| Abstract No.: | B-B2060 |
| Country: | Canada |
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| Title: | ENDOCANNABINOIDS AND GABA REGULATE INDUCTION OF LONG-TERM POTENTIATION OF GLUTAMATERGIC SYNAPSES ONTO MOUSE VENTRAL TEGMENTAL AREA DOPAMINE NEURONS. |
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| Authors/Affiliations: | 1 Christian Kortleven*; 1 Jean-Claude Lacaille; 1 Louis-Eric Trudeau;
1 Université de Montréal, QC, Canada
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| Content: | Objectives: The central dopamine (DA) system is critical for a number of physiological functions including motivated behaviours. DA neurons of the ventral tegmental area (VTA) are also involved in behavioural sensitization to drugs of abuse. It has been shown that glutamatergic transmission in the VTA is both critical and sufficient for induction of sensitization. A plausible mechanism underlying this induction is long term potentiation (LTP) of glutamate-mediated synaptic transmission. However, LTP in the VTA is widely known to be difficult to induce in vitro. Recent work has begun to identify factors that may negatively regulate LTP induction in the VTA. For example, GABA-mediated synaptic transmission has been shown to negatively regulate LTP in the rat VTA (Liu, Pu & Poo, 2005). Considering work showing that glutamatergic synaptic transmission onto VTA DA neurons is negatively regulated by endocannabinoids (EC) through the CB1 receptor (Melis et al., 2004), we hypothesize that EC release by the dendrites of DA neurons during LTP induction paradigms could also act to negatively regulate LTP-induction. Material and methods: Horizontal slices were prepared from TH-eGFP transgenic mice, a model that facilitates identification of DA neurons. Whole cell patch-clamp recordings were obtained from immunocytochemically-characterized DA neurons under current clamp conditions and excitatory post-synaptic potentials (EPSPs) were recorded in DA neurons in response to local extracellular stimulation of glutamatergic afferents. We used a physiologically relevant pairing protocol of spike-timing dependent plasticity to induce LTP at glutamatergic synapses. This protocol mimics burst-firing, which is considered to be a signature of activated DA neurons.
Results: The spike-pairing protocol was unable to induce LTP in artificial cerebral spinal fluid (aCSF) alone, but in the presence of the GABA-A receptor antagonist SR95531, a significant potentiation of synaptic transmission could be observed, as previously reported in rats. However, we found that simply blocking GABA-A receptors alone, without induction of LTP, also caused a modest, slowly developing increase of EPSP-amplitude, albeit of lower magnitude than with the LTP protocol. In addition, we found that in the presence of AM251, a CB1 receptor antagonist, LTP could be induced, whereas the antagonist alone had no effect by itself on EPSP-amplitude. Conclusions: Our results suggest that both GABAergic transmission and EC signalling act to prevent LTP induction in mouse VTA DA neurons. In addition, while a basal tone of GABAergic transmission my gate LTP induction, EC signalling appears to gate LTP induction in an activity-dependent manner. These results are a first step in identifying some of the factors that control glutamatergic synaptic plasticity in VTA DA neurons, which may be a critical mechanism for the induction of behavioural sensitization to drugs of abuse. |
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