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Ghrelin in the brain is a stress hormone that acts independent of cortisol



Senior Member
Oct 21, 2010
Ghrelin in the brain is a stress hormone that acts independent of cortisol. Whether this activity is good or bad depends on how long the GHSR1a is activated

Brain GHSR1a activation is biphasic:

Acute Ghrelin or agonists (GHRP-2, Ipamorelin, GHRP-6, Hexarelin):
- anti-depressive
- anti-anxiety
- protective of stress
- potentially neurologically protective

Chronic (non-pulsed) Ghrelin agonists (ibutamoren mesylate (MK-0677) :
- depression producing
- anxiety producing
- fear conditionoing producing effects of chronic stress
- potentially neurologically damaging

It's important to understand what follows. A tip toe through the literature often reveals the good that Ghrelin produces. However those studies used acute methodologies.

The recent study A ghrelin?growth hormone axis drives stress-induced vulnerability to enhanced fear, RM Meyer, Molecular Psychiatry (2014), 1284 ? 1294 distinguishes it's results by using a low dose but longer lasting Ghrelin mimetic (ibutamoren mesylate (MK-0677)) in creating a chronic situation. I will elaborate from the study...
GH is created not only in the pituitary but also in brain regions such as basolateral complex of the amygdala (BLA) . The growth hormone secretagogue receptor 1a (GHSR1a) is found in the BLA. This is the region that regulates emotional states such as fear.

Over-expression of recombinant GH in the BLA does not alter fear acquisition but it does enhance long-term fear memory that is created by chronic Ghrelin.

Chronic Ghrelin or long-lasting agonists such as ibutamoren mesylate (MK-0677) can create the fear/stress response, in the absence of an externally stressful event (in other words the chronic Ghrelin engenders the stressful state) and the presence of GH can amplify it.

Prolonged stress "load" and neuronal dysfunction are correlated. So one would expect chronic Ghrelin to lead to neuronal dysfunction.

Again it is important to remember that GHRPs do more than increase GH release from GH-releasing cells in the pituitary. They also do so peripherally. By peripherally I mean tissue that generally does not release factors systemically but rather uses what it makes locally within the neighboring tissue (paracrine). That tissue does not need to be all of the same type. For instance bone and muscle sometimes share locally released factors.

Not all GHRPs produce the same peripheral GH. They appear to differ somewhat in their ability to bring about GH locally via GHSR1a (growth hormone secretagogue receptor 1a).

In this RM Meyer study stimulation of the GHSR1a in BLA cells by ibutamoren mesylate (MK-0677) led to significantly elevated release of brain GH. Antagonizing the GHSR1a to prevent it's activation prevents the fear conditioning stress response.

However chronic stimulation of the GHSR1a led to the severe brain stress-enhancing effects.

How would Ghrelin or ibutamoren mesylate (MK-0677 readily crosses the blood?brain barrier and has a half-life of >6h) would be available in the amygdala (BLA):
"Ghrelin may also be synthesized by small populations of neurons in the hypothalamus, the cerebral cortex and the brainstem, where it may act as a paracrine hormone rather than being secreted into the blood stream. However, immunoreactive ghrelin-containing fibers have never been reported in amygdala. Thus, it seems that the most likely source of bioactive ghrelin affecting fear lies in the periphery, although a role for centrally derived ghrelin cannot be fully eliminated."

Thus higher amounts or long-lasting agonists would likley supply the activation of GHSR1a in the amygdala (BLA). Peptidyl Growth Hormone Releasing Hormone are short lived and would be expected to exert positive effects (as discussed in the follow on sections) and not likely be, if used physiologically, capable of the detrimental effects.

Whereas non-peptidyl longer lived agonists would be expected to exert negative effects and as the RM Meyer study demonstrates are capable of the detrimental effects.

Most of the Discussion from A ghrelin?growth hormone axis drives stress-induced vulnerability to enhanced fear, RM Meyer, Molecular Psychiatry (2014), 1284 ? 1294

They found that the
...effects of stress are not simply downstream from glucocorticoids or adrenal catecholamines. We also show that increased ghrelin receptor activity is sufficient and necessary for stress-enhanced fear and is dissociable from HPA activity. Repeated activation of ghrelin receptors in nonstressed animals significantly enhances fear learning without elevating HPA stress hormones, whereas systemic blockade of the ghrelin receptor during chronic stress prevents stress-related enhancement of fear, even in the presence of elevated adrenal stress hormones We demonstrate that the amygdala, a brain region that displays enhanced function in chronically stressed animals and in patients with trauma-related disorders, is likely the locus of the fear enhancing effects of repeated ghrelin receptor stimulation. Finally, we show that GH, a downstream effector of ghrelin receptor activation, is increased in the BLA by chronic stress, is sufficient to enhance fear learning and plays a necessary role in the fear potentiating effects of ghrelin. Thus, ghrelin and growth hormone act together in the amygdala to enhance fear.

