Full text of DOI:10.1007/BF03344031

J. Endocrinol. Invest. 25: 420-425, 2002
Alprazolam, a benzodiazepine, does not modify the ACTH
and cortisol response to hCRH and AVP, but blunts the
cortisol response to ACTH in humans
S. Grottoli, B. Maccagno, J. Ramunni, L. Di Vito, R. Giordano, L. Gianotti,
S. Destefanis, F. Camanni, E. Ghigo, and E. Arvat
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin,
Turin, Italy
ABSTRACT. Alprazolam (AL), a benzodiazepine
which activates gamma-amino butyrric acid (GA-
BA)-ergic receptors, exerts a clear inhibitory ef-
fect on the activity of the hypothalamo-pitu-
itary-adrenal (HPA) axis and is able to marked-
ly reduce the ACTH response to metyrapone-
induced inhibition of glucocorticoid feedback.
It has been suggested that its inhibitory action
could be regulated by CRH or AVP mediated
mechanisms. However, the effect of benzodi-
azepines on the HPA response to CRH or AVP is
contradictory. It has been shown that benzodi-
azepines have specific receptors on the adrenal
gland but it is unclear if they mediate biological
effects in humans. In order to further clarify the
mechanisms underlying the inhibitory effect of
benzodiazepine on HPA axis in humans, we
studied the effect of AL (0.02 mg/kg po at –90
min) or placebo in 7 healthy young volunteers (7
female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22
kg/m2) on: 1) the ACTH and cortisol responses
to hCRH (2.0 μg/kg iv at 0 min) or AVP (0.17
U/kg im at 0 min); 2) the cortisol, aldosterone
and DHEA responses to ACTH 1-24 (0.06 and
250 μg iv at 0 and 60 min, respectively). After
placebo, the ACTH and cortisol responses to
hCRH (peaks, mean SE: 29.8 4.4 pg/ml and
199.3 19.6 μg/l) were similar to those record-
ed after AVP (31.7 6.5 pg/ml and 164.8 18.0
μg/l); the cortisol response to 0.06 μg ACTH
(190.4 11.8 μg/l) was similar to that recorded
after hCRH and AVP but lower (p<0.01) than
that after 250 μg ACTH (260.6 17.4 μg/l). AL
did not modify the ACTH response to both
hCRH (42.5 7.1 pg/ml) and AVP (33.3 2.7
pg/ml), which even showed a trend toward in-
crease. AL also failed to significantly modify the
cortisol response to both hCRH (156.3 12.7
μg/l) and AVP (119.4 14.5 μg/l), which, on the
other hand, showed a trend toward decrease.
The cortisol peaks after 0.06 μg ACTH were sig-
nificantly reduced (p<0.02) by AL pre-treatment
(115.0 7.7 μg/l) which, in turn, did not modify
the cortisol response to the subsequent ACTH
bolus (214.7 16.6 μg/l). The DHEA and aldos-
terone responses to all the ACTH doses were
not significantly modified by AL. In conclusion,
these data show that the HPA response to AVP
as well as to hCRH is refractory to the inhibito-
ry effect of AL which, in turn, blunts the cortisol
response to low ACTH dose. These findings
suggest that both CRH- and AVP-mediated
mechanisms could underlie the CNS-mediated
inhibitory effect of AL on HPA axis; in the mean-
time, these results suggest that benzodiaze-
pines could also act on adrenal gland by blunt-
ing the sensitivity of the fasciculata zone to
ACTH.
(J. Endocrinol. Invest. 25: 420-425, 2002)
©2002, Editrice Kurtis
INTRODUCTION
Alprazolam (AL) is a benzodiazepine which pos-
sesses a marked inhibitory effect on the activity of
hypothalamo-pituitary-adrenal (HPA) axis both in
animal and in man (1-9). The inhibitory effect of
benzodiazepines, particularly of AL, on HPA in-
cludes their ability to increase central gamma-
amino butyrric acid (GABA)-A activity, which plays
Key-words: Alprazolam, hCRH, AVP, ACTH, cortisol.
