Aims: Chronic cocaine abuse decreases the inhibitory synaptic transmission via unknown mechanisms, while pharmacologically augmenting gamma-aminobutyric acid-ergic (GABAergic) transmission attenuates cocaine craving. Here, we propose that prolonged cocaine withdrawal downregulates GABAergic transmission and its important regulator gephyrin in medial prefrontal cortex (mPFC), in cocaine-conditioned place-preference (CPP) rats. Methods: CPP test, patch clamp, and Western blot analysis are engaged to test this proposal. Results: Two-week cocaine withdrawal further increased CPP score, as compared to the 24-hour withdrawn group. The amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) was decreased in 2-week-withdrawn mPFC neurons from cocaine-CPP rats, compared to that of saline-CPP rats. Two-week withdrawal did not alter the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) in mPFC in cocaine-CPP rats. Two-week withdrawal increased the ratio of EPSCs/IPSCs (E/I) in the same mPFC neuron in cocaine-CPP rats. In addition, Western blots showed 2-week cocaine-withdrawn down-regulated gephyrin at postsynaptic density (PSD) sites of mPFC. Conclusion: We found decreased GABAergic IPSCs and downregulated gephyrin in PSD at mPFC in 2-week cocaine-withdrawn rats that showed increased CPP, suggesting that an increased E/I ratio and neuron excitability in mPFC may associate with a cocaine-seeking tendency. Strategies aimed at GABAergic synapses in mPFC may therapeutically benefit to cocaine addiction treatment.

Keywords:
Cocaine, Conditioned place preference, Drug addiction, Electrophysiology, γ-Amino butyric acid
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