Glutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration

Abstract

Glutamate signaling in prefrontal cortex and ventral tegmental area plays an important role in the molecular and behavioral plasticity associated with addiction to drugs of abuse. The current study investigated the expression and postsynaptic density redistribution of glutamate receptors and synaptic scaffolding proteins in dorsomedial and ventromedial prefrontal cortex and ventral tegmental area after cocaine self-administration. After 14 days of extended-access (6h/day) cocaine self-administration, rats were exposed to one of three withdrawal regimen for 10 days. Animals either stayed in home cages (Home), returned to self-administration boxes with the levers withdrawn (Box), or underwent extinction training (Extinction). Extinction training was associated with significant glutamatergic plasticity. In dorsomedial prefrontal cortex of the Extinction group, there was an increase in postsynaptic density GluR1, PSD95, and actin proteins; while postsynaptic density mGluR5 protein decreased and there was no change in NMDAR1, Homer1b/c, or PICK1 proteins. These changes were not observed in ventromedial prefrontal cortex or ventral tegmental area. In ventral tegmental area, Extinction training reversed the decreased postsynaptic density NMDAR1 protein in the Home and Box withdrawal groups. These data suggest that extinction of drug seeking is associated with selective glutamatergic plasticity in prefrontal cortex and ventral tegmental area that include modulation of receptor trafficking to postsynaptic density.

Figure 1

Tissue and postsynaptic density (synaptosomal membrane fraction) levels of GluR1 protein after cocaine self-administration and Home, Box, and Extinction treatments. Animals self-administered cocaine for 14 days (extended-access, 6h/day) and were exposed to Home, Box, or Extinction conditions during 12–14 days of post-SA period. At the tissue level, GluR1 protein was not changed in any treatment group. However, the PSD level of GluR1 protein was selectively increased in dmPFC of Extinction group. The dotted line designates percent average saline self-administration groups. *p<0.05 compared to respective saline control.

Figure 2

Tissue and postsynaptic density (synaptosomal membrane fraction) levels of NMDAR1 protein after cocaine self-administration and Home, Box, and Extinction treatments. See Figure 1 legend for details. At the tissue level, VTA Extinction group showed near significant reduction in NMDAR1 protein (p=0.054), while mPFC was not changed. The PSD NMDAR1 protein levels in VTA displayed a near significant reduction in both Home (p=0.058) and Box (p=0.105) groups, while mPFC was not changed. + compared to respective saline control.

Figure 3

Tissue and postsynaptic density (synaptosomal membrane fraction) levels of mGluR5 protein after cocaine self-administration and Home, Box, and Extinction treatments. See Figure 1 legend for details. Since both mGluR5 monomer and dimer proteins showed the same trend in tissue and postsynaptic density plasticity in cocaine self-administrating animals we have only shown the data for the monomer protein. At the tissue level, dmPFC Extinction group showed a significant reduction. Moreover, in PSD, both Box (p=0.055) and Extinction (p=0.076) groups showed near significant reduction in mGluR5 protein. *p<0.05 compared to respective saline control. + compared to respective saline control.

Figure 4

Tissue and postsynaptic density (synaptosomal membrane fraction) levels of PSD95 protein after cocaine self-administration and Home, Box, and Extinction treatments. See Figure 1 legend for details. The tissue level of PSD95 protein was not changed following any post-SA treatment. However, the dmPFC PSD compartment in the Extinction group showed a significant increase in PSD95 protein. *p<0.05 compared to respective saline control.

Figure 5

Tissue and postsynaptic density (synaptosomal membrane fraction) levels of Actin protein after cocaine self-administration and Home, Box, and Extinction treatments. See Figure 1 legend for details. The tissue Actin protein was not changed following any post-SA treatment. However, dmPFC Extinction and vmPFC Box groups showed a significant increase in PSD Actin protein. Comparing cocaine self-administration groups across post-SA conditions, Actin levels were significantly higher in vmPFC Box and Extinction groups compared to Home group. *p<0.05 compared to respective saline control. #p<0.05 compared to Home cocaine group.