs such as opioids [36], methamphetamine [21, 62] and nicotine [63]. Similar results were shown in a study of alcohol addiction using the voluntary drinking paradigm, which confirmed a decrease in neuronal differentiation [64].…”

“…As for its effects on NSPC differentiation, the injection of nicotine was shown to decrease the number of PSA-NCAM- and NeuN-positive cells but had no effect on the number of GFAP-positive cells, indicating its role in neuronal inhibition but not astroglial differentiation [116]. However, it was found that extended access to nicotine self-administration and deprivation differentially regulates adult neurogenesis by increasing the number of NeuroD1-positive immature neurons in rat DG [63]. Thus, we may conclude that chronic but not acute administration of nicotine decreases adult NSPC proliferation and survival, but its effects on NSPC differentiation remain elusive.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Adult rats trained to intravenously selfadminister nicotine 0.04 or 0.08 mg/kg per infusion, achieving daily nicotine intakes of approximately 200 and 300 mg/kg, respectively, showed decreased cell proliferation and increased cell death in the dentate gyrus of the HC (Abrous et al, 2002). Nicotine SA under extended access (0.03 mg/kg/infusion, 21 hours/day for 4 days) with intermittent periods of deprivation (3 days) for 14 weeks, but not nicotine intake under limited access (1 hour/day for 4 days), enhanced proliferation and differentiation of hippocampal neural progenitors (Cohen et al, 2015). Together these data represent evidence for effects of nicotine on plasticity in cortical and hippocampal Drug-Induced Neuroplasticity pathways, but it is less clear that this plasticity is of any functional relevance to the persistent neuroplasticity underlying behaviors associated with addiction.…”

Insight into the Potential Factors That Promote Tobacco Use in Vulnerable Populations

“…A recent review summarizing the role of various nAChR subunits revealed that α2, α3, α5, α7, and β4 modulate physical signs, whereas α6 and β2 modulate affective states produced by nicotine withdrawal [7•]. Also, a recent study revealed that the physical signs of withdrawal were not correlated with high levels of anxiety or nicotine intake observed during abstinence from extended access to nicotine IVSA [8]. Together, these studies suggest that the physical versus negative affective states produced by withdrawal are modulated via distinct mechanisms.…”