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Keywords:

  • addiction;
  • drug abuse;
  • glutamate receptors;
  • mesolimbic dopamine system;
  • synaptic plasticity

Abstract

Excitatory glutamatergic synapses on dopamine (DA) neurons of the ventral tegmental area (VTA) undergo long-lasting changes during conditioning of natural rewards and in response to drug exposure. It has been suggested that the ensuing context-dependent behavioural changes are associated with an increased efficacy of synaptic afferents determined by the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the molecular nature of the forms of LTP/LTD involved remains elusive. Here, using acute rat brain slices, we describe a form of long-term depression (LTD) that was engaged by synaptic activity or exogenous agonists activating group I metabotropic glutamate receptors (mGluR) and was sensitive to mGluR1 antagonists. Prior to mGluR-LTD, AMPAR mediated excitatory postsynaptic currents (EPSCs) showed strong rectification at positive potentials and were sensitive to Joro spider toxin (JST), a selective blocker of GluR2-lacking AMPARs. After mGluR-LTD, AMPAR EPSCs had linear current-voltage relations and became insensitive to JST. We conclude that activation of mGluR1s triggers a redistribution exchanging native receptors for GluR2 containing AMPARs, ultimately causing LTD that may oppose pathological neuroadaptation.