Цитата: От пользователя: news@e1.ru THP или allopregnanolone служит естественным транквилизатором.
Neuroactive steroids, such as the 3-reduced metabolites of
progesterone, 3,5-tetrahydroprogesterone (3,5- THP or allopregnanolone ),
can positively
modulate GABAA receptors.
Neuroactive steroids, such as the 3-reduced metabolites of
progesterone, 3,5-tetrahydroprogesterone (3,5- THP or allopregnanolone ),
can positively modulate GABAA receptors.
Уж если природа придумала так, чтобы в переходный период человек вел себя так, а не иначе, значит так надо. В переходный возраст ребенок многому учится имхо психологически, а так вырастет вечный ребенок или неустойчивый к стрессам взрослой жизни человек, а ничего поделать уже будет нельзя.
Neuroactive steroids, such as the 3-reduced metabolites of
progesterone, 3,5-tetrahydroprogesterone (3,5- THP or allopregnanolone ),
can
positively modulate GABAA receptors.125 Interestingly, CSF
allopregnanolone levels are significantly lower in depressed patients,
and normalized by treatment with fluoxetine or fluvoxamine.126
Similarly, plasma levels of allopregnanolone are reported to be
decreased in
depression and levels restored by effective antidepressant
treatment.127 Fluoxetine and paroxetine have been shown to increase the
concentration of allopregnanolone in rat brain.128 Allopregnanolone
itself has been shown to have an antidepressant-like effect in rat and
mouse forced swim tests.129,130 These effects are thought to be
mediated by GABAA receptors as they are blocked by GABAA receptor
antagonists.129 Levels of allopregnanolone are also reduced in the
frontal cortex of mice that have undergone protracted isolation--a
behavioral manipulation that induces depression-like behaviors. In the
rat olfactory bulbectomy model of antidepressant-like activity, removal
of the olfactory bulbs caused a significant decrease in frontal cortex
levels of allopregnanolone which was reversed by chronic
treatment with
antidepressants of various classes.131 Interestingly, various SSRIs
have been shown to increase allopregnanolone production through
increasing the rate of synthesis of allopregnanolone.132
Neuroactive steroids, such as the 3-reduced metabolites of
progesterone, 3,5-tetrahydroprogesterone (3,5- THP or allopregnanolone ),
can positively modulate GABAA receptors.125 Interestingly, CSF
allopregnanolone levels are significantly lower in depressed patients,
and normalized by treatment with fluoxetine or fluvoxamine.126
Similarly, plasma levels of allopregnanolone are reported to be
decreased
in depression and levels restored by effective antidepressant
treatment.127 Fluoxetine and paroxetine have been shown to increase the
concentration of allopregnanolone in rat brain.128 Allopregnanolone
itself has been shown to have an antidepressant-like effect in rat and
mouse forced swim tests.129,130 These effects are thought to be
mediated by GABAA receptors as they are blocked by GABAA receptor
antagonists.129 Levels of allopregnanolone are also reduced in the
frontal cortex of mice that have undergone protracted isolation--a
behavioral manipulation that induces depression-like behaviors. In the
rat olfactory bulbectomy model of antidepressant-like activity, removal
of the olfactory bulbs caused a significant decrease in frontal cortex
levels of allopregnanolone which was reversed by chronic
treatment with
antidepressants of various classes.131 Interestingly, various SSRIs
have been shown to increase allopregnanolone production through
increasing the rate of synthesis of allopregnanolone.132
There is a wealth of data implicating GABAB receptors in
depression.
There are a number of reports in the literature of chronic
administration of antidepressants or electroconvulsive therapy
increasing the binding and function of GABAB receptors in the frontal
cortex of mice and rats.133-137 However, these findings have not
been
repeated by some groups.138,139 Furthermore, in the olfactory
bulbectomy model of depression, removal of the olfactory bulbs was
associated with a significant reduction in GABAB, and a significant
increase in GABAA receptor densities.140,141 The increase in GABAA
receptors was normalized by chronic treatment with antidepressants.142
In the learned helplessness model of antidepressant activity, GABA
release is diminished in the hippocampus in helpless rats and this is
reversed by desipramine treatment in line with the effects on
helpless
behavior.141 Interestingly, the selective GABAB receptor antagonist,
CGP36742, has been shown to be efficacious in the rat learned
helplessness model of antidepressant activity.143 Another GABAB
antagonist, CGP56433, also shows antidepressant-like effects in the
rat
forced swim test.144 Interestingly, GABAB1 knockout mice have an
antidepressant-like phenotype in the forced swim test.145 Furthermore,
GABAB receptor antagonists, CGP 36742, CGP 56433A, and CGP 56999A,
produce rapid increases in nerve growth factors, NGF and BDNF in
neocortex and hippocampus, an effect also seen after chronic
administration of antidepressants (see Neurotrophins).146
The putative role of GABA, GABAA, and GABAB receptors in depression
could be mediated directly by GABA or via other neurotransmitter
systems.
