Dopamine, fronto-striato-thalamic circuits and risk for psychosis
Introduction
Psychotic disorders such as schizophrenia are thought to arise from the dysfunction of distributed neural systems (Andreasen et al., 1998, Bullmore et al., 1997, Fornito et al., 2012, Friston, 1998, Stephan et al., 2009). In particular, pathology within a series of parallel, integrated circuits that link distinct regions of the frontal cortex with specific striatal and thalamic nuclei – the so-called fronto-striato-thalamic loops – are often implicated in pathophysiological models (Pantelis et al., 1992, Robbins, 1990) because their activity is heavily modulated by dopamine – the primary target of all currently available, therapeutically effective antipsychotic agents.
In this review, we consider recent work suggesting that dysfunction of one specific circuit, linking the dorsolateral prefrontal cortex (DLPFC), dorsal (associative) striatum, and mediodorsal nucleus of the thalamus, plays a particularly prominent role in the onset of psychotic systems. We consider the possible circuit-level abnormalities that may explain this dysfunction, and examine the role of altered signaling in systems that regulate dopamine, glutamate and gamma-amino-butyric-acid (GABA).
The discovery of the first antipsychotic drug Chlorpromazine and its application in psychiatry in 1952 heralded a promising new era in the treatment of psychosis (Lopez-Munoz et al., 2005). The drug's mechanism of action was later uncovered by Carlsson & Linqvist who showed that chlorpromazine and haloperidol block monoamine receptors in the mouse brain (Carlsson and Lindqvist, 1963). This discovery was followed by observations that the dopamine agonist amphetamine induces psychotic symptoms in otherwise healthy individuals and rekindles psychotic symptoms in schizophrenia patients (Angrist and Gershon, 1970, Janowsky and Risch, 1979). These findings suggested that excess dopamine transmission plays an important role in the pathogenesis of psychosis, and led to the dopamine hypothesis of schizophrenia (Carlsson et al., 1972, Meltzer and Stahl, 1976, Snyder, 1976). The striatum, which comprises the caudate nucleus and putamen and which represents the major input structure to the basal ganglia, was thought to be a key site for this dopaminergic dysregulation due to the high density of dopamine afferents to this region. Accordingly, a tight correlation was found between the therapeutically effective doses of different antipsychotic agents and their occupancy of striatal dopamine receptors (Creese et al., 1976, Seeman and Lee, 1975), with one caveat being that the larger doses required for some of the drugs were often sufficient to induce extrapyramidal side effects.
The dopamine hypothesis has continued to evolve since its inception (Davis et al., 1991, Howes and Kapur, 2009, Kapur and Mamo, 2003). According to one prominent variant, psychotic symptoms arise from increased dopamine transmission, or hyperdopaminergia, in the mesolimbic pathway, which primarily involves the ventral striatum and other limbic structures. The negative symptoms and cognitive impairments that often characterize schizophrenia are attributed to reduced dopamine signaling, or hypodopaminergia, in the mesocortical dopamine system, which involves dorsolateral prefrontal cortex (DLPFC) and other cortical and extrastriatal subcortical areas (Davis et al., 1991, Slifstein et al., 2015, Weinberger, 1987, Weinstein et al., 2016).
Evidence supporting a role for mesolimbic hyperdopaminergia in psychosis has come from in vivo microdialysis studies in freely-moving rats showing a preferential increase of extracellular dopamine in the ventral striatum following administration of dopamine agonists (Carboni et al., 1989, Robinson et al., 1988). Both post-mortem and in vivo positron emission tomography (PET) studies have reported evidence of increased density of dopamine receptors, particularly D2 receptors, in the striatum of treatment-naive and medicated schizophrenia patients (Howes et al., 2012, Lee and Seeman, 1980, Owen et al., 1978, Wong et al., 1986), although these increases may be partly driven by antipsychotic medication (for a discussion see (Howes et al., 2015)).
