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TitleMu-Opioids Suppress GABAergic Synaptic Transmission onto Orbitofrontal Cortex Pyramidal Neurons with Subregional Selectivity.
Publication TypeJournal Article
Year of Publication2020
AuthorsLau, Benjamin K., Brittany P. Ambrose, Catherine S. Thomas, Min Qiao, and Stephanie L. Borgland
JournalJ Neurosci
Volume40
Issue31
Pagination5894-5907
Date Published2020 07 29
ISSN1529-2401
KeywordsAnalgesics, Opioid, Animals, Cyclic AMP-Dependent Protein Kinases, Endorphins, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Frontal Lobe, gamma-Aminobutyric Acid, In Vitro Techniques, Interneurons, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Parvalbumins, Patch-Clamp Techniques, Pyramidal Cells, Receptors, Opioid, mu, Signal Transduction, Synaptic Transmission
Abstract

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion-specific manner. However, it is unknown how mu-opioid signaling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using patch-clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist DAMGO produced a concentration-dependent inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV)-expressing interneurons. The DAMGO-induced suppression of inhibition was long lasting and not reversed on washout of DAMGO or by application of the mu-opioid receptor antagonist CTAP, suggesting an inhibitory long-term depression (LTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/protein kinase A (PKA) signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Together, these results suggest that presynaptic mu-opioid stimulation of local PV interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC. Considering that both the orbitofrontal cortex (OFC) and the opioid system regulate reward, motivation, and food intake, understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Second, mu-opioids recruit parvalbumin inputs to suppress inhibitory synaptic transmission in the mOFC. Third, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.

DOI10.1523/JNEUROSCI.2049-19.2020
Alternate JournalJ Neurosci
PubMed ID32601247
PubMed Central IDPMC7392508
Grant ListFDN 148473 / / CIHR / Canada