title: Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia.
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.
authors: Department of Psychiatry, Harvard Medical School-McLean Hospital, Belmont, MA, USA.
authors: Catherine S
authors: CS
authors: John
authors: Karen L
authors: KL
authors: Smith
authors: Ashlee
authors: A
authors: Van't Veer
authors: Heinrich S
authors: HS
authors: Gompf
authors: William A
authors: WA
authors: Carlezon
authors: Bruce M
authors: BM
authors: Cohen
authors: Dost
authors: D
authors: Öngür
authors: Anita J
authors: AJ
authors: Bechtholt-Gompf
mesh_terms: D000704:Analysis of Variance; D059445:Anhedonia / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D058256:Brain Waves / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004569:Electroencephalography; D004576:Electromyography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012653:Self Stimulation; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; C020889:dihydrokainic acid; D013395:Sucrose; D007608:Kainic Acid