Modifications of the input currents on VTA dopamine neurons following acute versus chronic cocaine exposure

Excitatory synapses on dopamine (DA) neurons in the ventral tegmental area (VTA) are modulated following exposure to various addictive drugs, including cocaine. Previously we have shown that cocaine affects GABA _A receptor (GABA _AR)-mediated neurotransmission in VTA DA neurons. This finding led us to reexamine the modulation of the excitatory synapse on these neurons in response to cocaine exposure, while the activity of GABA _AR is uninterrupted. Using rat brain slices, evoked post synaptic currents (ePSC) were monitored and inhibitors of NMDA receptor (NMDAR) and AMPA receptor (AMPAR) were gradually added to inhibitors-free bath solution. Modifications in the efficacy of the excitatory synapses were evaluated by comparing AMPAR-mediated and NMDAR-mediated currents (AMPA/NMDA ratio). The lack of GABA _AR inhibitors enabled us to examine parallel changes in the relation between GABA _AR-mediated and NMDAR-mediated currents (GABA _A/NMDA ratio). First, we found that AMPA/NMDA ratio measured under complete availability of GABA _AR, is significantly higher than the ratio measured under GABA _AR blockade. In addition, GABA _A/NMDA ratio, but not AMPA/NMDA ratio, is augmented a few hours following in vitro acute cocaine exposure. When measured 24 h after in vivo single cocaine injection, no change in GABA _A/NMDA ratio was observed, however, the AMPA/NMDA ratio was found to be significantly higher. Finally, a decrease in both ratios was detected in rats repeatedly injected with cocaine. Taken together, these results lead to a better understanding of the means by which cocaine modifies synaptic inputs on VTA DA neurons. The parallel changes in GABA _A/NMDA ratio may suggest an interaction between inhibitory and excitatory neural systems.