Adolescent Nicotine Exposure Induces Molecular and Neuronal Features of Depressive Disorder in Adulthood in the Mesolimbic Dopamine System
Bibliographic record
Abstract
Introduction/Objectives Smoking tobacco is the leading cause of preventable death world‐wide and the main psychoactive component of tobacco, nicotine, is associated with short‐ and long‐term mood‐state alterations. Adolescent nicotine exposure has been shown to induce long‐term depressive and anxiety‐related symptoms in adulthood. Nicotine exposure increases ventral tegmental area (VTA) dopaminergic (DA) inputs to the nucleus accumbens shell (NAcSh), comprising the mesolimbic DA system. Disturbances in the mesolimbic system are well‐established neuropathological correlates of mood disorders, however, the mechanisms by which adolescent nicotine exposure may cause the later development of mood and anxiety disorders is not currently understood. Mood disorders precipitate changes in activation state of intra‐cellular targets, such as glycogen synthase‐3 (GSK3) and extracellular signal‐regulated kinase (ERK). The objectives of the present study are to examine the effects of adolescent nicotine exposure on later adulthood neurobiological phenotypes associated with mood disorders. Methods Adolescent male Sprague‐Dawley rats were either administered 0.4mg/kg nicotine or saline vehicle injections three times per day for 11 days during a critical period of rodent adolescent neurodevelopment (post‐natal day 35–45). Rats matured into early adulthood (post‐natal day 65) and the VTA and NAc were subjected to protein extraction to examine intracellular molecular protein expression and activation profiles. Separate vehicle and nicotine‐treated groups underwent electrophysiology to record VTA and NAcSh neuronal activity. The VTA and NAcSh DA and medium spiny neuron (MSN) activity was recorded in vehicle and nicotine treated groups using dual‐cell neuronal recordings. Baseline recordings were examined along with recordings following a 0.4mg/kg nicotine injection and a subthreshold dose of 0.1mg/kg. Results Consistent with phenotypes observed in human depression, molecular analyses of the NAc revealed significant increases in the phosphorylation states of ERK1/2 (1: p=0.0219, 2: p=0.0151), GSK3 phosphorylation state (1: p=0.0029, 2: p=0.0028), and pGSK3:tGSK3 (site1: p=0.0165, site2: p=0.0291) in nicotine vs. vehicle treated rats. Furthermore, consistent with dysregulated mesolimbic activity states present in mood disorders, preliminary electrophysiological results indicate a larger increase in VTA DA and NAcSh MSN cellular firing frequency and burst rate in the nicotine treated group compared to the control group when subjected to 0.4mg/kg and o.1mg/kg doses of nicotine in adulthood. Conclusion Our results indicate that nicotine exposure in adolescence elicits long‐term changes in neuronal activity and intracellular molecular activation states, consistent with phenotypes observed in clinical mood disorder populations. Together, these findings identify a novel molecular and neuronal mechanism directly in the mesolimbic DA system, underlying the effects of adolescent nicotine exposure on the later development of mood disorders in adulthood. Support or Funding Information This work was supported by the Canadian Institutes of Health Research (MOP‐123378). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".