Repeated 7-day exposure to ketamine induces anxiety-like behaviors and neuronal apoptosis in mice via DRD1-medicated inhibition of Akt/Gsk-3β phosphorylation.
Cell biology and toxicology – January 30, 2026
Source: PubMed
Summary
Ketamine abuse significantly drives anxiety-like behavior by causing brain cell death. Seven days of exposure to ketamine in mice induced marked anxiety-like behavior and cognitive dysfunction. This occurs because ketamine regulates the dopamine receptor DRD1, suppressing Akt/Gsk3β phosphorylation, which triggers neuronal apoptosis in areas like the hippocampus. Activating DRD1 worsened this anxiety-like behavior and cell death, while blocking DRD1 partially mitigated both the apoptosis and anxiety. Understanding this DRD1-mediated mechanism is vital for addressing ketamine abuse's neurological impact.
Abstract
Repeated exposure to ketamine leads to mental behavioral disorders and cognitive deficits in mice. As a neurotransmitter receptor, dopamine receptor 1 (DRD1) is involved in mental regulation and memory formation. However, the role of DRD1 in ketamine's behavioral disorder and neurotoxicity remains unclear. We found that seven-day ketamine exposure induced anxiety-like, depressive-like behavior and cognition dysfunction in mice. DRD1 activation can produce anxiety-like behavior similar to that induced by ketamine. Furthermore, DRD1 activation synergistically exacerbates this effect of ketamine, and DRD1 antagonism partially attenuates the anxiety-like behavior and further aggravated the depressive-like behavior induced by ketamine. Moreover, ketamine induced HT22 cell apoptosis by DRD1 dependent inhibition of Akt/Gsk3β phosphorylation. DRD1 agonist synergistically enhanced the apoptosis induced by ketamine, while DRD1 antagonist or the apoptosis inhibitor partially reversed this apoptosis in vitro. In vivo assay found that ketamine promotes neuronal apoptosis in the hippocampus and prefrontal cortex of mice, and antagonizing DRD1 partially attenuates ketamine-induced apoptosis. In contrast, cell-specific knockdown of DRD1 in neuronal cells exacerbated ketamine-induced neuronal apoptosis and anxiety-like behavior. In summary, ketamine regulates DRD1 to suppress Akt/Gsk3β phosphorylation, inducing neuronal apoptosis, ultimately leading to anxiety-like behaviors in mice.