Fig. 4.

Interactions of orexin and glutamate in ventral tegmental area. (a) Orexin potentiates glutamatergic control of VTA dopamine neurons. Top panels: Example of short-latency mPFC-evoked excitatory responses in a dopamine neuron before (left) and after microinfusion onto the recorded neuron (right) of orexin-A (ORX-A, 60 nl, 1.4 μM). Short-latency-evoked responses were enhanced both during and following ORX-A administration. Time 0.00 demarcates the time of mPFC stimulation (50 pulses, 0.5 Hz). Bottom panels: Example of long-latency-evoked responses before (left) and during microinfusion (stim+infusion; right) of ORX-A onto a recorded DA neuron. Long-latency-evoked responses were enhanced by ORX-A administration. Modified with permission from Moorman and Aston-Jones (2010). (b) Enhancing AMPA neurotransmission rescues cue-induced reinstatement blocked by OX1R antagonism. The allosteric modulator PEPA was used to facilitate effects of endogenously released glutamate at AMPA receptors in VTA. Intra-VTA PEPA alone failed to cause or potentiate reinstatement of cocaine seeking. VTA microinjections of SB-334867 blocked cue-induced reinstatement, which was reversed by coadministration of PEPA into VTA (see Mahler et al., 2012) for more details. (c) Hypothesized orexin–glutamate interaction in VTA leads to reinstatement. Upper panel: In VTA dopamine cells, orexin potentiates AMPA and NMDA responses to VTA glutamate inputs (Borgland et al., 2006). During reinstatement, orexin facilitates VTA AMPA responses to cue-related glutamate inputs, allowing cues to promote renewed drug-seeking behavior and relapse. Lower panel: When OX1Rs are blocked in VTA with local microinjections of SB-334867, AMPA signaling is not potentiated, reducing the motivational impact of cue-related glutamate inputs, and attenuating cocaine-seeking behavior. (For color version of this figure, the reader is referred to the online version of this chapter.)