Correspondence: Prof. Emanuela Arvat, Divisione di Endocrinologia,
Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy.
E-mail: emanuela.arvat@unito.it
Accepted November 26, 2001.
420

Inhibitory effect of alprazolam on HPA axis in humans
The study was approved by the local Ethical Committee of the
University of Turin and informed consent was obtained from all
subjects.
a major role in the neural control of HPA axis (10).
In humans, AL significantly reduces spontaneous
ACTH and cortisol secretion 24 h urinary cortisol
levels (11), the ACTH and cortisol response to
stress as well as to AVP, naloxone, an opioid an-
tagonist, and hexarelin, a synthetic GH secreta-
gogue (3, 5, 6-9, 11, 12). More recently, AL has
even been shown to markedly inhibit the corti-
cotroph response to metyrapone-induced removal
of the negative glucocorticoid feedback (13), sug-
gesting a crucial role of GABA-ergic pathways on
the neuroregulation of HPA axis. Animal and hu-
man studies suggested a CRH-mediated action for
benzodiazepines, in agreement with evidence that
GABA has an inhibitory role on CRH-secreting
neurons and that AL does not modify the cortisol
response to hCRH (4, 14-17). However, in humans
the HPA response to hCRH has been reported to
be reduced by temazepam, suggesting an AVP-
mediated mechanism of action of benzodiaze-
pines (18), in agreement with data in vitro and in
vivo showing that both benzodiazepines and GA-
BA inhibit hypothalamic AVP release (19-20). The-
se data are, however, in disagreement with the ev-
idence in humans showing that AL blunts HPA re-
sponse to AVP (8).
It has been demonstrated that benzodiazepines
have also specific receptor subtypes in animal and
human adrenal gland (21) and some data indicate
that these receptors are likely to play a major role
in the regulation of the adrenal steroidogenesis as
well as in the adrenal response to stress in infant
rats (22-24). However, the effect of benzodiazepines
on the adrenal response to ACTH has never been
studied in humans.
Based on the foregoing, we had 2 aims in the pre-
sent study of healthy young volunteers: 1) to fur-
ther verify the effects of AL on the ACTH and cor-
tisol response to hCRH or AVP; 2) to study the ef-
fects of AL pre-treatment on the adrenal response
to low and supramaximal ACTH doses.
All subjects underwent the following treatments, in random or-
der and at least 3 days apart, starting at 07:00 h after an
overnight fast and 30 min after venous cannulation kept patent
by slow infusion of isotonic saline: 1) placebo (po at –90 min) +
hCRH (2.0 μg/kg iv at 0 min); 2) placebo + AVP (0.17 U/kg im at
0 min); 3) AL (1.0 mg po at -90 min, approximatively 0.02 mg/kg
in subjects of 54.5 1.8 kg) + hCRH; 4) AL + AVP; 5) placebo +
ACTH (ACTH 1-24, 0.06 and 250 μg iv at 0 and 60 min, respec-
tively); 6) AL + ACTH.
In testing sessions 1-4, blood samples were taken at -90 and 0
min and then every 15 min up to 120 min after iv administration
of hCRH or AVP. In testing sessions 5 and 6, blood samples were
taken at –90 and 0 min and then at +15, +30, +60, +90 and
+120 min.
All samples from an individual subject were analyzed together
for ACTH and cortisol in testing sessions 1-4 or for cortisol, al-
dosterone and DHEA in testing sessions 5 and 6.
Plasma ACTH levels (pg/ml) were measured in duplicate by IR-
MA (Allegro HS-ACTH, Nicholls Institute Diagnostic, San Juan
Capistrano, U.S.A.). The sensitivity of the assay was 1.0 pg/ml.
The inter- and intra-assay coefficients of variation ranged from
2.4 to 8.5% and from 3.9 to 9.9%, respectively.
