Page 28 - JCBP-2-1

Journal of Clinical and
Basic Psychosomatics The endocannabinoid system

activates PKA, which phosphorylates various proteins, neurotransmitters, with a particular impact on dopamine
including transcription factors like CREB. Phosphorylated and serotonin, which are pivotal for mood regulation.
CREB then binds to cAMP response elements in the Dysregulation of the HPA axis, therefore, has the capability
promoter region of the proopiomelanocortin (POMC) to contribute to mood disturbances, including anxiety and
gene, initiating transcription (Figure 1B). depression, both of which are common facets of PSD [34-36] .

POMC is the precursor molecule for ACTH [26-30] . The dopaminergic system, another crucial player,
The synthesized POMC undergoes post-translational exerts a profound impact on the pathogenesis of numerous
processing, giving rise to the biologically active form, psychophysiological conditions. Distributed throughout
ACTH. Subsequently, ACTH is released into the the central nervous system, dopamine operates within
bloodstream and travels to the adrenal cortex, where it various neuronal pathways, predominantly in the
stimulates the synthesis and secretion of cortisol. The mesolimbic and mesocortical subsystems. The mesolimbic
binding of ACTH to its receptors on the cell membrane pathway is instrumental in processing and amplifying
elicits both the cAMP pathway and the phosphoinositide activating stimuli, thereby motivating behavioral responses
pathway. In the cAMP pathway, ACTH activates adenylate and stimulating goal-directed actions. Its inhibition can
cyclase, leading to the conversion of ATP to cAMP. Elevated lead to emotional indifference and a lack of initiative. This
cAMP levels activate PKA, which phosphorylates the system is highly sensitive to stress, with its functioning
transcription factor CREB. Activated CREB translocates to influenced by factors such as the controllability of the
the nucleus, where it binds to the cAMP response element situation, the organism’s genetic background, and its
(CRE) in the promoter region of genes crucial for cortisol life cycle. In contrast, the mesocortical pathway plays a
synthesis, such as those encoding steroidogenic enzymes. critical role in cognitive functions such as evaluating and
Simultaneously, the phosphoinositide pathway involves planning behavioral responses. Stress can exert differential
ACTH-induced activation of phospholipase C (PLC), effects on the functioning of dopamine in the mesocortical
leading to the production of inositol 1,4,5-trisphosphate system, contingent on various factors. Simultaneously, the
(IP3) and diacylglycerol (DAG). IP3 induces the release of mesocortical pathway is instrumental in higher cognitive
calcium ions, elevating intracellular calcium levels. Along functions, including the assessment and planning of
with DAG, this activates protein kinase C (PKC), which behavioral responses. Stress can exert diverse effects
modulates the activity of proteins involved in cortisol on dopamine functioning in the mesocortical system,
synthesis. These converging pathways collectively stimulate dependent on various factors such as the controllability of
the transcription and synthesis of cortisol, ensuring a the situation, genetic predisposition, and the individual’s
regulated response to stress and maintaining basal cortisol life stage. Alterations within this system have been linked
levels. The intricate feedback loop, wherein cortisol to cognitive deficits and impaired problem-solving
inhibits the release of ACTH and CRH, further fine-tunes abilities, contributing to emotional disturbances associated
the system to maintain hormonal balance. Dysregulation with PSD [37-40] .
of these signaling pathways can contribute to disorders
characterized by abnormal cortisol levels, thereby Serotonin, another key neurotransmitter, is integral to
impacting the body’s adaptive response to stressors [26,30] . the development of psychophysiological stress. Recognized
for its role in mood regulation, serotonin extends its
Cortisol, a biologically active hormone, plays a crucial influence to the HPA axis, a central component of the
role in aiding the body in adapting to stress [31-34] . Alterations body’s stress response system. Within the hypothalamus,
in cortisol levels, driven by activity in the HPA axis, can serotonin binds to receptors, notably 5-HT1A and 5-HT2
result in enduring detrimental changes within the limbic receptors, thereby modulating the release of CRH. This
system. Research has demonstrated a correlation between interaction acts as a regulatory mechanism, inhibiting the
elevated cortisol levels and past stress and depression. release of CRH and subsequently influencing the initiation
Notably, approximately 50% of newly diagnosed depression of the HPA axis response to stress [41] . Progressing to the
patients exhibit excessive cortisol secretion. As stress pituitary gland, serotonin maintains its regulatory role by
persists, cortisol concentrations remain elevated until the affecting serotonin receptors, thereby contributing to the
stressor is removed [32-34] . modulation of ACTH release. ACTH, in turn, stimulates
The HPA axis, central to this regulatory process, the adrenal glands to release cortisol, a pivotal stress
is intrinsically interconnected with the brain and hormone. The intricate interplay between serotonin and the
neurotransmitter systems. Cortisol, as the primary HPA axis is crucial for fine-tuning the stress response, with
glucocorticoid released in response to HPA axis activation, dysregulation potentially contributing to conditions such
exerts a profound influence on the equilibrium of as depression, anxiety, and other stress-related disorders.

Volume 2 Issue 1 (2024) 4 https://doi.org/10.36922/jcbp.2288