Schizophrenia: from dopaminergic to glutamatergic interventions
Introduction
Schizophrenia is a chronic and severe mental illness with a prevalence of 0.5–1% of the population. Quoting Insel [1] ‘Schizophrenia is a syndrome: a collection of signs and symptoms of unknown aetiology, predominantly defined by observed signs of psychosis. In its most common form, schizophrenia presents with paranoid delusions and auditory hallucinations late in adolescence or in early adulthood. These manifestations of the disorder have changed little over the past century’. In addition, to these ‘positive’ symptoms schizophrenics also exhibit ‘negative’ and ‘cognitive’ symptoms [1]. Negative symptoms include: flattening, speech poverty, apathy, lack of pleasure and withdrawal, whilst cognitive deficits include attention, executive functioning, memory and speed of processing. Some of the symptoms of schizophrenia have been modeled in man using specific pharmacological agents [2, 3]. The rationale for the choice of these agents has relied on current hypotheses of the aetiology of schizophrenia, as described below. However, data have suggested that schizophrenia is a neurodevelopmental disorder that involves alterations in brain circuits. Psychotic symptoms nearly always emerge during adolescence or early adulthood (i.e. between 18 and 25 years of age). However, this does not mean that earlier in life schizophrenics perform well [4, 5, 6]. These longitudinal population studies suggest delayed maturation, especially in the first year of life and that IQ is reduced early and persistently in children that will develop schizophrenia. If indeed schizophrenia is a developmental disease, it may not be possible to develop truly relevant models of schizophrenia in either animals or man. However, Thompson and Levitt [7] have suggested that a lesion early in development may not manifest itself until later in development when compensatory mechanisms may not apply (developmental allostasis). Puberty or its consequences seem to be the defining moment. If true, then circuit and neurotransmitter dysfunctions seen in full blown schizophrenia may be the consequences of the initial lesion.
While this aetiology of schizophrenia remains unclear, there is substantial evidence that suggests that there are changes in several neurotransmitter systems in the pathophysiological processes leading to the formation of schizophrenia. Initially, dopamine (DA) and two of its specific receptors in different brain areas received most attention. Subsequently, glutamate (GLU) and one of its receptors (N-methyl aspartate NMDA) have entered the scene [8, 9]. Other systems have also been suspected. These include the GABAergic, opioid, cholinergic or serotonergic systems.
It has been proposed that positive symptoms observed in schizophrenics are due to a hyperactivity of DA transmission [10]. Evidence for the DA hypothesis has come mainly from two sources: the finding of a correlation between clinical doses of antipsychotic drugs and their efficacy to block DA D2 receptors [8, 10] and the fact that DA enhancing molecules are psychotogenic (for review see [2, 9]). The classical DA hypothesis has become associated with subcortical regions of the brain such as the striatum and the nucleus accumbens, based on the high concentration of DA terminals and D2 receptors in these structures.
Resistance to D2 antagonists by negative and cognitive symptoms of schizophrenia has led to reformiting the DA hypothesis. The use of functional brain imaging has suggested that the prefrontal cortex (PFC) might be responsible for these symptoms (for reviews see [3]). Preclinical studies have shown the importance of prefrontal DA transmission at D1 receptors (the principle DA receptor in the neocortex) (for review see [11]). This has created a hypothesis that a deficit in DA transmission at D1 receptors in the PFC might be involved in the cognitive impairments and negative symptoms of schizophrenia [12, 13].
Much evidence supports the idea that schizophrenia might also be associated with a persistent defect in GLU transmission involving NMDA receptors (for reviews see [14, 15, 16, 17, 18]). Convergence of both preclinical and clinical data [14, 19, 20] suggest that dysfunction of DA systems in schizophrenia may be following to a deficit in NMDA receptor function. In addition, it is now understood that DA has a modulatory role on GLU performance. Thus, changes in DA function might in turn affect NMDA activity.
In this paper, we briefly review recent imaging evidence on the role in schizophrenia of DA dysfunction and that suggesting this dysfunction is secondary to NMDA dysfunction.
Section snippets
Striatal DA function in schizophrenia
Molecular imaging studies have proved to be a powerful tool in increasing our understanding of the structures and mechanisms involved in schizophrenia.
Several methodologies have been used to show that during psychotic episodes there is an increased D2 receptor activation [21, 22, 23, 24, 25, 26, 27, 28]. For example, increased rates of [18F]DOPA accumulation have been observed in schizophrenics indicating higher DA synthesis. A higher [18F]DOPA uptake was also seen in subjects with ‘prodromal’
A neuronal circuitry model of GLU–DA interactions
A model described by Carlsson et al. [29, 52] hypothesises that GLU can affect DA activity in the substantia nigra (SN) and ventral tegmental area (VTA). A deficiency of NMDA transmission leading to diminished prefrontal activity in schizophrenics might cause a lowering of mesocortical DA transmission making worse cognitive function. If maintained, this lesion of mesolimbic DA transmission is hypothesised to trigger positive symptoms.
Imaging studies of GLU–DA interactions
When NMDA antagonists are administered acutely there has been
DA–GLU interaction in the striatum
Stimulation of either D1 or D2 receptors in the striatum has divergent activity on NMDA transmission. From an anatomical point of view, GLU afferents from the cortex and DA projections coincide in the striatum on GABAergic medium spiny neurons. Here DA has strong consequences on GLU transmission (for reviews, see [55, 56, 57, 58, 59, 60]). It has been noted that D2 receptor excitement reduces NMDA-mediated GLU, and D1 receptor activation aids GLU transmission [61, 62].
Imaging data (see above)
Conclusions
Schizophrenia can be considered a neurodevelopmental disease that manifests itself in adolescence or young adulthood through a first psychotic episode. However, there are other domains of schizophrenia, such as cognitive impairment, that might be present prodromal.
Imaging data support the concept that there is an association between schizophrenia and an endophenotype consisting of a DA function deficit in the cortex together with an excess of DA activity in the AST. Imaging and animal data
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