Serum cortisol levels (μg/l) were measured in duplicate by RIA
(CORT-CTK 125, IRMA, SORIN, Saluggia, Italy). The sensitivity of
the assay was 0.2 μg/l. The inter- and intra-assay coefficients of
variation ranged from 4.3 to 14.6% and from 5.7 to 9.9%, re-
spectively.
Serum DHEA levels μg/l were measured in duplicate by RIA
(Active DHEA, Diagnostic Systems Laboratories, Webster,
U.S.A.). The sensitivity of the assay was 0.02 ng/ml. The inter-
and intra-assay coefficients of variations ranged from 11.2 to
13.7 % and from 5.2 to 6.2%, respectively.
Serum aldosterone levels (pg/ml) were measured in duplicate
by RIA (Aldosterone, MAIA, RIA Biochem Immunosystems
Company, Casalecchio di Reno, Bologna, Italy). The sensitivity of
the assay was 6 pg/ml. The inter- and intra-assay coefficients of
variations ranged from 11.9 to 14.1% and from 5.8 to 12.5%,
respectively.
The hormonal responses are expressed either as absolute values
or as AUC, calculated by trapezoidal integration.
The statistical analysis was carried out using a non-parametric
ANOVA (Friedman test) and then with Wilcoxon test. Results are
expressed as mean SE.
MATERIALS AND METHODS
RESULTS
Peptides and drugs
Vials containing 100 μg hCRH (Human CRH) were purchased
from Ferring (Kiel, Germany). Vials containing 20 U AVP were
purchased from Parke-Davis (Berlin, Germany). Vials containing
250 μg ACTH 1-24 (tetracosactin, Synacthen) were purchased
from Novartis Farma (Varese, Italy). Tablets containing 0.5 mg
AL (Xanax) were purchased from Pharmacia&Upjohn (Milan,
Italy).
Basal hormonal levels in various testing sessions
without AL pre-treatment were similar.
After placebo pretreatment, the ACTH and cortisol
responses to hCRH (peaks, mean SE: 29.8 4.4 vs
17.4 3.1 pg/ml and 199.3 19.6 vs 114.8 12.3
μg/l, p<0.05) were similar to those recorded after
AVP (31.7 6.5 vs 14.9 3.5 pg/ml and 164.8 18.0
vs 107.2 8.5 μg/l, p<0.05) (Fig. 1).
Study design
The cortisol response to 0.06 μg ACTH (190.4 11.8
vs 115.6 12.9 μg/l, p<0.05) was similar to that
Seven healthy young women (age 26-34 yr; wt 50-58 kg, BMI
20-22 kg/m2) were studied in their early follicular phase.
421

S. Grottoli, B. Maccagno, J. Ramunni, et al.
240
120
60
30
Placebo+h CRH
AL+hCRH
0
0
60
Placebo+AVP
AL+AVP
240
30
0
120
Fig. 1 - Mean SE ACTH and cortisol re-
sponses to hCRH or AVP preceded by
placebo or alprazolam (AL) in healthy
subjects.
0
-90
0
30
60
90
120
Time (min)
-90
0
30
60
90
120
recorded after hCRH and AVP but lower (p<0.01)
than after 250 μg (260.6 17.4 vs 136.1 12.3 μg/l,
p<0.05) (Fig. 2).
The cortisol response to 0.06 μg ACTH was sig-
nificantly reduced (p<0.02) by AL pre-treatment
(115.0 7.7 vs 78.4 4.5 μg/l) which, in turn, did
not modify the cortisol response to the subse-
quent ACTH bolus (214.7 16.6 vs 84.9 4.5 μg/l)
(Fig. 2).
