Cannabidiol as an add-on therapy to overcome the slow-onset and, possibly, resistance to antidepressant treatment: involvement of NAPE-PLD in the medial prefrontal cortex

Antidepressant drugs are the first-line treatment for chronic stress-related psychiatric disorders such as major depressive disorder, anxiety disorders, and post-traumatic stress disorder. However, their delayed-onset of therapeutic action, frequently occurring side effects, and incomplete clinical efficacy impose significant challenges for clinicians and patients adherence to treatment. Cannabidiol (CBD) is a major non-psychotomimetic phytocannabinoid with a wide range of potential clinical applications such as either a standalone drug or as an add-on treatment. In our study, we found that in chronically stressed male mice, CBD (30 mg/kg) rapidly induced behavioral improvement within 7 days, which was quicker than the high dose of escitalopram (ESC, 14 days). Additionally, repeated administration of a low and initially ineffective dose of CBD (7.5 mg/kg) potentiated the anti-stress effects of ESC (10 mg/kg) in mice subjected to 10 or 21 days of chronic unpredictable stress (CUS). Furthermore, our results suggested the involvement of N-acyl phosphatidylethanolamine phospholipase (NAPE-PLD) located in the prefrontal cortex (PFC) in the anti-stress effects of the 7-day treatment with ESC + CBD. This combination restored CUS-induced decreased expression of NAPE-PLD in the PFC. The behavioral effects of ESC + CBD were not observed in either constitutive NAPE-PLD knockout (KO) mice or mice with a CRISPR/Cas9-induced deletion of NAPE-PLD in the PFC. ESC + CBD treatment facilitated NAPE-PLD expression in parvalbumin (PV) interneurons in the PFC. As a conclusion, we suggest that CBD might be useful as an add-on therapy to optimize the action of (SSRI-)antidepressants, possibly by restoring the inhibitory/excitatory balance of the PFC via NAPE-PLD-mediated signaling. HighlightsO_LICBD (7.5 mg/kg) reduces the latency for anti-stress effects of escitalopram (ESC) C_LIO_LIESC + CBD increases neuroplasticity in the prefrontal cortex (PFC) C_LIO_LIESC + CBD reverses stress-induced loss of NAPE-PLD in PFC-Parvalbumin (PV)+ interneurons. C_LIO_LINAPE-PLD in the PFC participates in the anti-stress effects of ESC + CBD. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC="FIGDIR/small/441143v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@d61ef2org.highwire.dtl.DTLVardef@189e2ecorg.highwire.dtl.DTLVardef@1910213org.highwire.dtl.DTLVardef@11f6bbf_HPS_FORMAT_FIGEXP M_FIG Cannabidiol (CBD) enhances the antidepressant-like effects of escitalopram (ESC) in chronically stressed mice. While an effective dose of CBD (30mg/kg) alone rapidly improved stress-related behaviors when compared to a high dose of ESC (20mg/kg), ESC+CBD combination in sub-effective doses potentiated anti-stress responses and restored prefrontal cortex (PFC) function. These effects depended on N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) activity within PFC parvalbumin interneurons, highlighting NAPE-PLD-mediated signaling as a key mechanism by which CBD may optimize antidepressant efficacy and reestablish inhibitory/excitatory balance in the PFC. C_FIG Chemical compounds used in this articleCannabidiol (PubChem CID: 644019); Escitalopram oxalate (PubChem CID: 146571); URB597 (PubChem CID: 1383884); Ketamine hydrochloride (PubChem CID: 15851); xylazine hydrochloride (PubChem CID: 68554); 2,2,2-Tribromoethanol (PubChem CID: 6400); Flunixin meglumine (PubChem CID: 39212); Lidocaine hydrochloride (PubChem CID: 6314); Amoxicillin (PubChem CID: 33613).