Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol |
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Authors: | I Gaisler-Salomon I Weiner |
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Institution: | (1) Department of Psychology, Tel Aviv University, Tel Aviv, Israel, |
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Abstract: | Abstract
Rationale. Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure,
and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission,
which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been
reported to spare LI.
Objectives. To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent
LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic
clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models.
Methods. LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking
in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by
two (experiment 1) or five (experiments 2–5) tone – foot shock pairings.
Results. MK-801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05 mg/kg
dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning
trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued
to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI
perseveration was unaffected by both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was
reversed by clozapine but not by haloperidol administered in pre-exposure.
Conclusion. MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly
relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model
impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action
of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based
LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking
LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action
of the pro-psychotic drug.
Electronic Publication |
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Keywords: | Latent inhibition MK-801 Clozapine Haloperidol Perseveration Schizophrenia |
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