Ketamine induces dopamine-dependent depression of evoked hippocampal activity in the nucleus accumbens in freely moving rats

Abstract

Noncompetitive NMDA receptor antagonists, such as ketamine, induce a transient schizophrenia-like state in healthy individuals and exacerbate psychosis in schizophrenic patients. In rodents, noncompetitive NMDA receptor antagonists induce a behavioral syndrome that represents an experimentally valid model of schizophrenia. Current experimental evidence has implicated the nucleus accumbens in the pathophysiology of schizophrenia and the psychomimetic actions of ketamine. In this study, we have demonstrated that acute systemic administration of ketamine, at a dose known to produce hyperlocomotion and stereotypy, depressed the amplitude of the monosynaptic component of fimbria-evoked field potentials recorded in the nucleus accumbens. A similar effect was observed using the more selective antagonist dizocilpine maleate, indicating the depression was NMDA receptor dependent. Paired-pulse facilitation was enhanced concomitantly with, and in proportion to, ketamine-induced depressed synaptic efficacy, indicative of a presynaptic mechanism of action. Notably, the depression of field potentials recorded in the nucleus accumbens was markedly reduced after a focal 6-hydroxydopamine lesioning procedure in the nucleus accumbens. More specifically, pretreatment with the D2/D4 antagonist haloperidol, but not the D1 antagonist SCH23390 blocked ketamine-induced depression of nucleus accumbens responses. Our findings provide supporting evidence for the contemporary theory of schizophrenia as aberrant excitatory neurotransmission at the level of the nucleus accumbens.

Figure 1.

Placement of electrodes. A, Stimulating electrodes were placed in the fimbria. B, Recording electrodes were located in the medial shell (NAcSh) or shell/core (NAcC) border of the NAc. C, Example of a fimbria-evoked field potential recorded in the NAc with positive peak latencies at 10 and 21 msec.

Figure 2.

Effect of ketamine on fimbria-evoked field potentials recorded in the NAc. A, Ketamine (25 mg/kg; n = 7) or saline (n = 6) was injected 40 min after baseline responses (indicated by the arrow). Depression of the p10 amplitude of field potentials recorded in the NAc was detected after injection of ketamine but not saline. Injection of saline did not modify the p10 amplitude offield potentials. B, Comparison of complete input-output curves of the p10 amplitude obtained at baseline (BL) and 30, 60, and 90 min after injection of ketamine (n = 10). Representative examples of field potentials recorded in the NAc are shown in C. Values are expressed as mean ± SEM. ^*p < 0.05 and ^**p < 0.01 indicate a significant difference with respect to baseline, and ^##p < 0.01 indicates a significant difference 60 min after injection of ketamine with respect to baseline.

Figure 3.

A, Time course of MK-801-induced depression of the p10 component of fimbria-evoked field potentials recorded in the NAc (n = 6). B, Complete input-output curves were obtained for five of these rats at baseline (BL) and 90 min after injection of MK-801. ^**p < 0.01 indicates a significant difference from baseline. Values are expressed as mean ± SEM.

Figure 4.

Effect of ketamine on PPF. A, Ketamine significantly increased PPF of the p10 component at 30 and 60 min after injection (n = 9). B, Enhancement of PPF correlated with ketamine-induced depression at the highest stimulation intensity (800 μA). Representative PPF at baseline (BL) and 60 min after injection of ketamine are shown in C. ^*p < 0.05 and ^**p < 0.01 indicate a significant difference with respect to baseline. Values are expressed as the mean ± SEM percentage change with respect to baseline.

Figure 5.

DA mediates ketamine-induced depression of the p10 component of fimbria-evoked field potentials recorded in the NAc. A, Field potentials from 6-OHDA-treated rats (n = 7) were not significantly modified after injection of ketamine. A reduction in the amplitude of field potentials from sham-treated rats (n = 6) occurred after injection of ketamine. B, Pretreatment with haloperidol (n = 4) but not SCH23390 (n = 5) blocked ketamine-induced depression of field potentials. C, A time course of the effect of ketamine on the p10 component in rats pretreated with SCH23390. For comparison, the time course of ketamine alone is shown (adapted from Fig. 2 A). ^*p < 0.05 and ^**p < 0.01 indicate a significant difference from baseline (BL). Values represent mean ± SEM activity.