Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

Abstract

Dysregulation of the dopamine system is central to many models of the pathophysiology of psychosis in schizophrenia. However, emerging evidence suggests that this dysregulation is driven by the disruption of upstream circuits that provide afferent control of midbrain dopamine neurons. Furthermore, stress can profoundly disrupt this regulatory circuit, particularly when it is presented at critical vulnerable prepubertal time points. This review will discuss the dopamine system and the circuits that regulate it, focusing on the hippocampus, medial prefrontal cortex, thalamic nuclei, and medial septum, and the impact of stress. A greater understanding of the regulation of the dopamine system and its disruption in schizophrenia may provide a more complete neurobiological framework to interpret clinical findings and develop novel treatments.

Effective Connectivity and Dopaminergic Function of Fronto-Striato-Thalamic Circuitry in First-Episode Psychosis, Established Schizophrenia, and Healthy Controls

“…A primary role for VTA/SN dysregulation in psychosis is supported by our observations of consistent correlations between the connectivity of this region and positive symptom severity across illness stages [23,[51][52][53]. However, the specific connections implicated varied across the patient groups.…”

Resting-state dopaminergic cell firing in the ventral tegmental area negatively regulates affiliative social interactions in a developmental animal model of schizophrenia

“…Therefore, the present findings are alternatively explained; the higher baseline activity of VTA dopaminergic neurons resulted in the attenuation of event-triggered dopamine responses that was responsible for the observed social deficits. As the SWB of VTA dopaminergic cells were also elevated in this EGF model, the latter question remains to be addressed with respect to the reported distinct functions of their tonic and phasic firing properties 17 , 18 , 30 . Our preliminary study might indicate the limitation of post-synaptic contribution to the above phenomenon; protein concentrations of dopamine receptors D1R and D2R in the prelimbic cortex exhibited no significant difference between groups (Supplemental Fig.…”

“…Dysfunction of the brain dopaminergic system is implicated in the pathophysiology of schizophrenia, in particular its positive symptoms 17 , 18 . Previous brain imaging studies of schizophrenia patients suggest that hyperdopaminergic states in their nigrostriatal pathway (i.e., A9 pathway), as well as hypodopaminergic states in their mesocorticolimbic pathway (i.e., A10 pathway), are associated with the positive, cognitive, and potentially negative symptoms of schizophrenia 19 – 22 , although many controversies remain 23 , 24 .…”

ADHD: Reviewing the Causes and Evaluating Solutions

“…This does not imply a lack of importance of this variation, but rather highlights the variability in the genetic etiology of this condition. Moreover, while the dopaminergic system is highly involved in the pathophysiology of ADHD, given its role in CNS development, it is also strongly related with other neuropsychiatric conditions, such as autism [ 78 , 94 , 95 ] and schizophrenia [ 78 , 94 , 96 , 97 ].…”