Abstract
The role of glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been extensively studied in schizophrenia; however, less is known about its role in anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype. Although astrocytes are capable of modulating NMDAR activity through glutamate uptake transporters, the relationship between astrocytic glutamate uptake and the development of an anxiety phenotype remains poorly explored. Here, we aimed to investigative whether long-term antagonism of NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake. Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy adult CF-1 mice by oral gavage at doses of 5, 10, or 20 mg/kg. The mice were submitted to a sequential battery of behavioral tests (open field, light–dark box and elevated plus-maze tests). We then evaluated glutamate uptake activity and the immunocontents of glutamate transporters in the frontoparietal cortex and hippocampus. Our results demonstrated that long-term administration of memantine induces anxiety-like behavior in mice in the light–dark box and elevated plus-maze paradigms. Additionally, the administration of memantine decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the memantine-induced reduction in glutamate uptake was correlated with enhancement of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with memantine induces anxiety-like behavior that is associated with reduced glutamate uptake activity but that is not dependent on GLT-1 or GLAST protein expression. Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to the development of conditions that fall within the category of anxiety disorders.
Highlights
Anxiety disorders are among the most prevalent psychiatric conditions worldwide
Long-Term N-methyl-D-aspartate receptor (NMDAR) Antagonism does not Alter Spontaneous Locomotion but Induces Anxiety-Like Behavior Administration of memantine did not cause significant changes in either distance traveled [Figure 1A; F(3,36) = 1.642, p = 0.1967] or time spent in the central zone [Figure 1B; F(3,36) = 0.1697, p = 0.9162] in the open field
Long-Term NMDAR Antagonism Reduced Time Spent in the Light Compartment of the Light–Dark Box In the light–dark box (Figure 1G), all of the doses of memantine that were tested significantly reduced the time spent in the light compartment by the memantine-administered mice compared to the CO group [Figure 1D; F(3,36) = 7.364, MN5: p = 0.03, MN10: p = 0.002, MN20: p = 0.01]
Summary
Anxiety disorders are among the most prevalent psychiatric conditions worldwide. These disorders have been associated with social isolation, alcoholism, and increased suicide attempts and are considered to be risk factors for the development of additional psychiatric disorders (Gross and Hen, 2004). Glutamatergic neurotransmission offers multiple potential pharmacological targets for treating anxiety-related disorders, such as postsynaptic receptor signaling, presynaptic glutamate release, and astrocytic glutamate uptake (Szabo et al, 2009; Zarate et al, 2010; Riaza Bermudo-Soriano et al, 2012; Pilc et al, 2013). Antagonism of N-methyl-D-aspartate receptor (NMDAR) has been proposed as a feasible strategy for reducing the major symptoms that are linked to anxiety-like behavior (Cortese and Phan, 2005). The current data that are available regarding the association between the use of NMDAR antagonists and the presentation of anxiety-related behaviors refute a simple model of dose-effect and instead seem to be closely related to the regimen, type of drug, or route of administration (Silvestre et al, 1997; Riaza Bermudo-Soriano et al, 2012; Schwartz et al, 2012). It is prudent to consider that glutamatergic neurotransmission involves neuronal receptors (ionotropic and metabotropic) and astroglial transporters that participate in neuron-astrocyte coupling
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