Repeated cocaine administration promotes longterm potentiation induction in rat medial prefrontal cortex

Although drug-induced adaptations in the prefrontal cortex (PFC) may contribute to several core aspects of addictive behaviors, it is not clear yet whether drugs of abuse elicit changes in synaptic plasticity at the PFC excitatory synapses. Here we report that, following repeated cocaine administration (15 mg/kg/day intraper-itoneal injection for 5 consecutive days) with a 3-day withdrawal, excitatory synapses to layer V pyramidal neurons in rat medial prefrontal cortex (mPFC) become highly sensitive to the induction of long-term potentiation (LTP) by repeated correlated presynaptic and postsynaptic activity. This promoted LTP induction is caused by cocaine-induced reduction of g-aminobutyric acid (GABA)A receptor--mediated inhibition of mPFC pyramidal neurons. In contrast, in slices from rats treated with saline or a single dose of cocaine, the same LTP induction protocol did not induce significant LTP unless the blockade of GABAA receptors. Blockade of the D1-like receptors specifically prevented the cocaine-induced enhancement of LTP. Repeated cocaine exposure reduced the GABAA receptor--mediated synaptic currents in mPFC pyramidal neurons. Biotinylation experiments revealed a significant reduction of surface GABAA receptor a1 subunit expression in mPFC slices from repeated cocaine-treated rats. These findings support an important role for cocaine-induced enhancement of synaptic plas-ticity in the PFC in the development of drug-associated behavioral plasticity