There are pieces of evidence linking GABAB receptors to
noradrenergic and serotonergic systems. For example, administration of
GABAB receptor antagonists has also been demonstrated to cause
downregulation of Гџ-adrenoceptors-an effect common to chronic
administration of a
number of types of antidepressants.135,147 The
GABAB antagonist, phaclofen, as well as the GABAA receptor antagonist,
bicuculline, increased norepinephrine release in the median preoptic
nucleus in vivo. Conversely, locally applied agonists of GABAA and
GABAB receptors
(muscimol and baclofen, respectively) decreased
dialysate levels of norepinephrine in the same area. These data
indicate that GABAA and GABAB receptors are involved in the control of
norepinephrine release in this part of the rat brain.148 Given the
established role of
norepinephrine in depression and the treatment
thereof, such effects on the noradrenergic system could contribute to
the antidepressant effects of GABA receptor ligands.
There are also considerable data supporting a relationship between
GABAergic and serotonergic
systems in the CNS. Allopregnanolone has
been demonstrated to directly affect the serotonin system. In rats
treated with allopregnanolone for 7 days, the firing rats of
serotonergic neurones in the dorsal raphe were increased.149 Given the
hypothesis that serotonergic
neurotransmission is reduced in
depression, such an effect could contribute to the antidepressant-like
effects of allopregnanolone. Administration of the GABAB receptor
agonist, baclofen, increases serotonin release from the dorsal raphe as
well as, to a lesser extent,
striatum.150 Local infusion of the GABAA
receptor antagonist, bicuculline, increases serotonin release in the
dorsal raphe, indicating that GABA afferents exert a tonic inhibitory
influence on serotonin neurones in the dorsal raphe.151 Given the
serotonin hypothesis of
depression, the efficacy of GABAA receptor
agonists, and GABAB receptor antagonists could, at least in part, be
attributed to these effects on serotonergic transmission. In terms of
behavioral effects of GABAergic drugs, the profile of the GABAB
antagonist, CGP56433 in the
forced swim test indicates a
serotonin-mediated effect; CGP56433 decreases immobility and increases
swimming, a profile comparable with fluoxetine.144 Depletion of
serotonin prevents the effects of GABAB receptor antagonists in this
model, further suggesting that the effect
involves an interaction with
serotonin.144 Reports in the literature also support an interaction
between GABAergic and dopaminergic systems. Local application of a
GABAA receptor antagonist (bicuculline) increases striatal dopamine
release, whereas the GABAA receptor agonist
muscimol has the opposite
effect.152 Administration of a GABAB receptor agonist (baclofen) has no
effect on striatal dopamine levels alone; however, it has been shown to
attenuate nicotine-, morphine-, and cocaine-evoked dopamine release in
the shell of the nucleus
accumbens.153
In summary, GABA is strongly implicated in depression such that GABA
receptors are potential targets for the development of novel
antidepressants. As the GABAergic system is closely linked to
monoaminergic neurotransmitter systems, manipulations of the
GABAergic
system are very likely to affect other neurotransmitter systems and
vice versa. To what extent the effects of antidepressants on the
GABAergic system contribute to the efficacy of these drugs as
antidepressants remains to be determined.
In the
area of depression research, interest in central peptide systems
has focused on the high-profile efforts targeting receptors of the
central substance P [neurokinin 1 (NK1)] and corticotropin-releasing
factor (CRF1) systems. This has led to the development of numerous
compounds now in clinical trials for depression. In addition to NK1 and
CRF1, however, interest has also fallen on receptors involved in
mediating the effects of other central peptidergic systems. These
include examples such as melanin-concentrating hormone (MCH) and
arginine vasopressin, which are discussed below. Whereas interest in
peptidergic systems as platforms for antidepressant development has
grown, it is important to note the frustration recognized by the lack
of success in the clinic to date. In this section, we will provide a
brief overview of several central peptidergic systems, which have been
implicated in the pathophysiology of depression, and are currently
considered as emerging targets for novel antidepressant development.
Substance P
Substance P (SP) is an undecapeptide member
of the tachykinin family of
mammalian neuropeptides, which also include neurokinin A and neurokinin
B. SP is the most abundantly expressed of the tachykinins in the CNS,
and had originally been shown to modulate pain transmission in the
spinal cord.154 SP also acts as a
neuromodulator in the CNS acting to
regulate an array of stress-related behaviors, autonomic control of
cardiovascular and respiratory function, as well as emetic
reflexes.155-157
The rationale behind the SP system as a target for depression has been
reiterated
frequently and is assembled from several lines of evidence.
