Dihydrokainic acid (DHK) is an inhibitor of excitatory amino acid transporter 2 (EAAT2; Ki = 23 µM for glutamate uptake by COS cells expressing EAAT2).[1] It is selective for EEAT2 over EAAT1 and EAAT3 (Ki = >3 mM for both). DHK microinfusion (5 nmol) into the rat infralimbic cortex reduces the time spent immobile in the forced swim test, indicating antidepressant-like behavior, an effect that is blocked by the AMPA receptor antagonist NBQX and the serotonin (5-HT) receptor subtype 5-HT1A antagonist WAY-100635 .[2],[3] It also increases glutamate and serotonin levels and the expression of c-Fos in the dorsal raphe nucleus. In contrast, DHK microinjection (6.25 nmol) into the rat prefrontal cortex (PFC) increases the latency to drink sucrose in a sucrose intake test, indicating anhedonia-like behavior.[4] It also impairs memory acquisition, consolidation, and retrieval in mice in the novel object recognition test.[5]
Reference:
[1]. Arriza, J.L., Fairman, W.A., Wadiche, J.I., et al. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J. Neurosci. 14(9), 5559-5569 (1994).
[2]. Gasull-Camós, J., Tarrés-Gatius, M., Artigas, F., et al. Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats. Transl. Psychiatry 7(2), e1038 (2017).
[3]. Gasull-Camós, J., Martínez-Torres, S., Tarrés-Gatius, M., et al. Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex. Neuropharmacology 139, 41-51 (2018).
[4]. John, C.S., Smith, K.L., Van't Veer, A., et al. Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia. Neuropsychopharmacology 37(11), 2467-2475 (2012).
[5]. Tian, S.-W., Yu, X.-D., Cen, L., et al. Glutamate transporter GLT1 inhibitor dihydrokainic acid impairs novel object recognition memory performance in mice. Physiol. Behav. 199, 28-32 (2019).