Abstract
Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT−/−) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine‐seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine‐exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT−/− rats, which compared to wild‐type (SERT+/+) rats show increased ShA and LgA intake short‐access (ShA) and long‐access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT−/− rats, we observed a sharp increase in glial glutamate transporter 1 (GLT‐1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA‐induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed.
Highlights
Drug addiction is classified as a compulsive and relapsing psychiatric disease, characterized by the transition from limited to compulsive use
By comparing cocaine-naive rats to rats exposed to short access (ShA) or long access (LgA) of cocaine, we evaluated the effects of serotonin transporter (SERT) removal on critical determinants of glutamate homeostasis such as: 1) the glial glutamate transporter glutamate transporter 1 (GLT-1), which is responsible of the termination of glutamate neurotransmission by mediating reuptake of glutamate back into the presynaptic terminal; 2) the different subunits of the NMDA receptor (GluN1, GluN2B expression in SERT-/- rats (GluN2A) and GluN2B), which represent the main glutamate receptor complex responsible of calcium influx into the cell 31, as well as the scaffolding proteins PSD95 and SAP102, which are responsible of the anchoring of NMDA receptor tight to the post-synaptic density 32
Expression levels of the glial glutamate transporter in the homogenate of ILc and PLc and following ShA and LgA to cocaine in SERT+/+ and SERT-/- rats We first evaluated the expression of the main glial glutamate transporter responsible for the clearance of glutamate from the synaptic cleft, i.e. GLT-1, in the homogenate of ILc and PLc of SERT-/- and SERT+/+ under naive conditions and following the different paradigms of cocaine self-administration
Summary
Drug addiction is classified as a compulsive and relapsing psychiatric disease, characterized by the transition from limited to compulsive use. We found that cocaine intake was increased in SERT knockout (SERT-/-) rats under both ShA and LgA conditions, and that anxiety was increased 24 hrs into withdrawal from both conditions. This implies that increases in both regular and compulsive cocaine intake is, at least in part, driven by increased anxiety, adding critical information with respect to the neural mechanisms involved in the pathophysiology underlying addictive behavior
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