• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Implications of normal brain development for the pathogenesis of schizophrenia

Objective. —This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided. Data Sources. —Published original articles from human and animal studies and selected reviews. Literature was surveyed utilizing MEDLINE and the Index Medicus . Study Selection. —Original articles from the basic science and human literature consisted entirely of controlled studies based on verified methodologies and, with the exception of the most recent studies, replicated by more than one laboratory. Many of the basic science and clinical studies had been conducted in our own laboratories and clinical research units. Reviews cited were written by acknowledged leaders in the fields of neurobiology, endocrinology, and behavior. Data Extraction. —Independent extraction and cross-referencing by the authors. Data Synthesis. —Stress and related concepts can be traced as far back as written science and medicine. The stress system coordinates the generalized stress response, which takes place when a stressor of any kind exceeds a threshold. The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. There has been an exponential increase in knowledge regarding the interactions among the components of the stress system and between the stress system and other brain elements involved in the regulation of emotion, cognitive function, and behavior, as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of stress system dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders and/or susceptibility to such disorders. Conclusions. —We hope that knowledge from apparently disparate fields of science and medicine integrated into a working theoretical framework will allow generation and testing of new hypotheses on the pathophysiology and diagnosis of, and therapy for, a variety of human illnesses reflecting systematic alterations in the principal effectors of the generalized stress response. We predict that pharmacologic agents capable of altering the central apparatus that governs the stress response will be useful in the treatment of many of these illnesses. ( JAMA . 1992;267:1244-1252)

The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis

https://zenodo.org/record/1259653/files/article.pdf

Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.

Stress affects cognition and increases noradrenaline and dopamine levels in the prefrontal cortex (PFC). Amy Arnsten discusses the intracellular signalling pathways that mediate the effects of these catecholamines on PFC function during acute and chronic stress, focusing on working memory. An interview with Amy Arnsten for Neuropod is available for
 download
 . The prefrontal cortex (PFC) — the most evolved brain region — subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.

/pdf/stress-signalling-pathways-that-impair-prefrontal-cortex-2njc5rigi4.pdf

Stress signalling pathways that impair prefrontal cortex structure and function

Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity

It has been appreciated for many years that exposure to various forms of stress may result in a metabolic activation of central catecholamine-containing neurons. Although stressful events provoke a number of neurochemical and hormonal effects and influence a variety of neurotransmitter systems, certain stressors, such as low-intensity, shortduration footshock,' conditioned and exposure to a novel en~ironment,~ appear to selectively influence those dopamine (DA) neurons innervating the medial prefrontal cortex, a brain region believed to be involved in anticipatory phenomena and cognitive f ~ n c t i o n . ~ This report is focused on a characterization of the effects elicited by experimental stress paradigms and related pharmacological treatments that result in a robust and fairly selective activation of the subset of midbrain DA neurons projecting to the prefrontal cortex. Several years after the discovery of the mesocortical DA projections it began to be appreciated that midbrain DA neurons were not as homogenous as once believed, and that they possessed a number of different biochemical, physiological, and pharmacological properties. The first evidence indicating that certain mesocortical DA neurons may be functionally different from those of the mesolimbic and other midbrain DA systems was provided by examination of the effect of stress on these systems. DA utilization was found to be markedly increased in the prefrontal cortex but only slightly (nucleus accumbens) or not affected at all (olfactory tubercle, septum, amygdala, and striatum) in subcortical structures of rat brain following short periods (20 min) of intermittent footshock stress.' The high and selective reactivity of the mesoprefrontal DA neurons to intermittent footshock stress has since been confirmed by a number of other groups, although there are some reported inconsistencies concerning the responsiveness of other mesocortical DA s y ~ t e m s ~ . ~ ~ that are probably related to differences in the stress paradigms employed. Extensive evidence has also demonstrated that the mesoprefrontal DA system possesses other distinct characteristics as compared to its mesocortical, mesolimbic, and nigrostriatal co~n te rpa r t s .~~ '~ It has been suggested that many of these unique characteristics may be attributed to distinct control mechanisms regulating these mesoprefrontal DA neurons. Some of these unique characteristics, which are listed below, appear to be the consequence of the lack of impulseregulating somatodendritic and synthesis-modulating nerve terminal DA autoreceptors on these neurons.\

Stress and the mesocorticolimbic dopamine systems.

Footshock and conditioned stress increase 3,4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra.

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response

Selective increase in dopamine metabolism in the prefrontal cortex by the anxiogenic beta-carboline FG 7142.

Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25–200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic Β-carboline, FG 7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.

See-Ying Tam

Papers

Stress and the mesocorticolimbic dopamine systems.

Footshock and conditioned stress increase 3,4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra.

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response

Selective increase in dopamine metabolism in the prefrontal cortex by the anxiogenic beta-carboline FG 7142.

Mesocortical dopamine neurons: high basal firing frequency predicts tyrosine dependence of dopamine synthesis.