Glutamate transporter activator LDN‐212320 attenuates CFA‐induced cognitive deficits and anxiety‐like behavior in mice

Abstract

The astroglial glutamate transporter‐1 (GLT‐1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in acute and chronic nociceptive pain. We have previously shown that 3‐[[(2‐Methylphenyl) methyl] thio]‐6‐(2‐pyridinyl)‐pyridazine (LDN‐212320), a GLT‐1 activator, in the hippocampus attenuates acute and chronic nociceptive pain. The cellular and molecular mechanisms of GLT‐1 modulation in the hippocampus and ACC in chronic pain‐induced cognitive deficits and anxiety‐like behaviors are unknown. Here, we have examined the effects of LDN‐212320 in complete Freund’s adjuvant (CFA)‐induced cognitive deficits and anxiety‐like behaviors in mice. Furthermore, we have measured CFA‐induced impaired spatial, working, and recognition memory using Y‐maze and object‐place recognition test. In addition, we have determined chronic pain‐induced anxiety‐like behaviors using elevated plus maze and marble burying test. We have also evaluated the effects of LDN‐212320 on cAMP response element‐binding protein (pCREB) expression in the hippocampus and ACC during CFA‐induced cognitive deficits and anxiety‐like behaviors using Western blot analysis and immunofluorescence assay. Pretreatment of LDN‐212320 (20 mg/kg) significantly attenuated CFA‐induced impaired spatial, working, and recognition memory. The LDN‐212320 (20 mg/kg) significantly reduced CFA‐induced anxiety‐like behaviors. Additionally, LDN‐212320 (20 mg/kg) significantly reversed CFA‐induced decreased‐pCREB expression in the hippocampus and ACC. Overall, these results suggest that the LDN‐212320 prevents CFA‐induced impaired cognitive behaviors and neuronal deficits via GLT‐1 modulation in the hippocampus and ACC. Therefore, LDN‐212320 may have therapeutic utility for the prevention and treatment of chronic pain‐associated with cognitive impairments and anxiety‐like behaviors.