Novel Circuit Mechanism for Opioid-Induced Dopamine Elevations: Beyond Midbrain Dopamine Neuron Activity

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Project Summary/Abstract: Opioid use disorder is a major public health crisis with widespread socioeconomic consequences. Most drugs of abuse, including opioids, increase dopamine levels in the nucleus accumbens, and disruption of nucleus accumbens dopamine signaling reduces opioid seeking behavior. The canonical mechanism through which opioids increase dopamine is through actions on inhibitory mu-opioid receptors located on midbrain GABA interneurons of the rostromedial tegmental nucleus and ventral tegmental area. Under basal conditions, midbrain GABA interneurons exert an inhibitory influence on dopamine neuron activity in the ventral tegmental area. Activation of mu-opioid receptors decreases midbrain GABA interneuron activity leading to disinhibition of ventral tegmental area dopamine neurons and subsequent increases in nucleus accumbens dopamine. We recently demonstrated a novel mechanism through which opioids increase dopamine levels in the nucleus accumbens. Preliminary observations in isolated nucleus accumbens brain slices, which do not include the midbrain, indicate that the opioid oxycodone increases evoked dopamine by reducing dopamine uptake rate. Given that there are no mu-opioid receptors on dopamine terminals in the nucleus accumbens, the effects of opioids on dopamine transmission must involve mu-opioid receptors on other neuron types. We thus propose that oxycodone enhances dopamine signals in the nucleus accumbens through actions on a putative local circuit. Consistent with this, prior electrophysiological and molecular evidence suggests that mu-opioid receptors are expressed on GABA and cholinergic interneurons in the nucleus accumbens, both of which are known to regulate nucleus accumbens dopamine transmission through actions on dopamine terminals. However, it remains unclear to what extent GABA and/or cholinergic interneurons modulate dopamine uptake and whether opioids exert their effects on dopamine uptake through local mu-opioid receptor actions on these interneuron populations. The proposed studies will define the anatomical, pharmacological, and local circuit mechanisms by which oxycodone reduces dopamine uptake in the nucleus accumbens. We will first quantify mu-opioid receptor expression on GABA and cholinergic interneurons in the nucleus accumbens before determining if oxycodone’s influence on nucleus accumbens dopamine signaling requires changes in GABA and/or acetylcholine receptor activity. Next, we will knock down mu-opioid receptors selectively on GABA or cholinergic interneurons, individually and in combination, to determine if the local effects of opioids on dopamine transmission in the nucleus accumbens depend on mu-opioid receptors on these interneuron populations. Completion of the proposed studies will reveal a novel framework for understanding opioid-induced dopamine modulation, will provide molecular tools critical for defining the role of this novel mechanism in opioid reinforcement, and will ultimately inform the development of alternative treatments for opioid use disorders.