Alcohol, stress hormones, and the prefrontal cortex: A proposed pathway to the dark side of addiction
sci-hub.tw/10.1016/j.neuroscience.2014.06.053
Preclinical studies in rodents suggest
that the transition from alcohol use to abuse to dependence
is due to alterations in stress-related neural pathways
impaired functioning of the hypothalamic pituitary
adrenal (HPA) axis aka cortisol-ACTH axis.
we discuss the
bi-directional relationship between alcohol and stress
hormones.
we pull together information from various
studies that supports the following hypothesis: continued
heavy use of alcohol causes glucocorticoid-mediated
adaptations within the HPA axis and upstream in the
prefrontal cortex that lead to neuroendocrine dysfunction
and a heightened propensity to relapse.
Because the prefrontal
cortex provides top-down control over the HPA axis, it is
possible that neuroadaptive changes in this region could
underlie some of the changes in stress hormones
(Lovallo, 2006; Herman, 2012).
A variety of strategies can be used to elicit voluntaryaka EVIL - Low Frequency Spirit Possession!! THE DARK SIDE
binge drinking in animals, but a common theme in most
models is intermittent access to alcohol (Mcgregor and
Gallate, 2004; Rhodes et al., 2005; Simms et al., 2008;
Crabbe et al., 2009; Gilpin et al., 2012; Sharko et al.,
2013). If this episodic pattern of drinking persists, animals
may begin to show signs of motivational and emotional—
but not physical—dependence (Cox et al., 2013). Stress
regulatory systems begin to undergo neuroadaptive
changes and although alcohol may still have positive reinforcing
properties, the negative reinforcing properties of
alcohol are starting to become powerful motivators driving
excessive drinking (Baker et al., 1986; Koob, 2003; Sinha
et al., 2009; Koob et al., 2014; Wise and Koob, 2014).
This shift from non-dependence to
dependence has been described as a transition from the
light side to the dark side of addiction (Schulteis and
Koob, 1994; Koob and Le Moal, 2005).
neurons in the paraventricular
nucleus of the hypothalamus (PVN) release the
41-amino acid peptide corticotrophin-releasing factor
(also known as corticotropin-releasing hormone) from Corticotropin-releasing factor (CRF) travels
through the short portal system, binds to its Type 1
G-protein-coupled receptor (CRF1) (Chang et al., 1993;
Chen et al., 1993; Perrin et al., 1993), and stimulates
the release of adrenocorticotropic hormone (ACTH) from
the anterior pituitary gland (Rivier and Vale, 1983). ACTH
is released into the bloodstream and within minutes this
hormone reaches its target cells in the adrenal gland to
stimulate the release of glucocorticoids (cortisol in primates,
corticosterone in rodents, Rivier and Vale, 1983).
Experimenter-administered alcohol dose dependently
elicits elevations in PVN cellular activity and the release
of ACTH and corticosterone in male and female rats
(Ellis, 1966; Rivier, 1993; Rivier and Lee, 1996; Ogilvie
et al., 1997a; Willey et al., 2012). The tight link between
alcohol dose and HPA activity is further supported by correlated
blood alcohol and stress hormone levels after an
acute alcohol challenge (Ellis, 1966; Ogilvie et al.,
1997a). These findings suggest that alcohol may directly
activate HPA axis through regulating the PVN cellular
activity. Indeed, in vitro application of alcohol to hypothalamic
tissue or primary hypothalamic cells induces the
release of CRF (Redei et al., 1988; Li et al., 2005). In
addition, CRF heteronuclear RNA quickly elevates within
20 min after in vivo alcohol administration in rats (Rivier
and Lee, 1996; Ogilvie et al., 1998). This transcriptional
process is presumably initiated to replenish cellular stores
An intoxicating dose of alcohol administered ip or
ig modulates Fos expression in the prefrontal cortex,
bed nucleus of the stria terminalis, central nucleus of
the amygdala, and locus coeruleus (Chang et al., 1995;
Knapp et al., 2001). These targeted regions could regulate
HPA reactivity through direct or indirect pathways
and provide another layer of regulation in response to
alcohol stimulation (Ulrich-Lai and Herman, 2009;
Herman, 2012).
The most reliable indicator of chronic alcohol-induced
changes in HPA function is a reduced response of this
neuroendocrine system to an acute challenge of
alcohol—also known as ‘‘neuroendocrine tolerance.’’
