Long-lasting impairment of mGluR5-activated intracellular pathways in the striatum after withdrawal of cocaine self-administration

Background: Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors (mGluR1/5), with allosteric modulators showing particular promise.

Methods: We evaluated the capacity of mGluR1/5 receptors to induce functional responses in ex vivo striatal slices from rats with 1) acute cocaine self-administration (CSA), 2) chronic CSA and 3) 60 days CSA withdrawal by westernblot and extracellular recordings of synaptic transmission.

Results: We found that striatal mGluR5 are the principal mediator of the mGluR1/5 agonist DHPG-induced CREB phosphorylation. Both acute and chronic CSA blunted mGluR1/5 effects on CREB phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect which was maintained 60 days after chronic CSA withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic CSA blunted mGluR1/5 stimulation of ERK1/2 and CREB. Interestingly, the mGluR5 antagonist/inverse-agonist, MPEP, lead to a specific increase in CREB phosphorylation after chronic CSA specifically in the nucleus accumbens, but not in the striatum.

Conclusions: Prolonged CSA, through withdrawal, leads to a blunting of mGluR1/5 responses in the striatum. In addition, specifically in the accumbens, mGluR5 signaling to CREB shifts from an agonist-induced to an antagonist-induced CREB phosphorylation.