Evidence supporting a role for mesocortical hypodopaminergia in negative symptoms and cognitive deficits has come from studies showing that schizophrenia patients perform poorly on cognitive tasks subserved by the DLPFC, and which are thought to depend on D1 receptor signaling (Barch and Ceaser, 2012, Goldman-Rakic, 1995, Sawaguchi and Goldman-Rakic, 1994). Patients with established schizophrenia often show reduced prefrontal glucose metabolism and task-related activation, and administration of dopamine agonists can reverse this effect (Daniel et al., 1989, Daniel et al., 1991). PET studies of D1 receptor availability in prefrontal cortex have been inconsistent, with some reporting reduced receptor density while others have found increased density (Abi-Dargham, 2003, Abi-Dargham et al., 2002, Okubo et al., 1997). This inconsistency may be driven by a lack of binding specificity for some of the tracers used in this research (e.g., (Catafau et al., 2010)).
Where the focus of early models of dopamine dysfunction in psychosis was on diffusely projecting dopaminergic systems such as the mesolimbic and mesocortical pathways, recent work has attempted to more precisely delineate the specific neural circuits that mediate dopamine dysregulation. Particular attention has been paid to fronto-striato-thalamic circuits, which topographically link discrete regions of the frontal cortex with specific subregions of the striatum pallidum, substantia nigra and thalamus (Fig. 1). The organization of these loops is highly conserved across mammalian species (Haber, 2003, Molnar, 2000, Parent and Hazrati, 1995a, Sherman and Guillery, 2006), and has been characterized through various anatomical tract-tracing (McFarland and Haber, 2000, Parent and Hazrati, 1995a), electrophysiological (Alexander and DeLong, 1985), clinical (Cummings, 1993), behavioural (Chudasama and Robbins, 2006), neurocognitive (Pantelis et al., 1999, Pantelis et al., 1997), and neuroimaging studies (Di Martino et al., 2008, Harrison et al., 2009, Zhang et al., 2010).
The loops generally operate in a circuit-like fashion, such that information is relayed from the cortex through the basal ganglia, thalamus and then back to the same area of cortex (Alexander et al., 1986). The loops work as both independent “closed” circuits, in which each loop processes and relays certain types of information, and as an integrated and interdependent system, in which inputs from one loop can modify the output of other loops. Integration is made possible through neural projections that pass through restricted areas of the pallidum (Alexander et al., 1986). This organization supports the flexible modulation of internally generated and externally evoked behavioural responses to environmental cues (Haber, 2003).
The fronto-striato-thalamic loops may be categorized into three broad classes along a rostroventral-to-dorsocaudal gradient. This gradient is most easily understood with respect to distinct subregions of the striatum (Draganski et al., 2008, Haber, 2003): a ventral ‘affective’ circuit links ventromedial PFC to the nucleus accumbens, which in turn projects to the mediodorsal (MD) and the ventral anterior (VA) nucleus of the thalamus; a dorsal ‘associative’ circuit links DLPFC to the dorsal striatum, which then also projects to the MD and VA nucleus of the thalamus; and a caudal ‘sensorimotor’ circuit links motor and sensory cortices to the tail of the caudate and putamen, which in turn project to the ventrolateral (VL) nucleus of the thalamus (Fig. 1).
Recent studies using high-resolution positron emission tomography (PET) have localized dopaminergic dysfunction in patients with psychosis to specific subregions of the striatum, thus implying a preferential involvement of particular fronto-striato-thalamic circuits in disease pathophysiology. The majority of this work has measured uptake of 6-[18F] fluoro-l-DOPA ([18F]-DOPA) to index presynaptic dopamine synthesis capacity in the striatum, as this marker has proven to be a robust and reliable probe of dopaminergic dysfunction in psychotic patients and at-risk populations (Fusar-Poli and Meyer-Lindenberg, 2013, Howes et al., 2012, Huttunen et al., 2008). Contrary to early views prioritizing hyperdopaminergia in the ventral striatum and the mesolimbic pathway as critical for the onset of psychosis, this work has shown that the most robust elevations of dopamine synthesis are found in the dorsal, associative division of the striatum. For example, one study found significant [18F]-DOPA elevations in both patients with established schizophrenia and individuals with an at-risk mental state (ARMS) for psychosis compared to healthy controls (Howes et al., 2009). Moreover, the severity of prodromal symptoms in the ARMS group correlated with [18F]-DOPA levels in the dorsal but not ventral striatum. Later work showed that the [18F]-DOPA elevations in the ARMS group were specific to individuals who later developed psychosis (Howes et al., 2011b). Smaller elevations have been found in the sensorimotor division of the striatum of ARMS individuals, and these appear to increase longitudinally during the transition to psychosis (Egerton et al., 2013, Howes et al., 2011a). Increased [18F]-DOPA has also been found in the substantia nigra of patients with established schizophrenia, a result that is consistent with post-mortem evidence that patients show elevated nigral levels of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (Howes et al., 2013). Collectively, these results form part of a growing body of evidence indicating that striatal dopamine synthesis and release are consistently elevated in patients, particularly those experiencing acute psychotic symptoms (Abi-Dargham et al., 2009, Fusar-Poli and Meyer-Lindenberg, 2013, Laruelle et al., 1999, Mizrahi et al., 2012, Pogarell et al., 2012), and suggest that striatal hyperdopaminergia may be primarily associated with abnormalities of presynaptic, rather than postsynaptic, function (Howes et al., 2012). Some studies have identified relatively smaller dopaminergic changes in the ventral striatum of patients (Kegeles et al., 2010), but reports have been less consistent than those for the dorsal subregion.
