Plasticité synaptique dans l’aire tegmentaire ventrale : implication des endocannabinoïdes
The meso-corticolimbic dopamine (DA) system of the brain, originating in the ventral tegmental area (VTA), is strongly implicated in reward, motivation and drug addiction. Drugs of abuse activate this system and cause significant long term plasticity. DA neurons in the VTA receive are densely innervated by glutamatergic inputs. All major classes of drugs of abuse have been found to cause a long term potentiation (LTP) of glutamate transmission onto DA neurons of the VTA. LTP is an enduring increase of synaptic transmission, hypothesized to underlie memory and learning.  Endocannabinoids (ECs) are transmitters that act in a retrograde fashion on pre-synaptic receptors leading to a decrease in neurotransmitter release. DA neurons can release ECs from their somatodendritic compartment in response to afferent stimulation or depolarization. Neurotensin (NT) is a neuropeptide that presents an extensive interaction with the DA system. It was discovered that NT can induce production of ECs in the striatum.  In the first study of this thesis, we used a combination of immunohistochemical, pharmacological and electrophysiological techniques in mouse brain slices to demonstrate that CB1 EC receptors are present on glutamatergic afferents to DA neurons. Their activation induces a depression of glutamate release. We further showed that trains of afferent stimulation induce EC release from DA neurons and that in the presence of the CB1 antagonist AM251, there is a marked facilitation of the induction of LTP, suggesting that ECs produced in response to activation of glutamate synapses normally negatively regulate the induction, but not the expression of LTP. Finally, we found that 2-arachidonoylglycerol (2-AG) is the main EC implicated in this negative regulation of LTP and that LTP induced in the presence of a CB1 receptor antagonist is otherwise also dependent on NMDA glutamate receptors.  In the second study, we report that NT is present in a subset of glutamatergic axon terminals in the VTA and that activation of NT receptors by exogenous NT induces a long-lasting decrease of the amplitude of excitatory postsynaptic currents (EPSCs) in VTA DA neurons. This decrease was blocked by a broad-spectrum NTR antagonist, as well as by a specific antagonist of the type 1 NT receptor NTS1. The decrease was also blocked when CB1 receptors or 2-AG synthesis were blocked. Chelating intracellular calcium had no effect, but inhibiting G-proteins or phospholipase C blocked NT-mediated synaptic depression. The long-lasting nature of the synaptic depression induced by NT was due to protracted EC release and not to prolonged NT receptor activation. Finally, our observation that a NT receptor antagonist did not facilitate LTP induction, as did a CB1 receptor antagonist, suggests that repetitive stimulation of glutamatergic afferents required to induce LTP does not cause EC production through the release of NT, thus allowing us to conclude that secretion of NT does not act under such conditions as a negative regulator of LTP.
Dopamine Glutamate 2-arachidonoylglycerol patch-clamp CB1 VTA plasticity endocannabinoid neurotensin LTP