Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration - PubMed (original) (raw)

Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration

M Behnam Ghasemzadeh et al. Neurosci Lett. 2009.

Abstract

This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, or were placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic density were examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations as well as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function.

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Figures

Figure 1

Figure 1. Subcellular fractionation analysis

Panel A shows the dissection of the nucleus accumbens core and shell and dorsolateral striatum. The numbers on the coronal brain section represent distance from Bregma. Panel B shows a schematic of the subcellular fractionation procedure (adopted from [9]), as described in Materials and Methods. The H and LP1 fractions were used for western blot analysis. Panel C shows representative immunoblots from nucleus accumbens tissue characterizing the content of each fraction.

Figure 2

Figure 2. Tissue and synaptosomal membrane fraction levels of mGluR5 receptor protein after cocaine self-administration and Home, Box, and Extinction treatments

At the end of the withdrawal period, all animals were decapitated and brain tissue was dissected for the areas of interest. At the tissue level, mGluR5 protein was reduced significantly in the NAshell of Home and Extinction animals and showed near significant decrease in DL Striatum in Home animals but was not changed under other withdrawal conditions or in other brain regions. In the synaptosomal membrane fraction, mGluR5 receptor protein was increased in NAcore of Home animals and DL striatum of Extinction animals. However, the receptor protein was significantly decreased in the NAshell of extinction animals. N= 7–11 rats per treatment group. * p < 0.05, + p= 0.066 compared to respective saline control. @ p < 0.05 compared to Box treatment, # p < 0.05 compared to Home treatment.

Figure 3

Figure 3. Tissue and synaptosomal membrane fraction levels of Homer 1b/c scaffolding protein after cocaine self-administration and Home, Box, and Extinction treatments

At the end of the withdrawal period, all animals were decapitated and brain tissue was dissected for the areas of interest. At the tissue level, the protein level was not modified in any withdrawal treatment group in any region examined. In the synaptosomal membrane fraction, Homer 1b/c protein was reduced in NAshell and exhibited a decreasing trend in the dorsolateral Striatum of Extinction animals. There were no changes in the protein level in the NAcore. N= 7–11 rats per treatment group. * p < 0.05, + p= 0.065 compared to respective saline control. @ p < 0.05 compared to Box treatment, # p < 0.05 compared to Home treatment.

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