Smoke Extracts and Nicotine, but not Tobacco Extracts, Potentiate Firing and Burst Activity of Ventral Tegmental Area Dopaminergic Neurons in Mice

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.