Abstract
The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain ventral tegmental area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
Highlights
The essential role of the ventral tegmental area (VTA) in the motivational and reinforcing actions of mu opioid receptor (MOR) agonists is well established [1,2,3,4,5,6], the local circuit mechanisms are uncertain
Anatomy To unambiguously assess the percentage of VTA neurons that are GABAergic, we first co-labeled horizontal VTA slices using in situ hybridization against mRNA for GAD65/67 and an antibody against the nuclear neuronal marker neuronal nuclei (NeuN) (Figure 1A)
We found that 2363% of NeuN-labeled neurons in the VTA had a spatially correlated density of grains indicating GAD65/67 mRNA content (Figure 1D)
Summary
The essential role of the VTA in the motivational and reinforcing actions of MOR agonists is well established [1,2,3,4,5,6], the local circuit mechanisms are uncertain. Because MOR agonists in the VTA increase both dopamine release in the ventral striatum [7,8,9] and the firing of putative VTA dopamine neurons [10,11,12], and because dopamine contributes to the motivational actions of a variety of natural and drug rewards, the idea that activation of VTA dopamine neurons is required for opioid reward has been widely accepted. The canonical two neuron model of opioid reward proposes that, as in other brain regions [13], MOR excites midbrain VTA dopamine neurons indirectly by hyperpolarizing local GABAergic interneurons [14,15]. VTA neurons were ‘identified’ as dopaminergic if they were inhibited by dopamine
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