ACTH administration also induced a significant and
dose-related (p<0.02) DHEA increase (0.06 μg:
12.6 1.0 vs 8.1 0.5 μg/l, p<0.05; 250 μg: 19.1 2.5
vs 8.2 1.0 μg/l, p<0.05), while the aldosterone re-
sponse to 0.06 μg ACTH was lower than that to 250
μg, though this, difference did not attain statistical sig-
nificance (0.06 μg: 214.1 17.0 vs 146.3 15.4 pg/ml,
p<0.05; 250 μg: 266.4 30.0 vs 131.5 11.0 pg/ml,
p<0.05).
AL did not significantly modify DHEA and aldos-
terone responses to both 0.06 and 250 μg ACTH
300
ACTH
0.06 µg
ACTH
250 µg
AL pre-treatment lowered (p<0.05) basal cortisol
and DHEA but not ACTH and aldosterone levels.
AL pre-treatment did not significantly modify the
ACTH response to both hCRH (42.5 7.1 vs
12.7 1.7 pg/ml) and AVP (33.3 2.7 vs 14.4 2.8
pg/ml), which showed even a non-significant trend
toward increase.
AL did not significantly modify the cortisol response
to hCRH (156.3 12.7 vs 90.5 12.7 μg/l) or AVP
(119.4 14.5 vs 88.1 8.0 μg/l) which, however,
showed a trend toward decrease (Fig. 1).
By evaluating ACTH/cortisol ratios during hCRH
and AVP sessions both alone and after AL pre-
treatment, an increase in ACTH/cortisol ratios was
recorded when hCRH or AVP had been preceded
by AL (p<0.05).
200
100
0
*
*
Placebo+ACTH
AL+ACTH
-90
0
30
60
90
120
Time (min)
Fig. 2 - Mean SE cortisol responses to ACTH preceded by
placebo or alprazolam (AL) in healthy subjects. *p<0.02.
422

Inhibitory effect of alprazolam on HPA axis in humans
dose (DHEA, 0.06 μg: 8.8 1.0 vs 5.9 0.6 μg/l; 250
μg: 15.9 1.6 vs 6.6 0.9 μg/l; aldosterone, 0.06 μg:
240.1 54.5 vs 195.9 40.0 pg/ml; 250 μg: 393.0 96.0
vs 166.1 36.9 pg/ml).
inability of AL to inhibit the hCRH-induced ACTH
response which, in the present study, even sho-
wed a trend toward increase; this was coupled
with the opposite trend of cortisol response.
These findings fit well with the hypothesis that, at
least partially, the inhibitory effect of benzodi-
azepine on HPA axis involves negative influence
on CRH-secreting neurons.
Side-effects
Transient facial flushing was recorded in all subjects
after hCRH administration. Mild nausea and vaso-
constriction were recorded in all 3 subjects, re-
spectively, after AVP administration. No side-effect
was recorded after ACTH 1-24 administration. After
AL administration mild sleepiness was recorded in
4 subjects. No medication was required and there
was no need to interrupt the tests.
Our present results show that also the AVP-induced
corticotroph response is not reduced by AL pre-
treatment. Similarly to what observed after hCRH,
the ACTH response to AVP after AL even showed a
trend toward increase; once again this was coupled
with the opposite trend of cortisol release. Our re-
sults do not agree with previous ones showing a
slight but significant reduction of AVP-induced
ACTH and cortisol increase after AL (8). Different
study protocols and/or AVP or AL doses could ex-
plain this discrepancy. Indeed, our present findings
fit well with data in vitro and in vivo indicating that
benzodiazepines, as well as GABA, also play an in-
hibitory role on hypothalamic AVP release (19, 20).
Thus, our present results suggest that benzodi-
azepines exert their inhibitory effect on the HPA ac-
tivity via concomitant actions on both CRH- and
AVP-secreting neurons within the hypothalamus or
at a suprahypothalamic level within the hippocam-
pus, where GABA-A receptors have widely been
identified (27). This hypothesis could also explain
the marked inhibitory effect of AL on the corti-
cotroph responsiveness to metyrapone (13), which
probably acts concomitantly via central stimulation
of CRH and AVP release (28), and on HPA response
to canrenoate (29), an antagonist of the mineralo-
corticoid receptors.
