Tobacco smoke exposure induces nicotine dependence in rats

Department of Psychiatry, College of Medicine, McKnight Brain Institute, University of Florida, 100 S. Newell Dr., PO Box 100256, Gainesville, FL 32610, USA.
Psychopharmacology (Impact Factor: 3.88). 11/2009; 208(1):143-58. DOI: 10.1007/s00213-009-1716-z
Source: PubMed


Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.
The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.
The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central alpha7 nicotinic acetylcholine receptor (nAChR) and non-alpha7 nAChR levels (primarily alpha4beta2 nAChRs).
The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the alpha7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-alpha7 nAChR density in the dentate gyrus.
Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.

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Available from: Hartmut Derendorf, Dec 16, 2013
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    • "From days 4 to 14, the average total suspended particulate matter was about 100 mg/m 3 and the CO level about 350 ppm. A previous study by our laboratory demonstrated that these tobacco smoke exposure conditions led to nicotine dependence in rats and plasma nicotine levels of approximately 45 ng/ml and cotinine levels of 250 ng/ml (Small et al., 2010). "
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    ABSTRACT: Brain disorders and environmental factors can affect neurogenesis and gliogenesis in the hippocampus. These studies investigated the effects of chronic exposure to tobacco smoke on progenitor cell proliferation and the survival and phenotype of new cells in the dentate gyrus of adolescent rats. The rats were exposed to tobacco smoke for 4h/day for 14 days. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, ip) was administered 2h into the 4-h smoke exposure session on day 14. The rats were sacrificed 2-4h after the administration of BrdU. To investigate cell survival, the same dose of BrdU was administered 24h before the start of the 14-day smoke exposure period. These rats were sacrificed 24h after the last smoke exposure session. Tobacco smoke exposure decreased both the number of dividing progenitor cells (-19%) and the number of surviving new cells (-20%), labeled with BrdU in the dentate gyrus. The decrease in cell proliferation was not associated with an increase in apoptotic cell death, as shown by TUNEL analysis. Colocalization studies indicated that exposure to tobacco smoke decreased the number of new immature neurons (BrdU/DCX-positive) and transition neurons (BrdU/DCX/NeuN-positive) and increased the number of new glial cells (BrdU/GFAP-positive). These findings demonstrate that exposure to tobacco smoke diminishes neurogenesis and promotes gliogenesis in the dentate gyrus of adolescent rats. These effects may play a role in the increased risk for depression and cognitive impairment in adolescent smokers.
    Brain research 07/2011; 1413:32-42. DOI:10.1016/j.brainres.2011.07.041 · 2.84 Impact Factor
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    • "These preparations contain all compounds that potentially act upon neuronal activity. Tobacco smoke exposure activates DA neurons (Fa et al, 2000) and induces nicotine dependence (Small et al, 2010) in rats. ToEs and SmEs have been widely used to investigate the genotoxicity (for review, see DeMarini (2004)) and cytotoxicity (Bagchi et al, 1998, 1999; Tanaka et al, 2007; Yildiz et al, 1999) of tobacco intake. "
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    ABSTRACT: Nicotine prominently mediates the behavioral effects of tobacco consumption, either through smoking or when taking tobacco by snuff or chew. However, many studies question the exclusive role of nicotine in these effects. The use of preparations containing all the components of tobacco, such as tobacco and smoke extracts, may be more suitable than nicotine alone to investigate the behavioral effects of smoking and tobacco intake. In the present study, the electrophysiological effects of tobacco and smoke on ventral tegmental area dopaminergic (DA) neurons were examined in vivo in anesthetized wild-type (WT), β2-nicotinic acetylcholine receptor (nAChR) knockout (β2-/-), α4-/-, and α6-/- mice and compared with those of nicotine alone. In WT mice, smoke and nicotine had similar potentiating effects on DA cell activity, but the action of tobacco on neuronal firing was weak and often inhibitory. In particular, nicotine triggered strong bursting activity, whereas no bursting activity was observed after tobacco extract (ToE) administration. In β2-/- mice, nicotine or extract elicited no modification of the firing patterns of DA cells, indicating that extract acts predominantly through nAChRs. The differences between DA cell activation profiles induced by tobacco and nicotine alone observed in WT persisted in α6-/- mice but not in α4-/- mice. These results would suggest that tobacco has lower addiction-generating properties compared with either nicotine alone or smoke. The weak activation and prominent inhibition obtained with ToEs suggest that tobacco contains compounds that counteract some of the activating effects of nicotine and promote inhibition on DA cell acting through α4β2*-nAChRs. The nature of these compounds remains to be elucidated. It nevertheless confirms that nicotine is the main substance involved in the tobacco addiction-related activation of mesolimbic DA neurons.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2011; 36(11):2244-57. DOI:10.1038/npp.2011.112 · 7.05 Impact Factor
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    ABSTRACT: Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.
    Pharmacology Biochemistry and Behavior 03/2010; 95(4):401-9. DOI:10.1016/j.pbb.2010.02.018 · 2.78 Impact Factor
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