Firstly, the expression profile of SP and its receptors is observed
within regions of the CNS that are traditionally associated with the
regulation of stress responses (e.g., amygdala, hypothalamus,
hippocampus, and
frontal cortex). Secondly, both acute and chronic
stressors (e.g., immobilization, foot shock, maternal separation) have
been shown to increase SP content (synthesis/release) in these
areas.158-160 Central administration of SP or NK1 agonists induces
stress-related behaviors
in animal models.160-162 Elevated levels of
SP in plasma and CSF are observed in patients with depression.163
The effects that SP exerts are primarily mediated through the NK1
receptor, and subsequently this receptor has emerged as a target for
antidepressant
development. NK1 is a member of the class-A GPCR family
of receptors that also include NK2 and NK3.164 In the CNS,
autoradiographic and immunohistochemical techniques have revealed
extensive expression of NK1 receptors in regions involved in modulating
affective behaviors,
and the neurochemical response to stress (e.g.,
hypothalamus, hippocampus, nucleus accumbens, raphe nucleus).165 SP
exhibits inhibitory effects on monoaminergic neurotransmission under
physiological conditions that are mediated through NK1, and NK1
antagonists have been
shown to enhance firing rates of dopaminergic,
noradrenergic, and serotonergic neurons.166 Collectively, these data
have helped support the rationale behind the antidepressant hypothesis
of NK1 receptor antagonism, and has resulted in the development of
numerous
NK1-selective antagonists as potentially novel
antidepressants. To date, numerous NK1-selective antagonists have been
developed and reported by drug companies to demonstrate
antidepressant-like profiles in a range of preclinical animal
models.167
Despite the
preclinical evidence, the track record of NK1 antagonism in
humans has been one of disappointment. This has been largely influenced
by the rather high-profile failure of aprepitant in the clinic. In
initial phase II studies, aprepitant had shown promising antidepressant
results in a small population of depressed patients, but fell short of
reaching efficacy in five larger phase III studies, thus failing to
provide Merck a proof-of-concept for NK1 antagonism.168 Skepticism in
NK1 antagonism as a novel mechanism of action following these
results,
although widespread in the Pharmaceutical Discovery community, has not
slowed interest in the continued clinical development of other NK1
antagonists. This is evidenced by appearance of numerous other NK1
antagonists in clinical development (Table 2).
TABLE 2. Compounds Targeting Peptidergic Receptors with Potential
Utility as Antidepressants
In contrast to NK1, comparatively less interest has fallen on the NK2
receptor as target for depression. Clinical development of NK2
antagonists has historically focused on inflammatory conditions such as
obstructive airways disease.169 However, support from preclinical
findings in rodent models has suggested potential for novel
antidepressant-like activity for different, receptor-specific, approach
of the same system.170 Adding to the antidepressant rationale, NK2
antagonism has also been shown to attenuate stress induced increases in
locus coeruleus firing and norepinephrine release in the prefrontal
cortex.171 Compounds such as SR48968 (Saredutant) have now entered
clinical trials for depression where this approach will to be tested.
Novel approaches that target the central SP systems have also been
contemplated, which feature molecules that combine NK1 antagonism with
selective serotonin reuptake inhibition (SSRI). This has been based
in
large part by observations from neurochemical evidence. For instance,
increases in extracellular serotonin levels elicited with SSRI
(paroxetine) treatment are significantly more robust in NK1-/- mice
when compared with wild-type controls.172 Preclinical evidence
appears
to support this approach as coadministration of an NK1 antagonist
(GR205171 or L733060) and an SSRI (paroxetine) produced similar
increases in cortical extracellular serotonin, as well as
antidepressant-like activity in preclinical models of depression.173
Together, the evidence implies that the antidepressant-like effects of
NK1 antagonism may be mediated through modulation of serotonergic
activity, which may be potentiated by also including a SSRI component.
