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 a 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, as well as a 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 the reduction in psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. In the absence of NL3 expression, dopamine neurons in the ventral tegmental area showed diminished activation following chronic morphine exposure, as measured by in vivo calcium imaging with fiber 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 behavioral sensitivity to opioids, and further suggests that NL3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.
SIGNIFICANCE STATEMENT Exposure to opioids and other drugs of abuse can cause long-lasting changes in the brain. Some of the most durable alterations involve functional and structural changes at synapses in brain reward circuits, including dopamine neurons in the ventral tegmental area and their projection to the nucleus accumbens. Synaptic cell-adhesion molecules support structural and functional aspects of synaptic transmission. Dysregulation of these molecules has been implicated in addiction and other neuropsychiatric disorders. We find that a specific synaptic cell-adhesion molecule, neuroligin-3, mediates changes in brain reward circuits caused by morphine exposure. In the absence of neuroligin-3, male mice are less sensitive to the behavioral effects of chronic morphine exposure, and dopamine neurons in the ventral tegmental area do not function normally.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest statement: The authors declare no competing financial interests.