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 GABAA receptor (GABAAR)-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 GABAAR 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 GABAAR inhibitors enabled us to examine parallel changes in the relation between GABAAR-mediated and NMDAR-mediated currents (GABAA/NMDA ratio). First, we found that AMPA/NMDA ratio measured under complete availability of GABAAR, is significantly higher than the ratio measured under GABAAR blockade. In addition, GABAA/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 GABAA/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 GABAA/NMDA ratio may suggest an interaction between inhibitory and excitatory neural systems.

► Unblock of GABAA receptor during current recordings from VTA dopamine neurons affects the mean AMPA/NMDA ratio. ► Bath exposure to cocaine increases GABAA/NMDA but not AMPA/NMDA ratio recorded several hours later. ► Single injection of cocaine increases AMPA/NMDA but not GABAA/NMDA ratio recorded 24 h later. ► Repeated cocaine injections attenuate both AMPA/NMDA and GABAA/NMDA currents ratio.