Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression

Abstract

The dopamine (DA) system is unique among the brain’s modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. DA neurons exhibit several activity patterns — including tonic and phasic firing — that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions within these regulatory systems may underlie the pathophysiology of several psychiatric disorders including schizophrenia and depression.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

“…In addition, haloperidol, presumably acting as a D 2 receptor antagonist, blocked the antidepressant effects of ketamine in the mouse forced-swim test, whereas activation of D 2 /D 3 receptors enhanced its antidepressant effects (Li et al, 2015). These findings, along with the well established role of the DAergic system in the pathophysiology and treatment of depression (Willner et al, 2005;Papakostas, 2006;Dunlop and Nemeroff, 2007;Grace, 2016), suggest that ketamine might act via the regulation of the DAergic neurotransmission to exert its Ruin Moaddel and Irving W. Wainer are listed as coinventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Panos Zanos, Ruin Moaddel, Irving W. Wainer, and Todd D. Gould are listed as coinventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders.…”

“…These results extend our knowledge of ketamine's actions on mesolimbic DA release and highlight the need for the study of potential indirect interactions between glutamatergic and DAergic neurotransmitter systems to obtain a complete picture of ketamine's actions relevant to both therapeutic actions and side effects (see Grace, 2016 for a recent review). …”

Morphological picture of the estrous cycle at reserpine model of depression in rats

“…Показано, что снижение функциональной активности норадрено-и дофаминергической нейромедиаторных систем проявляется в нарушениях эмоционального баланса вплоть до возникновения депрессивной симптоматики, а также в функциональном сбое механизмов регуляции нейрогормональной системы «гипоталамус-аденогипофиз-яичники» [7][8][9][10][11][12][13]. В этой связи востребованными являются исследования, связанные с моделированием и комплексным изучением влияния сниженного уровня активности катехоламинергических систем (характерного нейрохимического маркера депрессии) на состояние половой функции.…”

“…Как известно, поддержание должного эмоционального баланса выстраивается за счет функционирования эмоциогенных структур головного мозга и активности, определенных нейротрансмиттерных систем. В частности, ключевая роль в поддержании положительного эмоционального статуса принадлежит моноаминоергическим нейромедиаторным системам: дофамин-, норадреналин-и серотонинергической [11][12][13]. Высокая плотность моноаминоергических терминалей в гипоталамических областях, связанных с экскрецией кисспептина и гонадолиберина, позволяет предполагать модулирующую роль медиаторов-моноаминов в контроле функционирования системы «гипоталамус-аденогипофиз-гонады».…”

Refinement of a neuronal differentiation protocol predominantly yields human iPS cell-derived dopaminergic neurons for the investigation of neurodegenerative pathomechanisms in vitro

“…The mesocortical pathway is formed by DA neurons of the VTA that project their axons to the prefrontal cortex. DA signaling of these pathways has been shown to contribute to reward-related cognition [7] and a dysfunctional mesocorticolimbic DA signaling is associated with addiction, attention deficit hyperactivity disorder and schizophrenia [6,8,9]. The nigrostriatal pathway is maintained by DA neurons located to the substantia nigra pars compacta in the midbrain, which grow their axons to the caudate nucleus and putamen inside the dorsal striatum.…”