Abstract | Schizophrenia is a severe psychiatric disorder with no clear cause. Recent
evidence suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction may
underlie the pathogenesis of schizophrenia. The posterior cingulate cortex (PCC) has
been shown to be the most susceptible brain region to damage caused by NMDA
hypofunction in rodents. This suggests that the PCC may play an important role in
schizophrenia pathology. However, studies examining neurotransmitter balance in the
PCC in schizophrenia have until now been neglected. Furthermore, the long-term
consequences of NMDA hypofunction on neurotransmitter balance in animal models
have not been studied. The aims of this study were to investigate neurotransmitter
receptor binding profiles in the PCC in schizophrenia, while also examining the effects
of chronic phencyclidine (PCP; an NMDA antagonist) treatment on neurotransmitter
receptor binding in mouse brain in the long-term following treatment. To achieve these
aims, the study was divided into two parts.
In experimental part A, PCC sections from 10 schizophrenia and 11 control
subjects matched for age, gender and post-mortem interval were obtained from the
Tissue Resource Center, Sydney. Using quantitative autoradiography, the density of
several neurotransmitter receptors was examined. The results demonstrated specific
alterations in neurotransmitter receptors in the PCC in schizophrenia. Specifically,
increased NMDA, gamma-aminobutyric acid A (GABAA) and cannabinoid 1 (CB1)
receptor density was found in this region, along with reduced muscarinic 1/4 (M1/4) and
serotonin 2A (5-hydroxy-tryptamine, 5HT2A) receptor density. No changes were found
in á-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate or M2/4
receptor density in the PCC in schizophrenia subjects compared to controls. These
Kelly Newell Page 9 2007
results have shown for the first time that there are specific neurotransmitter imbalances
in this region, and it is possible that these changes stem from NMDA hypofunction.
In experimental part B, mice were treated chronically (14 days) with PCP. Using
quantitative autoradiography the density of several receptors was examined in the short
(1hr and 24hr) and long-term (14 days) following chronic PCP treatment. In addition,
clozapine and haloperidol were tested for their ability to prevent the PCP-induced
alterations in neurotransmitter receptor density. The results showed opposing effects of
PCP treatment on neurotransmitter receptor density in the short compared to the longterm.
While there were limited increases in NMDA receptor density in the short-term,
there were widespread reductions in NMDA receptor density in the long-term following
chronic PCP treatment. Muscarinic M1/4 receptor binding, which was increased in the
short-term, showed reductions in the long-term in the limbic system, caudate-putamen
and cortex, but not in the thalamus in which no change was found. Clozapine and
haloperidol treatments were both unable to prevent the PCP-induced long-term changes
in receptor density.
In conclusion, this study has provided new information regarding
neurotransmitter alterations in the PCC in schizophrenia and in mouse brain in the longterm
following chronic PCP treatment. These findings may assist not only in
understanding the pathology of schizophrenia, but also for designing new
pharmacological treatments for this disease.
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