Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking

• Published in: European addiction research 2017, Vol.23 (1), p.28-36
• Main Authors: Yang, Wenqiong, He, Hongsheng, Pan, Yan, Duan, Falan, Zhao, Dan, Hu, Bo, Zhou, Qingzhen, Liu, Wanhong
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Carrier Proteins - biosynthesis; Cocaine; Cocaine - administration & dosage; Cocaine - adverse effects; Conditioning (Psychology) - physiology; Drug abuse; Drug-Seeking Behavior - physiology; Excitatory Postsynaptic Potentials - physiology; GABAergic Neurons - physiology; Inhibitory Postsynaptic Potentials - physiology; Male; Membrane Proteins - biosynthesis; Pharmacology; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Protein expression; Rats; Research Report; Substance abuse treatment; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - physiopathology
• ISSN: 1022-6877; 1421-9891
• DOI: 10.1159/000452657

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 Results: Two-week cocaine withdrawal further increased CPP score, as compared to the 24-hour withdrawn group. The amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) was decreased in 2-week-withdrawn mPFC neurons from cocaine-CPP rats, compared to that of saline-CPP rats.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 In addition, Western blots showed 2-week cocaine-withdrawn down-regulated gephyrin at postsynaptic density (PSD) sites of mPFC. Conclusion: We found decreased GABAergic IPSCs and downregulated gephyrin in PSD at mPFC in 2-week cocaine-withdrawn rats that showed increased CPP, suggesting that an increased E/I ratio and neuron excitability in mPFC may associate with a cocaine-seeking tendency.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.