Neurohormones & HPA
Normally when a stimulus is perceived as stressful, e.g. external or internal cues of threat, pain, or failure of expectation (Ladd et al., 2000), corticotropin releasing hormone (CRH) neural activity in the amygdala provides input to the locus coeruleus to stimulate noradrenergic neurons for sympathetic nervous system (SNS) activity (Melia & Duman, 1991) and the medial parvocellular region of the paraventricular nucleus (mPVNpc) of the hypothalamus for hypothalamic-pituitary-adrenal axis (HPA axis) activity (Heim & Nemeroff, 1999). As the synthesis of PVN CRH increases, CRH and arginine-vasopressin (AVP) are both released from the terminals in the median eminence into the hypothalamic hypophysial portal vascular system that connects the hypothalamus with the pituitary gland (Plotsky, 1991; Tsigos & Chrousos, 2003). CRH in the anterior pituitary facilitates the release of the analgesic pro-opiomelanocortin (POMC) gene expression and the release of two POMC-derived peptides, adrenocorticotropin hormone (ACTH) and β-endorphin (Arborelius et al., 1999). AVP as a co-secretatogue with CRH also stimulates ACTH secretion (Tsigos & Chrousos, 2003). ACTH induces the synthesis and release of glucocorticoids (GCs) in the adrenal cortex. GCs are the end products of the HPA axis (Ladd et al., 2000), sources of negative feedback inhibition to regulate HPA activity, and regulators of stress arousal (Sapolsky et al., 1990; Jacobson & Sapolsky, 1991). Central GC injection acting on PVN GRs downregulates CRH mRNA and inhibits medial parvocellular (mPVNpc) neurons (CRH and AVP) and in response to neural activity in the mPVNpc indirectly decreases ACTH secretion in the anterior pituitary (Makino et al., 1994; Herman & Cullinan, 1997).
Glucocorticoids (GCs), i.e. cortisol in primates and corticosterone in rats, are endogenous steroids (corticosteroids) that normally occupy or bind to glucocorticoid receptors (GRs) throughout the brain and central (CNS) nervous system. According to the “nucleocytoplasmic traffic model” of GR action, the GR in absence of ligand and in its “unactivated” form, resides primarily in the neuron’s cytoplasm in association with several heat shock and other proteins to form the cytoplasmic chaperon protein complex (Miller & Pariante, 2001). In response to ligand binding the protein complex dissociates from the cytoplasm and with the receptor’s continued association with the heat shock (e.g. hsp90) and other proteins translocates to the nucleus by tracking along the cytoskeleton to the nuclear pore (Galigniana et al., 1998; Hache et al., 1999; Pratt et al., 1999). Once in the nucleus the receptor dimerizes and binds to specific response elements called hormone or glucocorticoid responsive elements (HRE or GRE) or “dimers” that allow DNA to bind to the receptor (de Kloet et al., 1998; O’Connor et al., 2000). As the ligand-bound receptor dimerizes and binds to DNA responsive GREs, it stimulates receptor gene transcription (de Kloet et al., 1998; Owen, 2002). GRs along with activating protein (AP-I) and nuclear factor κB (NFκB) interact with other transcription factors, i.e. to attenuate stress-induced signals through the receptor’s membrane (de Kloet, 2003). Activated GRs also have the capacity to block other transcription factors from binding to their own transcription elements, such as those for certain proinflammatory cytokines (e.g. IL-1β and TNF-γ) and corticotropin releasing hormone (CRH) by direct protein to protein interaction (O’Connor et al., 2000). This process or transrepression (Meijer, 2002) inhibits other transcription factors from transcribing and this results in their receptor downregulation and instability in their messenger RNA (Chrousos, 1995; Tsigos & Chrousos, 2003).
Typically the circulating steroid binds to its receptor and this initiates the process of gene transcription. Reduced GR levels, binding, and reduced gene transcription in the affective disorder depression may be due to either GR failure to associate with chaperon proteins due to chronic levels of the circulating steroid (Pariante & Miller, 2001) or mutations in the GR DBD that impairs DNA binding serving to decrease ligand nuclear occupancy (Hache et al., 1999). As GRs downregulate, their binding of ligand decreases, circulating steroid levels increase, and structures that are dependent on the steroid to maintain their functional integrity are deprived of it. Thus, moderate amounts of circulating steroid can bind to receptors to enhance receptor functional integrity; however, high levels of circulating GCs seem to interfere in GR transcription. As noted in future sections of this web site the most common manifestation of an organism’s response to stress is circulating steroid, GCs, corticosterone, cortisol, etc. in the plasma, cerebrospinal fluid, saliva, and urine.
Interestingly, at therapeutic levels both tricyclic and bicyclic antidepressants in the steroid’s presence in vitro induce GR translocation from the cytoplasm to the nucleus and mediate gene transcription (Pariante et al., 1997, 2001) that allows for increased steroid binding to the receptor. Antidepressants in this context mediate transcription factors that allow for GR gene transcription. This facilitates the functional integrity of the glucocorticoid receptor. As a result of gene transcription the receptor and the respective neuron, in which it is housed, is better able to contain and express ligand and reduce ligand transport as it approaches and travels across the neuron’s synapse respectively. An antidepressant therapy’s efficacy is usually assessed within the context of decreased pre or post-synaptic ligand transport and increased reuptake at the synaptic level. It is actually the full functional genetic expression of the receptor that inhibits ligand synaptic transport. Antidepressant therapy also increases GR (Okugawa et al., 1999) and mineralocorticoid receptor (MR) binding in the hippocampus (Reul et al., 1993) and this decreases or inhibits HPA-related stress arousal (Deuschle et al., 2003). Section 1.42 will elaborate on how functional hippocampal GRs actively inhibit HPA activity (Jacobson & Sapolsky, 1991) and are the first line of defense to inhibit stress-induced HPA activity. Maintaining the functional integrity of both the mineralocorticoid and glucocorticoid receptor is essential for sustaining necessary negative feedback over HPA activity.
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