In Vivo Synaptic Plasticity Associated With Nicotine Addiction – NICOPLASTIC

First, we characterize the effect of chronic nicotine intravenous self-administration on the induction of a synaptic plasticity between cortical afferents and bed nucleus neurons in nicotine dependent rats. The aim is to demonstrate that the synaptic plasticity recorded is specific of the increased motivation for nicotine (recording in nicotine active, nicotine passive as well as saline rats). This particular neuronal pathway has been selected based on the key role of prefrontal cortex and bed nucleus of the stria terminalis in the integration of information crucial for the development of addiction. Secondly, in order to establish a time-course of the induction of the long-term potentiation, cellular recording are performed at different time points of the addictive process: initiation, maintenance and abstinence. An important objective here is also to determine whether there is a causal link between the synaptic plasticity and the compulsive nicotine seeking behavior. The mechanistic aspect of the long-term potentiation will be questioned and we’ll specifically focus on the endocannabinoid system.

Our first data indicate that acquired and motivated nicotine taking behavior is associated with the induction of a long-term potentiation of the cortical afferents onto the bed nucleus neurons. However, if rats did not consume nicotine or did not control their intake, there is no change in the synaptic strength at this particular synapse. Interestingly, we show that the long-term potentiation is dependent on the endocannabinoid system since it is blocked by a CB1 receptor antagonist (compound already suggested for the treatment of the addictive processes). Finally, our study indicates that the synaptic plasticity recorded is causal for the development of the compulsive behavior. Indeed, the stimulation of the cortical input induces compulsive nicotine seeking while immediate blockade of the CB1 receptors before the stimulation inhibits the compulsive behavior.

The highlighting of a neuronal circuit which activation or inhibition controls compulsive nicotine seeking is novel and opens on new therapeutic perspectives. Indeed, a new approach to treat nicotine addiction could be focused on the pharmacological or cognitive-behavioral inactivation of this circuit

These results have been presented at the international Federation of European neurosciences (FENS) meeting in Barcelona (Spain), 14-18 july 2012. These data will be pooled in a manuscript in preparation for publication.

In France in 2006, an estimated 15 million persons (25 percent of the population) were current cigarette smokers (Observatoire Français des drogues et des Toxicomanies, 2006). In France, cigarette smoking accounts for 90% of lung cancer cases, and is the largest single cause of mortality, killing 66 000 smokers per year as well as 5000 non-smokers (MILDT, 2009). Now, tobacco is one of the most addictive drugs. However, despite the enormous human and financial costs of tobacco dependence, the understanding of the processes involved in the development and treatment of nicotine addiction is still needed.
Nicotine is the main addictive constituent of tobacco both in humans and rodents. The general aim of our research project is first, to unearthing the neural circuit and the synaptic adaptation that underlie nicotine addiction, and second to characterize correlation between the dynamic installation and fading of the synapse strengthening and the longitudinal aspect of the vulnerability to nicotine addiction.
Our recent work recently showed i) the existence of an excitatory synaptic pathway from the The bed nucleus of the stria terminalis (BST) to the ventral tegmental area (VTA) dopaminergic (DA) neurons, and ii) that the majority of BST neurons projecting to the VTA was specifically excited by the infralimbic cortex (ILCx). Moreover, we demonstrated that nicotine self-administration in rats, but not passive delivery, triggers hyperactivity of ventral tegmental area (VTA) dopaminergic (DA) neurons. Motivation and reward related behaviors are largely mediated by the extended amygdala, the prefrontal cortex (PFC) and the mesocorticolimbic DA systems. Thus, all these findings strongly suggest that the BST (which is part of the extended amygdala) plays a critical role in nicotine addiction.
The general objective of our project is to understand how differential chronic exposures to nicotine (addict rats vs. non-addict rats) shape the “prefrontal cortex - bed nucleus of stria terminalis – ventral tegmental area” neural circuit, and how these neuroadaptations can be long lasting and responsible for the maintenance of the vulnerability to nicotine addiction. Thus, we propose to study, in nicotine addicted rats, the plasticity within the BST, combining behavioral and electrophysiological approaches in anesthetized and behaving animals. In order to determine the time-course for the development of the synaptic plasticity in the BST, we will first proceed to the electrophysiological recording in anesthetized animals since this kind of synaptic event will have been first characterized in this setting with a 24h drug free period. Then after, we will study the occurrence of synaptic plasticity at several stages of the addiction process by recording the VTA DA neurons phasic activity in behaving animals.