Neuroendocrine tolerance emerges after prolonged
drinking and the magnitude of decrease in
neuroendocrine sensitivity to alcohol appears to be
dose-dependently related to the overall amount of
alcohol consumed.
This 1 g/kg dose elicits bingelike
blood alcohol levels in all animals (Fig. 2A). However,
it stimulates robust ACTH and corticosterone responses
in low-drinking non-dependent rats, mid-range responses
in moderate drinking non-dependent rats, and blunted
responses in high drinking dependent rats (Fig. 2A).
Adaptations have been found at multiple levels within
the HPA axis, which may contribute to dampened
neuroendocrine function after chronic alcohol.
At the
level of the hypothalamus, CRF mRNA expression is
reduced in dependent animals 6–8 h after withdrawal
from chronic alcohol vapors compared to alcohol-naive
controls,
the fact that
a 1 g/kg (iv) alcohol challenge in the dark cycle elicited a
similar timeline of change in ACTH in the three drinking
groups, but a much more prolonged corticosterone
response in the low-drinking non-dependent rats suggests
that even moderate drinking may alter adrenal sensitivity
to ACTH (Fig. 2A). Alcohol-induced alterations in splanchnic
innervation of the adrenal glands could explain such
group differences (Ulrich-Lai et al., 2006). The mechanisms
upstream of the hypothalamus are largely unknown,
but enhanced inhibitory tone from peri-PVN GABA cells or
other direct and indirect targets of the prefrontal cortex are
a proposed role for the
prefrontal cortex in neuroendocrine tolerance after chronic
alcohol use and dependence
Reduced stress hormone levels may not
only be reliable indicators of the addictive stage of an
individual, but could also play a functional role in driving
escalated drinking and enhanced relapse. In support of
this hypothesis, blunted basal stress hormone levels in
alcoholics predict craving (Kiefer et al., 2002).
Perhaps deficits in HPA reactivity
upstream of the adrenal glands are driving forces in
increased drinking (Li et al., 2011).
This
seems paradoxical, but two important factors must be considered.
corticosterone levels remain significantly
elevated for several hours during the intoxication phase
second phase in which brain circuits
are exposed to high concentrations of glucocorticoids that
may be synthesized centrally (Brooks et al., 2008; Little
et al., 2008). Consequently, repeated cycling between
binge intoxication and periods of withdrawal would conceivably
give this stress hormone ample opportunity to
act on its receptors in the brain and affect transcriptional
regulation of multiple genes that could promote addiction.
After removal from chronic alcohol treatment,
peripheral corticosterone levels can remain dampened
for several weeks into abstinence (Rasmussen et al.,
2000; Zorrilla et al., 2001)—perhaps resulting in a compensatory
elevation in GR expression within some of
these brain regions important for addiction.
This could explain why repeated periods
of abstinence and relapse are key elements of alcoholism
As shown in Fig. 4, the mPFC [prefrontal cortex] may play a role in the
long-loop negative feedback of the HPA axis (Sullivan
and Gratton, 2002a). The GR [glucocorticoid receptor] has a four to fivefold higher
prevalence than mineralocorticoid receptor (MR) in the
mPFC, which is notably different from the equal
distribution of GR and MR in the hippocampus (Diorio
et al., 1993; Cintra et al., 1994).
In vitro studies support this hypothesis
showing that corticosterone administration suppresses
local GABA release in the dmPFC (prelimbic cortex)—a
disinhibitory effect that would, in turn, lead to higher pyramidal
cell activation and strengthen the overall dmPFC
breaking effect on HPA activity (Hill et al., 2011).
OK - fascinating! I was wondering the connection of cortisol to GABA levels from alcohol.
This is really fascinating! So there is a permanent Negative Feedback DARK SIDE BRAIN cortisol genetic expression damage in the Pre-frontal cortex - while the "peripheral" cortisol levels are LOWER due to increased tolerance levels. So it turns the whole frequency spirit level of the body upside down. Then during alcohol dosage the brain cortisol levels decrease due to the now positive feedback to react against the increased body cortisol levels (from the adrenal - liver processing of the alcohol).
And then during withdrawal the brain cortisol levels spike even worse until they get that positive feedback again from the alcohol through the adrenal cortisol levels.
Totally Fascinating! This is very similar to a Sugar High - causing sugar to have be sequestered from the extremities... after the sugar low....
But obviously with alcohol it's much worse....
and so there is permanent brain damage:
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