NeuropharmacologyNov 13, 2017

Restoring glutamate balance in the brain's reward area reduces depression and anxiety behaviors in rats after alcohol withdrawal

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Dihydrokainic acid (DHK) increased glutamatergic transmission to lateral habenula (LHb) neurons in ethanol naïve rats but not in those withdrawn from ethanol, indicating reduced GLT-1 function.

GLT-1 protein expression was found to be lower in the LHb of rats that had undergone ethanol withdrawal.
Systemic administration of ceftriaxone restored GLT-1 expression in the LHb and normalized the hyperactivity of LHb neurons in withdrawn rats.
Ceftriaxone treatment alleviated depression- and anxiety-like behaviors in ethanol withdrawn rats.
The effects of ceftriaxone on behavior were blocked by the intra-LHb application of DHK, indicating the importance of GLT-1 in the LHb for these behaviors.

Simplified

Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naïve rats; this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. This reduction was restored by systemic administration of ceftriaxone, a β-lactam antibiotic known to increase GLT-1 expression. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1's function in the LHb is critical. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal.

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Restoring glutamate balance in the brain's reward area reduces depression and anxiety behaviors in rats after alcohol withdrawal

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