Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Veronika Kondev
Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Niharika Loomba
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Eric Delpire
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Brad A. Grueter
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Sachin Patel
Northwestern Center for Psychiatric Neuroscience, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Corresponding author
Summary: The lateral habenula (LHb) encodes aversive states, and its dysregulation is implicated in neuropsychiatric disorders, including depression. The endocannabinoid (eCB) system is a neuromodulatory signaling system that broadly serves to counteract the adverse effects of stress; however, CB1 receptor signaling within the LHb can paradoxically promote anxiogenic- and depressive-like effects. Current reports of synaptic actions of eCBs in the LHb are conflicting and lack systematic investigation of eCB regulation of excitatory and inhibitory transmission. Here, we report that eCBs differentially regulate glutamatergic and GABAergic transmission in the LHb, exhibiting canonical and circuit-specific inhibition of both systems and an opposing potentiation of synaptic glutamate release mediated via activation of CB1 receptors on astrocytes. Moreover, simultaneous depression of GABA and potentiation of glutamate release increases the net excitation-inhibition ratio onto LHb neurons, suggesting a potential cellular mechanism by which cannabinoids may promote LHb activity and subsequent anxious- and depressive-like aversive states.