Our study is the first to explicitly examine the effects of protracted exposure to elevated ghrelin, as observed following chronic stress. We show that there are profound differences in the behavioral consequences of ghrelin exposure following different exposure durations, similar to the cumulative nature of stress. We also provide the first evidence to link prolonged exposure to elevated ghrelin with a specific, detrimental consequence of stress, enhanced fear memory, which typifies trauma-induced anxiety disorders such as PTSD. Because PTSD is a multifaceted disorder producing many symptoms, including those related to avoidance and hyperaroGloball, it will be interesting to determine whether chronically elevated ghrelin contributes to these sequelae of PTSD in addition to promoting changes in fear learning and memory.

Our study is also the first to show that GH is a critical downstream mediator of the effects of ghrelin in amygdala. Such a relationship between ghrelin and GH has not been described outside of the pituitary.51 We also provide the first evidence to link elevated amygdala GH with chronic stress and enhanced fear memory. Taken together, our data reveal that the amygdala may be especially sensitive to ghrelin-mediated effects of stress because chronic stress amplifies both ghrelin and GH.

In contrast to our findings that link ghrelin to a pathological condition, prior studies have argued that ghrelin promotes adaptive changes during stress, including antidepressant effects ( Lutter M, The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 2008; 11: 752?753) and reduction in anxiety.(Spencer SJ, Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol Psychiatry 2012; 72: 457?465) However, these studies are problematic because they either focused exclusively on acute ghrelin manipulations, which we show can have profoundly different effects from repeated ghrelin manipulations or used short- and long-term ghrelin manipulations interchangeably. In addition, the alterations in ghrelin levels were achieved through artificial states: heightened ghrelin levels were attained by extreme food deprivation or a single bolus injection of the short-lived peptide. The antidepressant effect of ghrelin requires extremely high levels of ghrelin, as found in food-restricted rodents after 10?15% weight loss.13 We find that this level of food deprivation leads to increased exploratory motor activity (Supplementary Figure 10; F(1, 13)?7.51, Po0.05). A recent study has also reported similar motor effects following acute ghrelin manipulations.57 These motor effects can be a significant confound for measures that require locomotor activity, such as social interaction or exploration. Thus, the ghrelin may alleviate the psychomotor effects of depression in a manner similar to amphetamine.58 It is also important to note that the antidepressant effect of ghrelin reported following a single injection of exogenous ghrelin was only a mild improvement of a stressmrelated impairment in social interaction;13 enhanced ghrelin signaling did not promote ?normal? function following stress. Indeed, our results reported here are consistent with limited human data showing that patients with treatment-resistant major depressive disorder have higher ghrelin levels than control patients.59

Here we demonstrate changes in endogenous ghrelin following stress and also use a low-dose, long-acting agonist to replicate the naturally occurring ghrelin state. We also provide clear evidence that acute and chronic ghrelin receptor manipulations have profoundly different effects. It is important to note that the changes in fear reported here occurred following small, but persistent, changes in ghrelin signaling, and all were in the absence of any locomotor effects. We suggest that the utility of ghrelin in the stress response may be similar to glucocorticoids: under ?normal? conditions, there is an optimal level of the hormone,60 and too little61,62 or too much hormonal signaling16 can lead to dysfunction in neuronal circuits. Repeated activation of ghrelin and glucocorticoid pathways together contributes to stress-induced ?load? on the body. In this regard, heightened ghrelin signaling may have both advantageous and undesirable consequences, but these must be carefully considered with respect to the length and level of elevated ghrelin exposure.

It is not clear why acute and repeated ghrelin receptor stimulation have opposite effects on fear learning. Although GHSR1a activation engages excitatory Gq-dependent molecular cascades, GHSR1 also exhibits an extremely high level of constitutive activity in the absence of bound ligand.77 Accordingly, transient stimulation of GHSR1a leads to rapid desensitization and internalization of the receptor that is slow to recover.78 Such a change is consistent with the decreased fear learning we observed 24 h after a single injection of ghrelin receptor agonist. It is also consistent with the observation that transient bath application of ghrelin to lateral amygdala slices leads to decreased excitatory neurotransmission.15 The electrophysiological changes elicited by chronic ghrelin receptor stimulation in amygdala are completely unexplored, but our work suggests that the change must be opposite to that seen after acute ghrelin receptor stimulation. We suggest that the internalization of the ghrelin receptor may habituate63 following either chronic administration of ghrelin receptor agonist or chronic stress exposure. The differences in receptor kinetics following acute versus chronic ghrelin receptor stimulation represent an especially promising area for future research.
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