It has been demonstrated that benzodiazepines
have specific receptor subtypes also in animal and
human adrenal gland (21). In animals these re-
ceptors play a role in the control of glucocorticoid
synthesis and release and there is evidence that
benzodiazepines influence the maturation of the
glucocorticoid responsiveness to stress in infant
rats (22-24). While the adrenal response to ACTH
has been reported to be reduced or unchanged
by benzodiazepines in animals (21), the effect of
these substances on the adrenal response to
ACTH in humans has never been studied. To ad-
dress this point we verified the effect of AL on cor-
tisol, DHEA and aldosterone responses to a very
low and the supramaximal ACTH doses, adminis-
tered as consecutive boluses. Our findings sho-
wed that AL clearly blunted the cortisol response
to the low but not to the supramaximal ACTH
dose. Notice that the cortisol response to the low
ACTH dose preceded by placebo was similar to
DISCUSSION
The results of the present study show that the HPA
response to AVP as well as that to hCRH are re-
fractory to the inhibitory effect of AL. The stimu-
latory effect of hCRH or AVP on HPA after AL pre-
treatment is characterized by an increase in ACTH/
cortisol ratios. Moreover, AL pretreatment blunts
the cortisol response to a low but not to the supra-
maximal ACTH dose. On the contrary, the re-
sponse of other adrenal steroids, namely DHEA
and aldosterone, to both low and supramaximal
ACTH doses is not modified by benzodiazepine
pre-treatment.
The strong central nervous system (CNS) mediated
inhibitory effect of AL, a benzodiazepine, on the ac-
tivity of HPA axis has clearly been demonstrated
both in animals and in humans (1-9, 12, 14, 15, 17).
The central mechanisms underlying the inhibitory
effect of benzodiazepines, particularly of AL, on
HPA activity involve the ability of benzodiazepines
to increase central GABA-A activity (10), which plays
a major role in the neuroregulation of HPA axis,
probably modulating the activity of CRH- and or
AVP-secreting neurons (4, 7-9, 14, 15, 17, 19, 20).
On the other hand, it has also been suggested that
AL may inhibit noradrenergic activity which, in turn,
plays stimulatory influence on corticotroph function
(5, 25-27).
In agreement with a CRH-mediated action for ben-
zodiazepines, AL has been shown to inhibit CRH
release in the locus coeruleus, in the paraventric-
ular nucleus and the serotonin-induced CRH re-
lease from rat hypothalamus (4, 14, 17), while it
does not modify either spontaneous or CRH-stim-
ulated ACTH release from isolated rat pituitary
cells (4, 15). In humans, AL has been reported to
be unable to modify the HPA response to hCRH
(9) which, however, was found blunted by te-
mazepam (18). Our present findings confirm the
423

S. Grottoli, B. Maccagno, J. Ramunni, et al.
7. Torpy D.J., Grice J.E., Hockings G.I., Walters M.M.,
Crosbie G.V., Jackson R.V. Alprazolam blocks the nalox-
one-stimulated hypothalamo-pituitary-adrenal axis in man.
J. Clin. Endocrinol. Metab. 1993, 76: 388-392.
that after hCRH or AVP. Thus, these findings point
toward direct inhibitory effect of AL on the adrenal
gland and agree with evidence that, after AL pre-
treatment, the HPA response to hCRH or AVP is
characterized by an increase in ACTH/cortisol ra-
tios. Therefore, benzodiazepines probably act on
the adrenal gland by reducing the sensitivity of
the fasciculata zone to ACTH; in fact, both DHEA
and aldosterone responses to ACTH were unaf-
fected by AL pre-treatment.
In conclusion, our study indicates that both CRH-
and AVP-mediated mechanisms are likely to un-
derlie the central inhibitory effect of AL on HPA
axis and points toward the hypothesis that ben-
zodiazepines also act on the adrenal gland by
blunting the sensitivity to ACTH in adrenal fasci-
culata zone. From a clinical point of view, these
results also point toward potential contraindica-
tion of AL administration in patients with sus-
pected hypoadrenalism.
