NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine

Abstract

The present study was performed to assess the role of excitatory amino acid and dopamine receptors on associative functions of the prefrontal cortex (PFC) of the rat. Spatial delayed alternation was used as a PFC-sensitive cognitive task. In addition, in vivo microdialysis was used to assess the release of dopamine in the PFC. The noncompetitive NMDA antagonists ketamine (10-30 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) dose-dependently impaired the spatial delayed alternation performance compared with the saline-treated control group. Administration of the dopamine antagonists raclopride (0.1 and 0.5 mg/kg), SCH-23390 (0.1 mg/kg), or haloperidol (0.1 mg/kg) was without a significant effect. However, haloperidol and raclopride (but not SCH-23390) reversed the disruptive effect of 30 mg/kg ketamine on spatial delayed alternation performance. Microdialysis studies revealed that this dose of ketamine preferentially increased the release of dopamine in the PFC compared with the striatum. These findings indicate that attenuation of glutamatergic neurotransmission at the NMDA receptor impairs PFC-dependent cognitive functions. Furthermore, activation of dopamine neurotransmission contributes, at least in part, to this impairment.

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

“…d Allen and Young (1978). e Cosgrove and Newell (1991 Deutch et al 1987;Verma and Moghaddam 1996; Jentsch et al 1997a); whereas, longterm PCP administration reduces frontal dopamine transmission (Jentsch et al 1997b,c; see below). Because hypofrontality and some cognitive deficits of schizophrenia have been associated with reduced dopamine transmission within the prefrontal cortex (Weinberger et al 1988; Daniel et al 1989Daniel et al , 1991Dolan et al 1995; reviewed in Davis et al 1991;Knable and Weinberger 1997), these findings suggest that long-term administration of NMDA receptor antagonists produces effects that are most consistent with schizophrenia.…”

“…As noted above, acute administration of noncompetitive NMDA receptor antagonists is associated with a dramatic activation of dopamine transmission in forebrain (Doherty et al 1980; Bowers and Hoffman 1984;Deutch et al 1987;Verma and Moghaddam 1996; Jentsch et al 1997a), and this effect is likely directly implicated in the cognitive dysfunction exhibited by subjects acutely treated with PCP or ketamine (Verma and Moghaddam 1996), because increased dopamine transmission in prefrontal cortex has been reported to impair spatial working memory (Murphy et al 1996a; Jentsch et al 1997d). In rodents, an acute dose of PCP seems to augment prefrontal cortical and ventral striatal dopamine transmission; whereas, the dopaminergic innervation of the dorsal striatum is relatively unaffected (Deutch et al 1987; Jentsch et al 1997a).…”

“…Administration of PCP, ketamine, or MK-801 (another noncompetitive NMDA receptor antagonist) to rats has been shown to impair performance on tasks that seem to depend upon hippocampal or amygdalar function; for example passive avoidance, acquisition of the Morris water maze task, or a conditional discrimination or performance of a spatial continuousrecognition memory task (Heale and Harley 1990; Jones et al 1990;Kesner and Davis 1993;Murray and Ridley 1997). In addition, although delayed alternation deficits have been reported after ketamine and MK-801, suggesting spatial working memory dysfunction (Verma and Moghaddam 1996), spontaneous (no-delay) alternation is likewise affected (Fraser et al 1997), complicating this interpretation. Furthermore, administration of noncompetitive NMDA receptor antagonists has been shown to impair even simple behavioral measures, such as acquisition of a conditioned emotional response (Hoehn-Saric et al 1991), of a flavor aversion (Aguado et al 1994), of an operant response (Pallares et al 1995), of a brightness discrimination (Tang and Franklin 1983;Tang and Ho 1988), or of a conditioned cue preference (Stevens et al 1997).…”

“…This concept is not, however, supported by a recent study by Moghaddam and Adams (1998) in which systemic administration of a group II metabotropic glutamate receptor agonist was shown to prevent the PCP-induced augmentation in cortical glutamate release without blocking the increase in cortical dopamine efflux. Moreover, taken together with the result that dopamine receptor antagonism alone ameliorates PCPinduced cognitive dysfunction (Verma and Moghaddam 1996), it appears that cortical glutamate release after NMDA antagonist administration may not be necessary or sufficient to produce altered prefrontal cortical dopamine efflux and associated cognitive deficits.Further evidence for PCP effects on NMDA and non-NMDA glutamatergic systems comes from the elegant studies of Tamminga and colleagues This group has shown that acute administration of PCP results in biphasic changes in brain glucose metabolism and glutamate receptor density. Studies of the uptake of 2-deoxyglucose in the brains of PCP-treated rats have NEUROPSYCHOPHARMACOLOGY 1999-VOL.…”

Regulation of Working Memory by Dopamine D4 Receptor in Rats

“…Acute challenge with various D 2 -like receptor antagonists has been reported to impair working memory and delayspecific PFC neuronal activity in some studies (Arnsten and Goldman-Rakic, 1998;Didriksen, 1995;Murphy et al, 1996), but not others (Aultman and Moghaddam, 2001;Bushnell and Levin, 1993;Sawaguchi and Goldman-Rakic, 1994;Verma and Moghaddam, 1996;Williams and GoldmanRakic, 1995). Working memory deficits induced by the noncompetitive NMDA antagonist ketamine (Verma and Moghaddam, 1996), the benzodiazepine inverse agonist FG-7142, or physiological stress (Arnsten and Goldman-Rakic, 1998) (Van Tol et al, 1991). In mammalian species, D 4 receptor is detected mainly in the corticolimbic areas, with particularly high levels in PFC (Oaks et al, 2000;Tarazi and Baldessarini, 1999).…”