Mechanism and Time Course of Cocaine-Induced Long-Term Potentiation in the Ventral Tegmental Area

Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D(5) receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.