Neuroligin-3 in dopaminergic circuits promotes behavioural and neurobiological adaptations to chronic morphine exposure

Dieter D Brandner, Cassandra L Retzlaff, Adrina Kocharian, Bethany J. Stieve, Mohammed A Mashal, Paul G. Mermelstein, Patrick E. Rothwell

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 (NL3) is an X-linked postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of NL3 alters responses to chronic morphine in male mice. Constitutive NL3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure and change in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of NL3 from cells expressing the Drd1 dopamine receptor, whereas reduced psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. Without NL3 expression, dopamine neurons in the ventral tegmental area exhibited diminished activation following chronic morphine exposure, by measuring in vivo calcium signals with fibre photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of NL3: dopamine neurons lacking NL3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioural sensitivity to opioids and further suggests that NL3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behaviour.

Original languageEnglish (US)
Article numbere13247
JournalAddiction Biology
Volume28
Issue number1
DOIs
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This research was supported by the University of Minnesota's MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) initiative, as well as NIH grants F30 DA007234 (DDB), T32 DA052109 (PGM, DDB), F30 MH124404 (AK), R00 DA037279 (PER) and R01 DA048946 (PER). The University of Minnesota MnDRIVE Optogenetics Core provided technical support for fibre photometry experiments. Some of the viral vectors used in this study were generated by the University of Minnesota Viral Vector and Cloning Core. We thank Marc Pisansky for technical assistance; Mark Geyer and Richard Sharp for assistance with analysis of the spatial scaling exponent, and Emilia Lefevre, Joshua Melander, Robert Meisel, Bailey Remmers, Carlee Toddes and Brian Trieu for stimulating discussions.

Funding Information:
This research was supported by the University of Minnesota's MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) initiative, as well as NIH grants F30 DA007234 (DDB), T32 DA052109 (PGM, DDB), F30 MH124404 (AK), R00 DA037279 (PER) and R01 DA048946 (PER). The University of Minnesota MnDRIVE Optogenetics Core provided technical support for fibre photometry experiments. Some of the viral vectors used in this study were generated by the University of Minnesota Viral Vector and Cloning Core. We thank Marc Pisansky for technical assistance; Mark Geyer and Richard Sharp for assistance with analysis of the spatial scaling exponent, and Emilia Lefevre, Joshua Melander, Robert Meisel, Bailey Remmers, Carlee Toddes and Brian Trieu for stimulating discussions.

Publisher Copyright:
© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Keywords

  • dopamine
  • morphine
  • neuroligin-3
  • opioid
  • sensitization

PubMed: MeSH publication types

  • Journal Article

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