Role of the lateral habenula in nicotine addiction : interaction with the dopaminergic system

Abstract

Tobacco smoking represents a leading cause of preventable death. So far, existing smoking cessation therapies have not been proven very successful to help one stop and a better understanding of the neurobiology of tobacco dependence is still needed. Nicotine is the neuro-active compound contained in tobacco that is responsible for its rewarding/reinforcing and aversive properties by acting on the midbrain dopaminergic system. The lateral habenula (LHb) is an epithalamic structure involved in pain, stress, depression and in encoding aversive stimuli. This structure is known to modulate the DA system both directely and through activation of the RMTg, a GABA-ergic area located caudally to the ventral tegmental area (VTA). Thus, the LHb might represent a possible target for the action of nicotine in the eNS. Using both biochemical (western blot) and histological (immunohistochemistry) approaches we first verified that nicotinic receptors containing a4/a7 subunits are expressed In the lateral habenula and that they can undergo plastic changes following chronic exposure to nicotine and its discontinuation. Second, we used an in vivo electrophysiological recording technique to investigate the nicotine-induced response of single LHb neurons. Our data show that systemic administration of nicotine increases the LHb neuronal activity in vivo in rats. Following nicotine chronic treatment, this response is drastically decreased while after 1 day of withdrawal only low doses of nicotine are able to significantly affect the firing rate of the

LHb neurons compared to controls. To further elucidate the role of the LHb in central nicotine effects, we recorded the activity of VTA putative-DA neurons following LHb electrolytic lesion in both drug-naive and nicotine chronically treated animals. Systemic administration of nicotine induced a significant increase of putative-DA neuron activity. Overall, acute LHb electrolytic lesion did not modify this effect in drug-naive rats, however, segregation of neurons on the basis of their localization within the VTA revealed a stronger effect of nicotine on ventro-medial neurons located at the level of the paranigral nucleus. This effect was completely abolished by LHb ipsilateral lesion. Conversely, dorso-Iateral neurons, located in the parabrachial pigmented nucleus of the VTA, did respond significantly to nicotine administration only after LHb lesion. Following chronic nicotine treatment, a further acute challenge with nicotine failed to increase VTA putative-DA cells neuronal activity compared to sham-Iesioned and control rats. Our evidence strongly suggests that nicotine modulates LHb activity and plays an important role in mediating the effects of nicotine on the midbrain DA system thus participating in the mechanisms of addiction and aversion to this drug. In conclusion, the LHb might represent a new target for nicotine cessation. Our data suggest that a drug capable of counteracting the decreasing response of the LHb to nicotine following its chronic administration might represent a successful strategy in nicotine addiction.

Keywords: nicotine, lateral habenula, ventral tegmental area, dopamine, acetyl choline