A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets μ-δ opioid receptor heterodimers on astrocytes. This interaction activates Gs-coupled signaling, increases intracellular cAMP, and elevates phosphorylated CREB levels and calcium dynamics in astrocytes, restoring key astrocytic proteins and functions in depression models. Disrupting the assembly of these opioid receptor heterodimers or Gs signaling eliminates HNK's antidepressant effects both in cells and in animals. The findings indicate that astrocytic opioid receptor heterodimers are critical for antidepressant responses and suggest HNK as a prototype for targeting astrocyte dysfunction in brain disorders.
Blocking glutamate transporter 1 (GLT1) with dihydrokainic acid (DHK) prevents ketamine's antidepressant-like effects in mice and reduces phosphorylation of mTOR in the prefrontal cortex. Inhibiting AMPA receptors or L-type voltage-dependent calcium channels (L-VDCC) also abolishes ketamine's antidepressant-like effect. L-VDCC inhibition blocks ketamine-induced upregulation of GLT1 and BDNF, while AMPA receptor inhibition only reduces BDNF. GLT1 appears to be a critical presynaptic molecule in depression's pathophysiology and ketamine's mechanism, with AMPA receptors and L-VDCC both essential for the immediate antidepressant-like effect.