Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2015-06, Vol.40 (7), p.1700-1708
• Main Authors: John, Catherine S, Sypek, Elizabeth I, Carlezon, William A, Cohen, Bruce M, Öngür, Dost, Bechtholt, Anita J
• Format: Article
• Language: English
• Subjects: Alcoholism; Animals; Anxiety; Anxiety - chemically induced; Central Amygdaloid Nucleus - drug effects; Central Amygdaloid Nucleus - metabolism; Comorbidity; Conditioning (Psychology) - drug effects; Depression - chemically induced; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Emotional disorders; Excitatory Amino Acid Transporter 2 - antagonists & inhibitors; Excitatory Amino Acid Transporter 2 - metabolism; Fear; Kainic Acid - analogs & derivatives; Kainic Acid - toxicity; Male; Maze Learning - drug effects; Maze Learning - physiology; Mental depression; Metabolism; Mood disorders; Original; Rats; Rats, Sprague-Dawley; Self Administration
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.16

Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.