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.