Scientific questions on brain reward systems were prompted by the discovery that animals learn to lever-press for electrical stimulation of certain brain areas, a phenomenon known as intracranial self-stimulation. Since then, numerous studies using anatomy, pharmacology and electrophysiology methods have established dopamine neurons in the ventral tegmental area (VTA projecting to the nucleus accumbens (NAc) as a key reward substrate. Recent studies using optogenetics confirmed that animals learn to self-stimulate VTA dopamine neurons, suggesting that excitation of dopamine neurons is sufficient in inducing reward. The question remains how excitation of VTA dopamine neurons influences downstream brain areas. We sought to identify firing patterns that encode dopamine neuron-mediated reward in the NAc. We injected the AAV-ChR2 viruses and implanted optical fibers in the VTA area of TH::Cre mice, a procedure that allowed us to specifically activate dopamine neurons through optical stimulation;a bundle of 8 tetrodes (32 wires) was implanted in the NAc shell for neural activity recording. We found that VTA optical stimulation in freely-behaving mice evoked fast excitatory local field potential (LFP) responses in the NAc, and the amplitudes of this LFP correlated well with the animals self-stimulation rates. Consistent with the LFP activity, 35% of the recorded NAc neurons showed fast phasic excitations, suggesting an excitatory input to the NAc from VTA dopamine neurons. We also recorded neurons that showed phasic inhibitions (17%). To determine whether these firing pattern changes were mediated by dopamine, mice were systemically injected with the dopamine D1 receptor antagonist SCH 23390. Although the antagonist decreased most basal firing in the NAc, it did not abolish optical stimulation-evoked neural responses, suggesting that transmitters other than dopamine were released by VTA dopamine neurons. In light of recent in vitro studies showing that dopamine neurons can also release glutamate and GABA to depolarize or hyperpolarize post-synaptic neurons, our results may be explained by excited dopamine neurons releasing glutamate or GABA. VTA dopamine neurons may employ multiple neural transmitters for inducing reward.

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National Institute on Drug Abuse
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