Abstract
Major depression is associated with both dysregulated glutamatergic neurotransmission and fewer astrocytes in limbic areas including the prefrontal cortex (PFC). These deficits may be functionally related. Notably, astrocytes regulate glutamate levels by removing glutamate from the synapse via the glutamate transporter (GLT-1). Previously, we demonstrated that central blockade of GLT-1 induces anhedonia and c-Fos expression in the PFC. Given the role of the PFC in regulating mood, we hypothesized that GLT-1 blockade in the PFC alone would be sufficient to induce anhedonia in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the PFC and examined the effects on mood using intracranial self-stimulation (ICSS). At lower doses, intra-PFC DHK produced modest increases in ICSS thresholds, reflecting a depressive-like effect. At higher doses, intra-PFC DHK resulted in cessation of responding. We conducted further tests to clarify whether this total cessation of responding was related to an anhedonic state (tested by sucrose intake), a nonspecific result of motor impairment (measured by the tape test), or seizure activity (measured with electroencephalogram (EEG)). The highest dose of DHK increased latency to begin drinking without altering total sucrose intake. Furthermore, neither motor impairment nor evidence of seizure activity was observed in the tape test or EEG recordings. A decrease in reward value followed by complete cessation of ICSS responding suggests an anhedonic-like effect of intra-PFC DHK; a conclusion that was substantiated by an increased latency to begin sucrose drinking. Overall, these results suggest that blockade of astrocytic glutamate uptake in the PFC is sufficient to produce anhedonia, a core symptom of depression.
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Acknowledgements
Funding for this work was provided by the Jerome Lyle Rappaport Charitable Foundation, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health MH087695 (to AJB); the Shervert Frazier Research Institute (to BMC and DO); Englehard Foundation (to BMC); and MH063266 (to WAC).
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The authors declare no conflict of interest. Dr Carlezon has a US patent covering the use of κ antagonists in the treatment of depression (Assignee: McLean Hospital) and is a member of a collaborative group, including Dr Cohen, that has submitted a patent application covering the synthesis and use of salvinorin derivatives (Assignees: McLean Hospital and Temple University). In the past 3 years, Dr Carlezon has received compensation for professional services from The American College of Neuropsychopharmacology and Myneurolab.com. Dr Öngür is a Principal Investigator on a research contract with Rules Based Medicine, and has received income from Archives of General Psychiatry for services in 2012. Dr Cohen has three additional pending patents on Pyrimidines to treat bipolar disorders, κ agonists in bipolar mania, and Mitochondrial replacement therapy, and a book on bipolar disorder that has been published by Jossey-Bass/Wiley.
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John, C., Smith, K., Van'T Veer, A. et al. Blockade of Astrocytic Glutamate Uptake in the Prefrontal Cortex Induces Anhedonia. Neuropsychopharmacol 37, 2467–2475 (2012). https://doi.org/10.1038/npp.2012.105
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DOI: https://doi.org/10.1038/npp.2012.105
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