| First Author | Adhikary S | Year | 2022 |
| Journal | J Neurosci | Volume | 42 |
| Issue | 12 | Pages | 2404-2417 |
| PubMed ID | 35091505 | Mgi Jnum | J:353419 |
| Mgi Id | MGI:7706239 | Doi | 10.1523/JNEUROSCI.1039-21.2022 |
| Citation | Adhikary S, et al. (2022) Mu Opioid Receptors Acutely Regulate Adenosine Signaling in Striatal Glutamate Afferents. J Neurosci 42(12):2404-2417 |
| abstractText | Endogenous adenosine plays a crucial role in maintaining energy homeostasis, and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS), adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influence adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of micro opioid receptors, but not delta opioid receptors or kappa opioid receptors, inhibits tonic activation of adenosine A(1)Rs via a cAMP-dependent mechanism in both male and female mice. Further, selectively knocking out micro opioid receptors from thalamic presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of micro opioid receptors on D(1)R-positive MSNs, but not D(2)R-positive MSNs, is necessary to inhibit tonic adenosine signaling on presynaptic terminals. Given the role of D(1)R-positive MSNs in movement and motivated behaviors, these findings reveal a novel mechanism by which these neurons regulate their own synaptic inputs.SIGNIFICANCE STATEMENT Understanding interactions between neuromodulatory systems within brain circuits is a fundamental question in neuroscience. The present work uncovers a novel role of opioids in acutely inhibiting adenosine accumulation and subsequent adenosine receptor signaling in the striatum by inhibiting the production of cAMP. Adenosine receptor signaling regulates striatal neurotransmitters, including glutamate, GABA, dopamine, and acetylcholine. Furthermore, interactions between adenosine(2A) receptors and numerous other GPCRs, including D(2) dopamine and CB(1) cannabinoid receptors, suggest that endogenous adenosine broadly modulates striatal GPCR signaling. Additionally, this work discovered that the source of resting endogenous extracellular adenosine is likely D(1), but not D(2) receptor-positive medium spiny neurons, suggesting that opioid signaling and manipulation of D(1)R-expressing medium spiny neuron cAMP activity can broadly affect striatal function and behavior. |
