mGlu5 receptor antagonist blocks bromocriptine-induced conditioned place preference in bilateral mesolimbic-lesioned rat

• Dopamine replacement therapy induces dopamine dysregulation syndrome in PD patients by sensitizing the pVTA-NAc pathway.
• Dopamine receptor agonist bromocriptine induces a positive reinforcement in bilateral pVTA-lesioned rats.
• This reinforcement is due to the activation of mGluR5. This receptor and glutamate are over expressed in the NAc shell of pVTA-lesioned rats.
• Antagonizing mGluR5 blocked the conditioned place preference expression and acquisition in pVTA-lesioned rats.
• Bromocriptine-induced reinforcement is due to the activation of the mGluR5 pathway in the NAc of pVTA-lesioned rats.

Dopamine dysregulation syndrome (DDS) has been attributed to both dopamine replacement therapies (DRT) and the mesencephalic dopaminergic lesion. The DRT reinforcement effect is due to its action on the reward system, particularly on the nucleus accumbens (NAc). This nucleus receives two major projections, a glutamatergic from the prefrontal cortex and a dopaminergic from the posterior ventral tegmental area (pVTA). The latter modulate the former within the NAc. pVTA has been demonstrated to be implicated in the motivational effect of bromocriptine (dopamine 2 receptor (D2R) agonist) in bilateral pVTA-lesioned animals. Therefore the potential implication of the metabotropic glutamate receptor 5 (mGluR5) antagonist (MTEP: 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine) on bromocriptine-induced conditioned place preference (CPP) was explored. Results showed that the administration of the MTEP blocked completely the bromocriptine-induced CPP in bilateral pVTA-lesioned rats. Both the CPP acquisition and expression were abolished. These effects are due, at least to an increase of the glutamate concentration and that of mGlu5 receptor expression in the NAc shell of the pVTA-lesioned animals. Altogether these data demonstrated the importance of the mGlu5 receptor in the bromocriptine induced-reinforcement and that DDS is probably due to DRT effect on this glutamate receptor.