The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl- d-aspartate and D 1 receptor binding in rats

Abstract

Glutamate and dopamine disturbances are implicated in frontal cortical dysfunction in schizophrenia. Little, however, is known about the nature of dopamine D 1 and N-methyl- d-aspartate (NMDA) receptor interactions in the illness, nor of the extent of their co-involvement in antipsychotic drug response. It is well known that early life adversity may pre-date the development of schizophrenia. Using a neurodevelopmental model of schizophrenia, namely post weaning social isolation rearing (SIR), we studied the effect of SIR (post natal day 21–61) on frontal cortical NMDA and D 1 receptor binding characteristics with/without chronic haloperidol (0.1 mg/kg/day i.p.) or clozapine (5 mg/kg/day i.p.) treatment, undertaken from post-natal day 50–60. SIR increased frontal cortical NMDA-density, with decreased affinity (decreased pK D), but reduced D 1 receptor density (without effects on pK D). In socially reared animals, clozapine but not haloperidol increased NMDA receptor density without effects on pK D. Neither drug markedly affected D 1 receptor density, although clozapine increased D 1 affinity. Increased NMDA density in SIR animals was unaffected by haloperidol, but further increased by clozapine. However, SIR-associated decrease in NMDA affinity remained unaltered despite drug treatment. Reduced D 1 receptor density in SIR animals was exacerbated by haloperidol, but unaltered by clozapine, without changes in pK D. SIR thus induces opposing effects on frontal cortical NMDA and D 1 radio-receptor binding characteristics, which has direct bearing on the mutual interplay of these receptors in schizophrenia. The ability of SIR to affect NMDA receptor affinity warrants deeper study. Furthermore, at the doses examined, in contrast to haloperidol, clozapine bolsters frontal cortical glutamatergic but stabilizes D 1 dopaminergic pathways in a neurodevelopmental animal model of schizophrenia, possibly explaining the atypical clinical characteristics of this drug.