Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Abstract

We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the caudal entorhinal cortex. Induction of c-fos mRNA is delayed and it is inhibited by antipsychotic drugs. Cultured entorhinal neurons are killed by high doses of MK-801 and PCP but c-fos expression is not induced in these neurons indicating that this in vitro model does not fully replicate the in vivo effects of PCP-like drugs in the entorhinal cortex. Excitatory effects of the NMDA receptor antagonists may be connected with the psychotropic side effects of these drugs and might become a useful modelNMDA receptor antagonists, such as phencyclidine, ketamine, and MK-801 (dizocilpine) produce in humans psychotogenic side effects which clinically closely resemble schizophrenia and are characterized by distorted body image, hallucinations, vivid dreams, and delirium (Johnson and Jones 1990;Javitt and Zukin 1991). Ketamine also frequently induces psychotic "emergence reactions" in adults (Krystal et al. 1994). Because of these parallels between the psychotomimetic state produced by the NMDA receptor antagonists and schizophrenia, PCP-induced psychosis has widely been used as an experimental model of schizophrenia (Javitt and Zukin 1991).In a series of pioneering studies, Olney and coworkers demonstrated that NMDA receptor antagonists produce reversible neurotoxic effects in neurons in the posterior cingulate and retrosplenial cortices (RSC) of rat brain (Olney et al. 1989(Olney et al. , 1991 Farber 1995a, 1995b). These effects are characterized by reversible intracellular vacuolization (Olney et al. 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al. 1993;Näkki et al. 1996), heat shock protein 70 (HSP70) (Sharp et al. 1991(Sharp et al. , 1994Näkki et al. 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al. 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas. These excitatory actions may be connected with the psychotomimetic side effects produced by PCP-like drugs Farber 1995a, 1995b). We have previously observed that MK-801 increases mRNA for BDNF not only in the retrosplenial cortex but also in the entorhinal cortex (EC) . EC is the input and output station of the information going to and coming from the hippocampus (Jones 1993;Amaral and Witter 1995). It is thought that the EC-hippocampus loop is very important in the processing of sensory information and defects in its normal function might produce cognitive disturbances (Jones 1993). Therefore, neurons i...

Effects of NMDA-Receptor Antagonist Treatment on c-fos Expression in Rat Brain Areas Implicated in Schizophrenia

“…In the entorhinal cortex, c-fos mRNA expression was strongly induced specifically in layer III (Fig. 2(B)), which is consistent with previous observations (Väisänen et al, 1999). In other temporal areas, hippocampus showed a more moderate increase in the c-fos mRNA expression levels ( Fig.…”

“…Both ketamine and MK-801 have been shown to increase dopamine release in the prefrontal cortex (Kashiwa et al, 1995;Schmidt and Fadayel, 1996;Verma and Moghaddam, 1996). We have previously shown that MK-801 and ketamine produce similar c-fos mRNA responses in cortex, although ketamine needs to be administered repeatedly due to its very short plasma half-life (Väisänen et al, 1999). On the other hand, ketamine does not produce increased motor activity which is observed after MK-801 injection and which hampers sample collection in microdialysis.…”

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…In summary, it appears that dopamine D2 antagonism in the mPFC may be pathway specific, affecting only a reduced number of pyramidal cells (Wang and Goldman-Rakic, 2004). In line with our results, both clozapine and haloperidol inhibit MK-801-induced induction of cortical c-fos mRNA (Väisänen et al, 1999), which further suggests that this effect may result from blockade of glutamate efflux. When administered alone, neither clozapine nor haloperidol, given systemically, altered the concentrations of 5-HT and glutamate, which is consistent with previous results (Daly and Moghaddam, 1993;Yamamoto et al, 1994;Cartmell et al, 2001;Heidbreder et al, 2001).…”

“…This was previously shown for PCP (Adams and Moghadam, 2001). The kinetics of MK-801-induced changes in glutamate strongly paralleled those of induction of cortical c-fos mRNA, which also peaked at 3-4 h after the administration of MK-801 (Väisänen et al, 1999). This coincidence suggests that induction of c-fos mRNA synthesis would likely result from increased cortical glutamate efflux.…”

Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia†

“…However, a reduction of the NMDAR-dependent excitatory drive onto a normally active inhibitory input to projection neurons could result in a disinhibition. Recently, evidence for induction of gene transcription factors in the hippocampal, entorhinal, olfactory bulb, and cingulate cortical regions of the limbic system as well as the parietal cortex and thalamus in response to noncompetitive NMDA antagonists was shown, that is consistent with dis-inhibition in these regions (Vaisanen et al, 1999;Storvik et al, 2000;.…”