Glutamate and dopamine in schizophrenia: An update for the 21^st century

Abstract

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

“…Current antipsychotics lack selective discrimination of dopamine D2 and D3 receptors, however recent positron emission tomography studies (Howes et al, 2015) show these have a differential brain distribution. The D3 receptor is abundant in the ventral striatal mesolimbic system and frontal cortex but (unlike the D2 receptor) low in the dorsal striatum, which may account for the paucity of effect of D3 antagonists on locomotor activity in rodents and provides potential for few extrapyramidal symptom in clinical use in man (see reviews; (Heidbreder and Newman, 2010; Millan and Brocco, 2008).…”

“…Second generation atypical antipsychotics were developed in an attempt to improve therapy but still have limited effect on cognitive deficits or negative symptoms and many cause weight gain and metabolic abnormalities (Miyamoto et al, 2012). Thus new therapeutic agents operating through different pharmacological mechanisms are essential for more effective management of schizophrenia.One potential mechanism, preferential targeting of the dopamine D3 receptor over the dopamine D2 receptor, might provide effective relief of positive and negative symptoms combined with improved cognitive function (Gyertyán et al, 2008; Laszy et al, 2005; Millan and Brocco, 2008; Millan et al, 2008).Current antipsychotics lack selective discrimination of dopamine D2 and D3 receptors, however recent positron emission tomography studies (Howes et al, 2015) show these have a differential brain distribution. The D3 receptor is abundant in the ventral striatal mesolimbic system and frontal cortex but (unlike the D2 receptor) low in the dorsal striatum, which may account for the paucity of effect of D3 antagonists on locomotor activity in rodents and provides potential for few extrapyramidal symptom in clinical use in man (see reviews; (Heidbreder and Newman, 2010; Millan and Brocco, 2008).…”

The quest for biomarkers in Schizophrenia: from neuroimaging to machine learning

“…Two of the most influential hypotheses concerning the underlying neurobiology of the disorder involve dopamine and glutamate [11]. The first evidence supporting these hypotheses goes back to the 1970s originating from in vitro studies on dopamine receptors and antipsychotics.…”

“…In the last decade, considerable research efforts revealed a vast array of chemical [11] functional [12] and structural brain abnormalities [13] that may constitute the 'organic surrogate' of the illness [14]. The field of neuroimaging leveraged unprecedented insight into brain biology, showing promising progress towards the identification of putative biomarkers, which could be used for early diagnosis, treatment planning, and monitoring of disease progression.…”

Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls

“…6,7 The dopamine hypothesis, based on evidence from pharmacological and in vivo imaging studies, is considered the final common pathway for psychotic symptoms in schizophrenia. 8 The enzyme catechol-O-methyltransferase (COMT) metabolizes several catecholamines, but is especially relevant to dopaminergic transmission in the prefrontal cortex (PFC), in which it is a key element to dopamine availability. 9 COMT is encoded by a single gene (also COMT) located on chromosome 22q11.2, a region that is commonly missing in 22q11.2 microdeletion syndrome, which has long been associated with predisposition for schizophrenia.…”