Small molecules that combine NK1 antagonism with serotonin
reuptake
inhibition (NK1/SSRI) have now been reported, and these compounds
exhibit antidepressant-like activity in animal models sensitive to
either SSRI and NK1 antagonists.174
CRF
CRF is a 41-amino acid peptide.175 The CRF system extends throughout
the
CNS and plays an important role integrating the body's endocrine,
autonomic, immune, and behavioral responses to stress.176,177 Through
neurosecretory terminals in the median eminence, CRF-synthesizing
neurons of the hypothalamic paraventricular nucleus (PVN) release CRF
into portal circulation of the anterior pituitary, where CRF stimulates
release of ACTH from corticotrophs into peripheral circulation. This
positions CRF as an important mediator of
hypothalamic-pituitary-adrenal (HPA) axis activity. CRF projections are
also observed in
numerous extrahypothalamic sites, including key limbic
areas (e.g., amygdala, bed nucleus of the stria terminalis), consistent
with its involvement in affective behavioral responses to stress.177
CRF neurons are also found in several brain stem nuclei (e.g., locus
coeruleus,
nucleus of solitary tract) involved in controlling autonomic
components of the stress response.177
Several lines of evidence have linked hyperactivity of the central CRF
system with depression in humans. The best understood link is drawn
from the well-described role
of CRF as the principle mediator of ACTH
release from the pituitary, which is central to regulation of the HPA
axis. This is relevant to depression as hyperactivity of the HPA axis
is one of the most consistent clinical findings in depressed patients,
and can be normalized
after successful antidepressant treatment.178,179
Increased levels of CRF are directly associated with HPA disturbances
in subpopulations of depressed patients.179,180 Moreover, elevated
levels of CRF in CSF, decreased CRF receptor binding in the frontal
cortex, and
increased numbers of CRF neurons in the PVN are all
observed in depressed patients.181,182
The biological effects of CRF are mediated by two class-B GPCRs, CRF1
and CRF2. CRF1 has emerged as the target of interest for antidepressant
development based on the following
lines of evidence. CRF1 is the
receptor subtype expressed on corticotrophs of the anterior pituitary,
and thus responsible for mediating CRF effects on ACTH release and the
HPA axis. CRF1 antagonists exhibit the ability, in preclinical animal
models, to block many of the
behavioral and endocrine responses to
stress. For example, CP-154,526 (antalarmin), one of the first CRF1
antagonists to reach clinical trials in humans in depression, produces
antidepressant-like activity in learned helplessness (rats) and chronic
mild stress (mice)
paradigms, as well as attenuation of stress-induced
hyperthermia, distress vocalizations, and cortical norepinephrine
release.183-185 DMP696, SSR125543, and R278995/CRA0450 are examples
of other CRF1 antagonists that have been developed which also have
antidepressant-like
activity reported in preclinical rodent models,
helping to further support the proof of concept for this mechanism of
action.186,187
Despite the preclinical picture for CRF1 antagonism as a novel
mechanism of action for antidepressant development, only one compound
to date, R121919 (Janssen), has demonstrated antidepressant efficacy in
clinical trials.188 Unfortunately, clinical development of this
compound was ultimately discontinued (believed to be because of
hepatotoxicity), and the initial report was never confirmed in larger
studies. This has left the field to wait for the outcome of clinical
evaluation of the numerous other CRF1 antagonists that have undergone
development as antidepressants.
MCH receptors
MCH is a 19-amino acid cyclic neuropeptide synthesized by
neurosecretory
cells of the mammalian lateral hypothalamus and zona
incerta.189 MCH-synthesizing neurons of these nuclei project throughout
the CNS comprising a broad circuitry of innervation, modulating areas
involved in regulating energy homeostasis, feeding and mood-related
behaviors,
arousal, sensorimotor integration, and autonomic
control.190,191
Two GPCRs mediate the effects MCH in primates, MCH1-R and MCH2-R. To
date, MCH1-R (also known as somatostatin-like receptor 1 or SLC-1) is
the only subtype identified in rats. Drug discovery interest in
the
central MCH system has historically focused on targeting the effects of
this peptide on feeding behavior (orexigenic) and energy homeostasis
(metabolic), with MCH1-R antagonism emerging as a novel approach for
development of anorectic and anti-obesity compounds.
Evidence, however,
has also implicated the MCH system in regulating mood and the stress
response. Local administration of MCH into the nucleus accumbens shell
has been reported to produce depressant-like behavioral effects in the
rat forced swim test.191 MCH also produces
stimulatory effects on HPA
axis reactivity, as evidenced by the increases in circulating ACTH and
cortisol levels reported following central administration of MCH or
direct infusion of MCH into the hypothalamic paraventricular
nucleus.192 MCH also increases CRF release from
hypothalamic explants,
an effect that could be blocked by a selective SLC-1 (rat ortholog of
MCH1-R) antagonist.192
MCH1-R antagonists have been the preferred approach for targeting the
central MCH system for antidepressant development. Although T-226296
was the
first MCH1-R selective antagonist to be reported, SNAP-7941 was
the first compound to have behavioral effects in preclinical models of
depression reported. SNAP-7941 produced antidepressant-like
