Cocaine self-administration, extinction training and drug-induced relapse change metabotropic glutamate mGlu5 receptors expression: Evidence from radioligand binding and immunohistochemistry assays

Several behavioral findings highlight the importance of glutamatergic transmission and its metabotropic receptor type 5 (mGlu(5)) in the controlling of cocaine reward and seeking behaviors. The molecular or neurochemical nature of such interactions is not well recognized, so in the present paper we determine if cocaine self-administration and extinction/reinstatement models with the yoked triad control procedure alter mGlu(5) receptor density in rats. [H-3]MPEP was used to evaluate mGlu(5) receptors density and affinity in selected brain structures, while immunofluorescence analysis was used to detect changes in mGlu(5) receptors' brain location. Cocaine self-administration and yoked cocaine delivery evoked a significant elevation in mGlu(5) receptors' density in the dorsal striatum, while receptor protein expression was importantly elevated in the substantia nigra and reduced in the nucleus accumbens shell. Cocaine administration followed by 10 extinction training sessions resulted in biphasic mGlu(5) receptor density changes in the prefrontal cortex-nucleus accumbens pathway. mGlu(5) receptors' up-regulation was noted for cocaine self-administration and extinction training in the hippocampus and in yoked cocaine controls following drug abstinence in the dorsal striatum. A cocaine priming dose (but not a saline priming) resulted in a significant decrease of mGlu(5) receptors' density in the nucleus accumbens of rats previously treated with the drug and in the hippocampus of rats previously self-administered cocaine. The latter decrease in mGlu(5) receptors' density and protein expression in the hippocampus was parallel to an increase in [H-3]MPEP affinity and opposite to a rise observed after single cocaine administration (ip) to drug-naive yoked saline controls. Additionally, we also observed a significant elevation in the protein expression of the tested receptors in the limbic cortex in both cocaine groups. The present results shown modality dependent and brain-region specific changes in mGlu(5) receptors' localization and membrane specific binding.