Periaqueductal Gray and Rostromedial Tegmental Inhibitory Afferents to VTA Have Distinct Synaptic Plasticity and...

The ventral tegmental area (VTA) is a major target of addictive drugs and receives multiple GABAergic projections originating outside the VTA. We describe differences in synaptic plasticity and behavior when optogenetically driving two opiate-sensitive GABAergic inputs to the VTA, the rostromedial tegmental nucleus (RMTg), and the periaqueductal gray (PAG). Activation of GABAergic RMTg terminals in the VTA in vivo is aversive, and low-frequency stimulation induces long-term depression in vitro. Low-frequency stimulation of PAG afferents in vitro unexpectedly causes long-term potentiation. Opioid receptor activation profoundly depresses PAG and RMTg inhibitory synapses but prevents synaptic plasticity only at PAG synapses. Activation of the GABAergic PAG terminals in the VTA promotes immobility, and optogenetically-driven immobility is blocked by morphine. Our data reveal the PAG as a source of highly opioid-sensitive GABAergic afferents and support the idea that different GABAergic pathways to the VTA control distinct behaviors.