The dopaminergic system has been the most consistently targeted in schizophrenia. Blockade of dopamine receptors can reliably reduce psychosis in schizophrenia. On the basis of this observation, decades of research have been carried out focused on discovering abnormal dopaminergic function in schizophrenia. Other than a few "false starts" [215-217], the bulk of these studies have been either negative or non-contributory, i.e. demonstrating only a drug effect [34]. Still, because of the power and consistency of the drug treatment model, dopamine has continued to be taken as a pivotal player, although perhaps no longer considered singular in schizophrenia pathophysiology.

Carlsson's original construct gradually evolved to include the entire dopa-mine influenced cortico-striato-thalamo-cortical circuit potentially involved in schizophrenia. Moreover, as striatal pharmacology has become more fully described [218-220] at a systems and a cellular level, the need for a broader conceptualization of the neurotransmitter system involvement in schizophrenia has become apparent. Laruelle et al. [37] have used a clever in vivo ligand displacement technique to estimate synaptic dopamine release in striatum in schizophrenia. They have demonstrated increased dopamine release in response to amphetamine in schizophrenic subjects compared to control volunteers, but only in their florid state [221]. This has focused interest again on dopamine regulation in schizophrenia. Yet, most investigators now assume that regional changes in an entire system of neurotrans-mitters are likely to be involved in schizophrenia.

The recent characterization of a mouse knock-out, one which lacks the presynaptic dopamine transporter protein (DAT knock-out), has provided the field with a genetically altered mouse which is able to model the effects of increased dopaminergic activity and is available as an animal model for aspects of schizophrenia. Because the pharmacology of this model resembles the pharmacology of schizophrenia in several key respects, the link between increased dopamine neurotransmission and schizophrenia is strengthened. Considerable work is focused on additional characterization of this animal preparation.


Because PCP can cause schizophrenia-like symptoms in humans, and its weaker congener ketamine can exacerbate psychotic symptoms in schizophrenia, the idea that schizophrenic psychosis might be due to reduced NMDA-sensitive ionophore activity was proposed and began to be explored. Subsequent studies showing abnormalities in NMDA and non-NMDA glu-tamatergic measures in schizophrenia tissue (see section on Post-Mortem Studies) strengthen this idea. Some current data suggest that regional changes in glutamatergic transmission in hippocampus can alter function in that brain area [71, 72, 222] and by inference can affect the projection areas of hippocampus, implicating regional limbic areas of hippocampus, amygdala, anterior thalamus and ACC in schizophrenia pathophysiology. Several additional kinds of data from post-mortem, in vivo imaging and cognitive evaluation are consistent with the idea of glutamatergic involvement in schizophrenia.

Based on a hypothesis of reduced glutamatergic transmission at some population of NMDA-sensitive receptors being associated with schizophrenia, two animal preparations have been pursued as potential models for aspects of schizophrenia: (a) the PCP, MK801 or ketamine administration paradigm [223-227], and (b) the more elegant NK1 subunit knock-down genetically altered mouse model [228]. Both of these models (one pharmacological and the other genetically engineered) reduce NMDA-mediated glutamatergic transmission. PCP in its lower doses is a non-competitive antagonist of the NMDA receptor. Because of the behavioural actions of PCP and its agonists in humans, this action has been linked with psychosis generation. Moreover, competitive antagonists at the NMDA site are also psychotomimetic. Therefore, the behavioural and biochemical consequences of PCP administration are taken to be putative models of psychosis (reviewed in [42]). These include PPI disruption [229], disruption of memory and immediate early gene activation/suppression patterns [227]. The NK1 subunit knock-down genetically engineered mouse is viable

(whereas the NKi knock-out is not). Because the NK1 subunit is necessary for the related ionophore to gate Ca++ as well as K+, membership of at least one NK1 subunit is essential in the multimeric NMDA receptor for its full function [230]. The knock-down mouse has NK1 expression reduced by over 90%, so it is likely to have NK1-free NMDA receptors and reduced NMDA-mediated transmission. Since the pathology in this genetically engineered mouse parallels in one respect the pathology actually reported in schizophrenia hippocampus [73], this model has solid face validity. This mouse continues to be characterized and its role in testing theories and treatments continues to emerge.

Was this article helpful?

0 0
Beat Depression Now

Beat Depression Now

Let me be up front. My intention is to sell you something. Normally, it's not wise to come out and say that. However, I can do so because I have such an incredible deal for you that you'd be crazy to pass on it.

Get My Free Ebook

Post a comment