Currently prescribed
antipsychotics attenuate the positive symptoms of
schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the
NMDA receptor antagonist
MK-801 on
sucrose preference. We sought to validate the model by examining the effects of
clozapine and D-
serine, for which there are positive clinical data regarding their effects on negative symptoms, and
haloperidol which is clinically ineffective. We extended our analysis by examining
CDPPB, an mGlu5 receptor positive allosteric modulator. Acute
MK-801 produced effects indicative of a shift in the hedonic experience of
sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in
sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%)
sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on
quinine intake. Sub-chronic
clozapine and acute d-
serine attenuated the
MK-801-induced deficit in 1.2%
sucrose consumption, whereas sub-chronic
haloperidol (0.02 mg/kg) did not. Finally, acute treatment with
CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance
NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.