Pathway-Specific Dopamine Abnormalities in Schizophrenia

Abstract

In light of the clinical evidence implicating dopamine in schizophrenia, and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. Here we review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions, and even to other extrastriatal subcortical regions not previously considered to be “hypodopaminergic” in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. In this review we discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.

Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

“…Our findings suggest that Arc function is important for establishing the proper activity balance between mesocortical and mesostriatal dopaminergic circuits. Moreover, our studies further suggest that these circuit deficits can arise together from the same genetic background, which has been difficult to determine in humans due to different dopamine molecular imaging methods in striatal and cortical regions and genetic diversity (Weinstein et al, 2016). …”

“…To investigate how Arc genetic mutations might affect the dopaminergic system, we first analyzed Arc mutants for dopamine content in PFC and striatum, two major areas involved in the dopamine hypothesis of schizophrenia (Koch et al, 2014, Simpson et al, 2010, Weinstein et al, 2016, Winterer and Weinberger, 2004). In the PFC, an Arc effect was present on dopamine tissue content (F 2,71 =6.72, p=0.002, Figure 4A), but not on noradrenaline (Figure S3).…”

“…We did not attempt to find a mouse model of an entire psychiatric disorder, but rather focused on disease-related functional dimensions of behavior. Particularly, because one of the long-standing pathophysiological hypotheses of schizohprenia involves a dysregulated dopaminergic system (Weinstein et al, 2016), we investigated the effects of Arc genetic disruption on different aspects of dopaminergic system functions. We found that Arc gene disruption leads to behavioral abnormalities comprising a broad range of cognitive, negative and positive schizophrenia-like symptoms.…”

Approaches to neuromodulation for schizophrenia

“…48 Both VS and AS have been indirectly implicated in generating the psychotic symptoms. Four studies have identified higher dopamine activity in the AS relative to SMS in patients with SZ (table 1).…”

“…The DBS clinical trials to date have been funded through grants (NCT0237505 and NCT01725334), and by seeking FDA, IDE along with Centers for Medicare and Medicaid Services approval for reimbursement (NCT02361554). 48 …”