8. Torpy D.J., Grice I.E., Hockings G.I., Walters M.M., Crosbie
G.V., Jackson R.V. Alprazolam attenuates vasopressin-stim-
ulated adrenocorticotropin and cortisol release: evidence
for synergy between vasopressin and corticotropin-re-
leasing hormone in humans. J. Clin. Endocrinol. Metab.
1994, 79: 140-144.
9. Roher T., von Richthofen V., Schulz C., Beyer J., Lehnert H.
The stress, but not corticotropin-releasing hormone-induced
activation of the pituitary-adrenal axis in man is blocked by al-
prazolam. Horm. Metab. Res. 1994, 26: 200-206.
10. Prichett D.B., Sontheimer H., Shivers B., et al. Importance
of a novel GABA A receptor subunit for benzodiazepine
pharmacology. Nature 1989, 338: 582-585.
11. Lopez A.L, Katol R.G, Noyes R. Reduction in urinary free
cortisol during benzodiazepine treatment of panic disor-
der. Psychoneuroendocrinology 1990, 15: 23-28.
12. Arvat E., Maccagno B., Ramunni J., et al. Effects of dex-
ametasone and alprazolam, a benzodiazepine, on the stim-
ulatory effect of Hexarelin, a synthetic GHRP, on ACTH,
cortisol and GH secretion in humans. Neuroendocrinology
1998, 67: 310-316.
ACKNOWLEDGEMENTS
This study was supported by MURST (n. 9906153187), Uni-
versity of Turin (grant 1998) and SMEM Foundation. The
Authors wish to thank Dr. M. Maccario for his support of the
study and A. Bertagna and A. Barberis for their skillful techni-
cal assistance.
13. Arvat E., Maccagno B., Ramunni J., et al. The inhibitory ef-
fect of alprazolam, a benzodiazepine, overrides the stim-
ulatory effect of metyrapone-induced lack of negative cor-
tisol feedback on corticotroph secretion in humans. J. Clin.
Endocrinol. Metab. 1999, 84: 2611-2615.
14. Cedarbaum J.M., Aghajanian G.K. Catecholamine recep-
tors on locus coeruleus neurones: pharmacological char-
acterization. Eur. J. Pharmacol. 1977, 44: 375-385.
REFERENCES
1. Charney D.S., Breier A., Jatlow P.I., Heninger G.R. Be-
havioural, biochemical and blood pressure responses to
alprazolam in healthy subjects: interactions with yohim-
bine. Psychopharmacology (Berl.) 1986, 88: 133-140.
15. Hashimoto K., Yunoki S., Takahara J., Ofuji T. ACTH re-
lease in pituitary cell cultures. Effects of neurogenic pep-
tides and neurotransmitter substances on ACTH release
induced by hypothalamic corticotropin releasing factor
(CRF). Endocrinol. Jpn. 1979, 26: 103-109.
2. Calogero A.E, Galactic W.T., Chrousos G.P., Gold P.W.
Interaction between GABAergic neurotransmission and rat
hypothalamic corticotropin-releasing hormone secretion
in vitro. Brain Res. 1988, 463: 28-36.
16. Gaillard R.C., Al-Damluji S. Stress and the pituitary-adrenal
axis. Baillieres Clin. Endocrinol. Metab. 1987, 2: 319-349.
3. Risby E.D., Hsiao J.K., Golden R.N., Potter W.Z. Intra-
venous alprazolam challenge in normal subjects. Bio-
chemical, cardiovascular, and behavioral effects. Psycho-
pharmacology (Berl.) 1989, 99: 508-514.
17. Owens M.J., Bissette G., Neneroff C.B. Acute effects of al-
prazolam and adinazolam on the concentrations of corti-
cotropin – releasing factor in the rat brain. Synapse 1989,
4: 196-202.
