MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain

Gao, Xiaohan; Tamminga, Carol A.

doi:10.1007/bf01271549

Cited by 24 publications

(19 citation statements)

References 27 publications

(21 reference statements)

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“…While such an effect seems a plausible mechanism for the previously observed effect of PCP on LI given the involvement of the hippocampus in LI (61), this effect is most likely a compensatory response to NMDA receptor antagonism, and thus would not likely be elicited by DTG. In fact, a similar upregulation of NMDA receptors was seen following 1.0 mg/kg MK-801 (19). This finding suggests that PCP's action as an NMDA receptor antagonist is sufficient to induce NMDA receptor upregulation, and that DTG would be unlikely to elicit such an effect.…”

Section: Discussionsupporting

confidence: 54%

“…Decreases in regional cerebral glucose metabolism seen 24 h after a high dose of PCP are argued to be mediated by PCP's action as an NMDA receptor antagonist, as similar decreases can be produced by low, NMDA-receptor specific doses of PCP (17). Likewise, PCP-induced increases in hippocampal NMDA receptor binding seen 24 h postinjection (18) are mimicked by the selective NMDA receptor antagonist MK-801 (19). However, the sigma receptor antagonist NE-100 was found to reverse the cognitive dysfunction induced by the delayed effects of PCP in a water maze task (44).…”

Section: Latent Inhibitionmentioning

confidence: 98%

See 1 more Smart Citation

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Turgeon¹,

Auerbach²,

Duncan-Smith³

et al. 2000

Pharmacology Biochemistry and Behavior

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. The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm. PHARMACOL BIOCHEM BEHAV 66 (3) 533-539, 2000.-The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. LATENT inhibition (LI) is the impaired acquisition of a conditioned response to a stimulus that has been previously presented without reinforcement (35). LI is thought to be a measure of an organism's capacity to ignore irrelevant stimuli, and has been demonstrated in a variety of species including humans (4,35,36). Disruption of LI has been observed in nonmedicated acute schizophrenics (4) as well as animals and humans treated with the psychotomimetic drug amphetamine (14,22,49,(64)(65)(66)(67). Medicated schizophrenic patients do not demonstrate disrupted LI (4,37). In addition, antipsychotic medications reverse amphetamine-induced disruption of LI in animals (49,68), and can enhance LI on their own (11,15). These observations suggest that the disruption of LI is a useful animal model for this specific attentional deficit seen in schizophrenia (12,15). Phencyclidine (PCP) is a drug that can produce a psychotomimetic effect in humans (3,28,38) as well as a number of behavioral and cognitive changes in animals...

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Section: Discussionsupporting

confidence: 54%

Section: Latent Inhibitionmentioning

confidence: 98%

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Turgeon¹,

Auerbach²,

Duncan-Smith³

et al. 2000

Pharmacology Biochemistry and Behavior

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show abstract

“…The mechanism of PCP-induced psychosis, inferred from animal studies done in this laboratory (27,28), is reduced glutamatergic transmission at the NMDA receptor within the trisynaptic hippocampal glutamatergic pathway (25). These findings suggest the simplistic idea that schizophrenia tissue would evidence the same up-regulation of the NMDA receptor (as a marker of glutamatergic transmission at those hippocampal synapses) as the rat PCP preparation (28). The rat studies of chronic haloperidol administration showed no difference in these parameters with antidopaminergic actions, suggesting that findings for NMDA receptors could be distinguished from the effects of chronic drug treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in neuronal activity and immediate early gene activation/repression in rat brain after PCP occur predominantly in limbic regions, including hippocampus (26,27). Moreover, an increase in N-methyl-Daspartic acid (NMDA)-sensitive glutamate receptor binding occurs exclusively in rat hippocampus 12-24 hours after PCP administration (28,29). The selective PCP agonist MK801 also demonstrates these actions.…”

mentioning

confidence: 90%

Ionotropic Glutamate Receptors and Expression of N-Methyl-d-Aspartate Receptor Subunits in Subregions of Human Hippocampus: Effects of Schizophrenia

Gao

Sakai²,

Roberts³

et al. 2000

AJP

352

193

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Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.

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“…We have previously reported that a single administration of PCP across a dose range in rats produces a dose-sensitive increase in NMDA-sensitive 3H-glutamate binding in hippocampal CAI at 24 hours (Gao and Tamminga, 19941, a n effect which is mimicked by MK801 (Gao and Tamminga, 1995). In this study we looked for the pattern of regional changes in glutamate receptor subtype densities in hippocampus after PCP over 48 hours.…”

Section: Introductionmentioning

confidence: 95%

Phencyclidine produces changes in NMDA and kainate receptor binding in rat hippocampus over a 48-hour time course

Gao

Tamminga

1996

Synapse

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Phencyclidine (PCP) is a psychotomimetic drug associated with acute and delayed mental effects in normal humans and psychosis exacerbation in already psychotic schizophrenic individuals. We have previously described a dose-sensitive, delayed action of PCP on regional cerebral metabolism in the rat which occurs over 48 hours and a late (24 hour) change in N-methyl-d-aspartate (NMDA) and kainate binding in hippocampal areas. Now, we report the complex time course of PCP action on NMDA-sensitive glutamate receptor binding in rat in distinct subregions of the hippocampus extending over 48 hours. Selectively, in the hippocampal CA1 region, a single dose of PCP (8.6 mg/kg) produced an increase in receptor binding at 12 hours (+24%), sustained to 24 hours (+29%) compared with the 3 hour post-PCP value (-15%) and then a return to control levels of receptor binding at 48 hours. Other regions of hippocampus showed distinctive time-dependent changes in NMDA-sensitive glutamate receptor binding as well. In addition, PCP produced a change in kainate receptor binding in the dentate gyrus across the 48-hour time period. In other representative brain regions, PCP did not alter NMDA or kainate binding over the same time course. This extended neurochemical effect of PCP on glutamate receptors in rat hippocampus parallels, in time, certain delayed psychological actions of PCP in humans and thus may be relevant to psychosis, especially to PCP-induced psychosis.

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MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain

Cited by 24 publications

References 27 publications

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Ionotropic Glutamate Receptors and Expression of N-Methyl-d-Aspartate Receptor Subunits in Subregions of Human Hippocampus: Effects of Schizophrenia

Phencyclidine produces changes in NMDA and kainate receptor binding in rat hippocampus over a 48-hour time course

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