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, 17 (8), 2921-7

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway From NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated With the Prefrontal Cortex

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Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway From NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated With the Prefrontal Cortex

B Moghaddam et al. J Neurosci.

Abstract

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.

Figures

Fig. 1.
Fig. 1.
Effect of intraperitoneal injections of subanesthetic doses of ketamine on the extracellular levels of glutamate in the prefrontal cortex. All doses tested increased these levels significantly compared with the saline injected groups.Asterisks (*) denote significant differences from saline-treated groups as determined by Kruskal–Wallis ANOVA (n = 6 for 30 mg/kg; n = 7 for 20 mg/kg; n = 7 for 10 mg/kg groups).
Fig. 2.
Fig. 2.
Effect of intraperitoneal injections of anesthetic doses of ketamine on the extracellular levels of glutamate in the prefrontal cortex. Asterisks (*) denote significant differences as compared with saline-treated group (n = 6 for 50 mg/kg;n = 5 for 200 mg/kg).
Fig. 3.
Fig. 3.
Effect of intraperitoneal injections of 30 mg/kg ketamine on the extracellular levels of dopamine in the prefrontal cortex in the presence or absence of local infusion of CNQX. Ketamine increased dopamine release significantly compared with saline-injected groups as determined by two-way repeated- measures ANOVA (p < 0.001, n = 9 for ketamine-treated group; n = 5 for saline-treated group). Infusion of CNQX (50 μm) started 1 hr before ketamine injection (n = 6). After this treatment, injection of ketamine only produced a trend toward an increase (p = 0.07). Furthermore, the effect of ketamine in CNQX-treated animals was significantly lower than CNQX-untreated animals (p < 0.05).
Fig. 4.
Fig. 4.
Effect of intraperitoneal injections of 30 mg/kg ketamine on the extracellular levels of dopamine (n = 7) and glutamate (n = 5) in the striatum. This treatment caused a trend toward an increase in extracellular levels of glutamate; however, because of high variability, there was no statistically significant effect. The striatal extracellular levels of dopamine did increase after the injection of 30 mg/kg ketamine (p < 0.01); however, this increase was significantly smaller than that observed in the prefrontal cortex (demonstrated on Fig. 3, p < 0.005).
Fig. 5.
Fig. 5.
Effect of ketamine (30 mg/kg) and LY293558 (0.1 and 1.0 mg/kg) on spatial delayed alternation performance in rats. Each animal received 10 trials per day, and the mean ± SEM percentage of correct responses per session is presented. The trials were performed with a delay of 10 sec. The values inparentheses represent the doses in mg/kg. Saline(veh) and LY293558 (LY) were injected 15–20 min before ketamine (ket) in groups designated as veh/ket and LY/ket, respectively. Pretreatment with LY293558 produced a significant reversal of ketamine-induced decrease in percentage of correct choice in saline-treated rats (*p < 0.01, as compared with the veh group, + p < 0.01 as compared with the veh/ket group).
Fig. 6.
Fig. 6.
Effect of intraperitoneal pretreatment with saline or LY293558 (1.0 mg/kg) on ketamine (30 mg/kg)-induced increase in dopamine release in the prefrontal cortex. Treatment groups paralleled the behavioral studies depicted on Figure 5. Injections were 20 min apart. Significant increases in dopamine release were observed in both LY293558+ketamine and saline+ketamine group (n = 7,p < 0.01; n = 8, p < 0.01, respectively). However, the increase after LY293558+ketamine was significantly smaller than that observed after saline+ketamine (p < 0.05, as determined by two-way repeated-measures ANOVA).

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