Abstract
Single sub-anesthetic doses of ketamine can exacerbate the symptoms of patients diagnosed with schizophrenia, yet similar ketamine treatments rapidly reduce depressive symptoms in major depression. Acute doses of the atypical antipsychotic drug clozapine have also been shown to counteract ketamine-induced psychotic effects. In the interest of understanding whether these drug effects could be modeled with alterations in neuroplasticity, we examined the impact of acutely-administered ketamine and clozapine on in vivo long-term potentiation (LTP) in the rat’s hippocampus-to-prefrontal cortex (H-PFC) pathway. We found that a low dose of ketamine depressed H-PFC LTP, whereas animals that were co-administrated the two drugs displayed LTP that was similar to a saline-treated control. To address which signaling molecules might mediate such effects, we also examined phosphorylation and total protein levels of GSK3β, GluA1, TrkB, ERK, and mTOR in prefrontal and hippocampal sub-regions. Among the statistically significant effects that were detected (a) both ketamine and clozapine increased the phosphorylation of Ser9-GSK3β throughout the prefrontal cortex and of Ser2481-mTOR in the dorsal hippocampus (DH), (b) clozapine increased the phosphorylation of Ser831-GluA1 throughout the prefrontal cortex and of Ser845-GluA1 in the ventral hippocampus, (c) ketamine treatment increased the phosphorylation of Thr202/Tyr204-ERK in the medial PFC (mPFC), and (d) clozapine treatment was associated with decreases in the phosphorylation of Tyr705-TrkB in the DH and of Try816-TrkB in the mPFC. Further analyses involving phosphorylation effect sizes also suggested Ser831-GluA1 in the PFC displayed the highest degree of clozapine-responsivity relative to ketamine. These results provide evidence for how ketamine and clozapine treatments affect neuroplasticity and signaling pathways in the stress-sensitive H-PFC network. They also demonstrate the potential relevance of H-PFC pathway neuroplasticity for modeling ketamine-clozapine interactions in regards to psychosis.
Highlights
The relative failure in developing new therapeutic drugs for psychiatric disorders that act upon single brain targets has encouraged research that examines the full range of variation—from normal to abnormal—in brain circuits implicated in the pathophysiology of these psychiatric disorders [1]
The results from a pair of pilot experiments conducted in our laboratory suggested that (a) pre-treatment with 0.3 mg/kg clozapine did not markedly alter the induction or expression of long-term potentiation (LTP) in the hippocampus-to-PFC pathway (H-PFC) pathway (S1A and S1B Fig), whereas (b) pre-treatment with 10 mg/kg ketamine was associated with a depression of this form of neuroplasticity (S1C and S1D Fig)
We followed up these pilot experiments with one that was designed to address two issues: (1) to confirm whether a low, non-anesthetic dose of ketamine depresses the induction of activity-dependent synaptic plasticity in the H-PFC pathway, and (2) to determine whether a low dose of clozapine might prevent the hypothesized influence of ketamine on the LTP
Summary
The relative failure in developing new therapeutic drugs for psychiatric disorders that act upon single brain targets has encouraged research that examines the full range of variation—from normal to abnormal—in brain circuits implicated in the pathophysiology of these psychiatric disorders [1]. The atypical anti-psychotic drug clozapine (which is often used to treat the psychotic symptoms of treatment-resistant schizophrenic patients [28]) has been shown to reverse ketamineinduced psychotic symptoms in healthy humans [29], and to reduce the ketamine-induced exacerbation of positive symptoms in patients [30] The mechanisms for these effects are not well understood, but evidence from animals studies have shown that clozapine counteracts several ketamine-induced phenomena, including: alterations in medial PFC (mPFC) glutamate metabolism [31] and oxygenation levels [32], deficits in sensory-evoked gamma oscillations [33], disruptions in paired-pulse inhibition [33, 34], and in the release of serotonin in the PFC [35]
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