When a smoker inhales from his cigarette, molecules of nicotine travel to the ventral tegmental area (VTA) of his brain, where they stimulate a network of neurons involved in the brain's reward mechanism. But while this mechanism governs our motivations and pleasures, it also plays a role in addiction.
It is through various types of so-called “nicotinic receptors” that nicotine, but also its endogenous equivalent–acetylcholine–stimulates VTA neurons, which in turn release dopamine, a neurotransmitter central to the reward system. How different nicotinic receptors regulate the activity of dopaminergic neurons at the molecular level is still largely unknown.
“Each receptor may have a specific role in the reward system, but could also play a part in addiction,” says Philippe Faure, from the Institut Pasteur.1 “They are all potential targets for pharmacological drugs.”
In a recent study,2 Faure's team, together with researchers from the Karolinska Institute3 in
The scientists first recorded the discharge activity of dopaminergic neurons in normal mice, in the presence of nicotine and acetylcholine. They then compared these measurements with those recorded in knockout mice lacking b2 nicotinic receptor. Their results showed that without b2, dopaminergic neurons are unreactive to nicotine, and less reactive to acetylcholine. However, re-establishing b2 in the VTA through genetic manipulation restored the dopamine response to both substances.
“Although previous experiments offered an indication of the importance of b2 receptors in this regulatory pathway, we had no idea that b2 was so acutely involved in the dopaminergic response to acetylcholine,” says Faure.
Similar experiments with a7 knockout mice suggest that a7 comes into play only once b2 has switched neurons on, giving a7 the more subtle task of modulating neuronal responses into more complex states.
“It is important to bear in mind that these neurons are modulated by many other substances and stimuli in natural conditions,” says Faure. “This is one point of entry into the system, but not the only one.”
1. Unité Récepteurs et Cognition (CNRS / Institut Pasteur joint lab), headed by Jean-Pierre Changeux.
2 Mameli-Engvali et al., “Hierarchical Control of Dopamine Neuron–Firing Patterns by Nicotinic Receptors,” Neuron. 50: 911-921. 2006.
3 Karolinska Institute, Department of Physiology and Pharmacology, Stockholm, Sweden.
Institut Pasteur, Paris.