Pathology in one component of a neural circuit seldom remains isolated; instead, it will spread to affect the functions of interconnected system elements (Fornito et al., 2015). Accordingly, elevated [18F]-DOPA in the dorsal striatum of ARMS individuals correlates with altered prefrontal glucose metabolism (Meyer-Lindenberg et al., 2002) and prefrontal activation during the performance of executive function tasks (Fusar-Poli et al., 2010, Fusar-Poli et al., 2011). In particular, there appears to be an inverse relationship between subcortical dopamine levels and measures of prefrontal activity. For example, prefrontal lesions in rats lead to increased striatal dopamine transmission (Pycock et al., 1980), dopamine agonism in prefrontal cortex can reduce dopamine signaling in the striatum (Scatton et al., 1982), and human imaging studies have found a strong negative correlation between striatal dopamine synthesis capacity and prefrontal glucose metabolism (Meyer-Lindenberg et al., 2002). However, an open question is whether striatal dopaminergic abnormalities are a cause or consequence of circuit-wide dysfunction in the associative fronto-striato-thalamic system.
Section snippets
Functional dysconnectivity of fronto-striato-thalamic circuitry
Circuit-level dysfunction in psychosis can be directly probed with in vivo magnetic resonance imaging (MRI) of structural or functional connectivity. In particular, studies of functional connectivity in task-free, so-called resting-states (Fornito and Bullmore, 2010, Fox and Raichle, 2007), have proven to be very popular in psychosis because the data are relatively easy to acquire, the neural dynamics recorded under a ‘rest’ design are robust across individuals and time (Damoiseaux et al., 2006
Mechanisms of fronto-striato-thalamic disruption in psychosis
The complex interconnectivity of fronto-striato-thalamic circuitry makes it difficult to identify a single lesion that can cause the dopaminergic dysfunction and systems-level changes observed in clinical samples. The preceding discussion suggests that any mechanistic model must account for three key findings: (1) increased dopamine synthesis and release in the striatum; (2) a possible reduction of dopamine transmission in the prefrontal cortex; (3) and reduced functional connectivity between
Treatment implications
In this article, we have focused on the role of dopamine signaling and fronto-striato-thalamic systems in the genesis of psychotic symptoms. The link between increased dopamine and psychosis is well-known and, more than 60 years after the discovery of the first antipsychotic, treatments for schizophrenia are still based on dopamine receptor blockade and modulation (Kapur and Mamo, 2003). However, the side effects of these drugs are often poorly tolerated and compliance is a problem (Manschreck
Contributors
Author contribution: where the authors were involved as first authors OD, AF, and CP had full access to the data in the studies mentioned in the review and take responsibility for the integrity of the data and the accuracy of the data analysis.
Review concept and design: OD & AF.
Data search, analysis, or interpretation of data: all.
Drafting of the manuscript: OD.
Critical revision of the manuscript for important intellectual content: all.
Statistical analysis: OD & AF.
Administrative, technical, or
Role of the funding source
CP was supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (628386 & 1105825). AF was supported by NHMRC Project grants (3251213 and 3251250) and by the Australian Research Council (ID: FT130100589).
Conflict of interest
The authors declare no conflict of interest.
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