Stress is relatively common medical condition which is many times considered as nonmedical common physiological condition by most the population. However, this article is focused on the severity of chronic stress which is like the state of drug addiction. Chronic stress shares similar pathways of neurotoxicity as psychostimulants.
Keywords: Stress; Drug addiction; Neurotoxicity; Psychostimulants
Stress is a state which threatens homeostasis of neurochemicals, caused by an intrinsic or extrinsic adverse forces (stressors) and is counteracted by an intricate repertoire of physiological and behavioural responses . Although the entire Central Nervous System (CNS) is directly or indirectly involved in conserving the overall body homeostasis, specific areas of the brain have critical and distinct roles in stress response. Following regions of CNS specifically reported in stress pathophysiology, the central components of stress system are located in the hypothalamus, the brainstem, include paravacecullar corticotrophin releasing hormone (CRH), arginine-vasopessin (AVP), neurons of paraventricular nuclei (PVN) of hypothalamus, the CRH neurons of paragigantocellular and parabranchial nucli of the medulla, the locus coeruleus (LC), catecholaminergic, norepinephrine (NE)-synthesizing cell groups of the medulla, pons (central sympathetic nervous system) . The peripheral limbs of hypothalamic-pituitary-adrenal (HPA)axis, together with efferent sympathetic nervous system/ adrenomedullary system creates the peripheral component of this interconnected system .
Hypothalamic-Pituitary-adrenal axis (HPA) and stress: The HPA axis is a vital component of both central and peripheral limb of the stress system . HPA’s integrity and precise regulation of its function are essential characteristic of the successful
adaptive response to any stressor . Corticotropin releasing
hormone (CRH) is one of the important hormone involved in
stress pathology acts through HPA axis. It is released into the hypophyseal portal system and acts as a principle regulator of adrenocorticotropic hormone (ACTH) secretion . While the AVP acts as a potent synergistic factor to CRH with a little ACTH secretagogue activity by itself [7,8]. Under non-stressful conditions, both CRH and AVP are secreted into portal system in circadian and highly concordant pulsatile fashion [9,10]. The HPA axis activity is characterised not only by typical circadian rhythm but also by a pattern of discrete pulsatile release of glucocorticoids, with pulse of production for every 1-2 hours . Thus, the circadian release of CRH/AVP/ACTH in their distinctive pulsatile manner appears to be controlled by one or more CNS pace makers. These diurnal deviations are disturbed by alterations in lighting, feeling and physical activity patterns, whilst they are disrupted when stressor is imposed . During acute stress, the amplitude and synchronisation of both CRH and AVP secretory pulses increases, with additional recruitment of PVN, CRH and AVP secretion . The adrenal cortex constitutes the peripheral target organ of the pituitary derived circulating ACTH. Current evidences primarily suggest that, the adrenal cortisol secretion is further regulated by hormones and cytokines coming from the adrenal medulla or the systemic circulation, and by neuronal signals via autonomic innervation of the adrenal cortex .
Psychostimulants and neurotoxicity: Psychostimulants are essentially ‘CNS stimulants’ . The mistreatment is a major public issue because it is associated with serious health complications; including devastating consequences of CNS. The neurotoxic effects of these drugs have been extensively studied.
The neuronal function and neurotransmission in the brain can be
altered by the Psychostimulant which has the strongest ability to
do so. It is known that these substances increase extracellular
level of several neurotransmitters including Dopamine (DA),
Serotonin (5-HT) and norepinephrine by competing with
monoamine transporters; this can further induce physical
tolerance and dependence. Further to these findings, it also
suggests that psychostimulants may damage brain neurons
through various mechanisms . In recent years it has been
demonstrated that almost all psychostimulants are able to affect
the neurotrophins in peripheral and central nervous system.
Altered neurotrophins may participate in the pathogenesis
of psychiatric disorders, which is a common reason of these
disorders in drug users . Neurotrophins such as nerve growth
factor (NG) and brain derived neurotrophic factor (BDNF) have
relevant action neurons involved in psychostimulant action such
as DA, serotonin and play dual roles: first, in neuronal survival
and death; second in activity dependent plasticity . In this
review, we will focus on similarities of mechanisms involved in
psychostimulant induced neurotoxicity and stressor induced
A peculiar cause of psychostimulant induced neurotoxicity
is apoptosis. Psychostimulants increases extracellular
concentration of Glutamate (GLU) . It has been demonstrated
that spectrin proteolysis resulting from activation of glutamate
receptors, is through influx of calcium (ca2+) ions and
subsequent activation of the calcium dependent proteases such
as calpain and caspaces which are established pathophysiology
of neurotoxicity involved in traumatic brain injury. The
psychological chronic stress is being associated by elevations
in GLU; Furthermore, it’s reported in many researches that an
increase in extracellular glutamate in various brain regions after
exposer to various stressors are attenuated by adrenaleoctomy.
Furthermore, an elevation in glucocorticoids and extracellular
glutamate due to chronic stress leads to spectrin proteolysis in
the hippocampus produced by kinetic acid .
Many researches have demonstrated an interdependent
relationship between unpredictable chronic stress induced an
augmentation of extracellular GLU and psychostimulant induced
GLU response shares a similar pathological pathway. Stress has
a high transitional value for the targeted prevention and /or
management of broad spectrum of clinical conditions. It is now
recognized that a strong interdependent link exists between
neurobehavioral/phychoemotional stress and certain classic
disease states relating to autoimmunity, metabolic disorders
. Understanding the organization and assimilation of specific
stress system pathways and neurochemical networks which
facilitates these links constitutes a significant step forward in
exploring the pathogenesis of stress related complications .
As of now a persuasive body of experimental, epidemiologic
and clinical evidence strongly supports the significant impact of
acute and chronic stress on both physical health and emotional
well-being, highlighting the need of further ongoing research in