4. Kalogeras K.T., Calogero A.E., Kuribayiashi T., et al. In vit-
ro and in vivo effects of the triazolobenzodiazepine alpra-
zolam on hypothalamo-pituitary-adrenal function: phar-
macological and clinical implications. J. Clin. Endocrinol.
Metab. 1990, 70: 1462-1471.
18. Korbonits M., Trainer P.J., Edwards R., Besser J.M.,
Grossman A.B. Benzodiazepines attenuate the pituitary-
adrenal responses to corticotrophin-releasing hormone in
healthy volunteers but not in patients with Cushing’s syn-
drome. Clin. Endocrinol. 1995, 43: 29-35.
5. Zemishlany Z., McQueeney R., Gabriel S.M., Davidson M.
Neuroendocrine and monoaminergic responses to acute
administration of alprazolam in normal subjects. Neuro-
psychobiology 1990, 23: 124-128.
19. Wible J.H., Zerbe R.L., Di Micco J.A. Benzodiazepine re-
ceptor modulate circulating plasma vasopressin concen-
tration. Brain Res. 1985, 359: 368-370.
20. Hillhouse E.W., Milton N.G.N. Effect of noradrenaline
and gamma-aminobutyrric acid on the secretion of
corticotrophin-releasing factor-41 and arginine vaso-
pressin from rat hypothalamus in vitro. J. Endocrinol.
1989, 122: 719-723.
6. Breier A., Davis O., Buchanan R., et al. Effects of alprazo-
lam on pituitary-adrenal and catecholaminergic respons-
es to metabolic stress in humans. Biol. Psychiatry 1992, 32:
880-890.
424

Inhibitory effect of alprazolam on HPA axis in humans
21. Papadopolous V. Pheripheral-type benzodiazepine/di-
azepam binding inhibitor receptor: biological role in
steroidogenic cell function. Endocr. Rev. 1993, 14: 222-
240.
adrenoceptors involved in the regulation of rat growth hor-
mone secretion? Life Sci. 1986, 39: 1491-1498.
26. Plotsky P.M., Cunningham E.T., Widmaier E.P. Catechola-
minergic modulation of corticotropin-releasing factor and
adrenocorticotropin secretion. Endocr. Rev. 1989, 10:
437-445.
22. Yanagibashi K., Ohno Y., Nakamichim N., et al. Peripheral-
type benzodiazepine receptors are involved in the regu-
lation of cholesterol side chain cleavage in adrenocortical
mitochondrial. J. Biochem. 1989, 106: 1026-1029.
27. De Kloet E.R., Vreugdehil E., Oitzl M.S., Joels M. Brain cor-
ticosteroid receptor balance in health and disease. Endocr.
Rev. 1998, 19: 269-301.
23. Van Oers H.J.J., de Kloet E.R., Li C., Levine S. The on-
togeny of glucocorticoid negative feedback: influence of
maternal deprivation. Endocrinology 1998, 139: 2838-
2846.
28. Conte-Devolx B., Guillaume V., Boudouresque F., et al.
Effects of metyrapone infusion on corticotropin-releasing
factor and arginine vasopressin secretion into the hy-
pophysial portal blood of conscious, unrestrained rams.
Acta Endocrinol. 1992, 127: 435-440.
24. Zilz A., Hua L., Castello R., Papadopoulos V., Widmaier
E.P. Developmental expression of the peripheral-type ben-
zodiazepine receptor and the advent of steroidogenesis
in rat adrenal glands. Endocrinology 1999, 140: 859-864.
29. Arvat E., Maccagno B., Giordano R., et al. Mineralo-
corticoid receptor blockade by canrenoate increases both
spontaneous and stimulated adrenal function in humans. J.
Clin. Endocrinol. Metab. 2001, 86: 3176-3181.
25. Eriksson E., Carlsson M., Nilsson C., Soderpalm B. Does
alprazolam, in contrast to diazepam, activate alpha-2-
425