Neuroendocrine effects of benzodiazepines

J. psychiat. Rev., Vol. 24, Suppl. Printed in Great Briram

2, pp.

111-119,

0022.3956/90 $3.00 + .OO Cl 1990 Perganlon Prers plc

1990

NEUROENDOCRINE

EFFECTS OF BENZODIAZEPINES ERROL B. DE SOUZA

Laboratory of Neurobiology. Neurowience Branch, NIDA Addiction Research Center. Baltimore, MD 21224. U.S.A. Summary-Benzodiazepine administration has been associated with alterations in neuroendocrme function both in experimental animals and in humans. Clinical and laboratory data indicate that the beta-carbolines, a clabs of active benz,odiaLepine receptor inverse agoni%. cause behavioral and neuroendocrine changes characteristic of anxiety and stress. In contrast, the “classic” benlodiazepine receptor agonists such as diazepam can reduce anxiety and inhibit stress-induced increases in anterior pituitary hormone secretion. Although the site of action and mechanisms by which ben7odiarepines alter anterior pituitary hormone secretion are still under investigation, evidence suggests that the effects are mediated in the brain, primarily through actions at berxodiazepine receptors in the hypothalamus. The benLodiarepinea may act at GABA-coupled benrodiazepine receptors in the hypothalamus or other regions of rhe brain to potentiate the effects of endopenous GABA. It also is believed that brain monoamines may modulate the effects of endogenous GABA. Brain monoamines have also been reported to modulate the effects of benrodiazepines on stress-induced hypothalamic-pituitary-adrenocortical function. Direct effecta of the benzodiazepines on central- and peripheral-type benzodialepine receptors in the anterior pituitary have also been documented.

INTRODUCTION

has been implicated in the etiology of a variety of illnesses. including cancer, myocardial infarction, and various psychiatric disorders. It also is associated with a wide variety of physiological and behavioral responses characteristic of SELYE’S “general adapation syndrome” (1956). Data obtained both in clinical and laboratory settings have demonstrated that while the beta-carbolines, (a class of active benzodiazepine receptor inverse agonists) elicit behavioral and neuroendocrine changes reminiscent of anxiety and stress (FILE et ul., 1982; MAIEWSKI et ul., 1985; NINAN et ~1.. 1984). benzodiazepine receptor agonists such as diazepam can alleviate anxiety and inhibit stress-induced increases in anterior pituitary hormone secretion (GRANDEON. 1983). Substantial evidence suggests that the brain-particularly the hypothalamus-exerts a primary influence on anterior pituitary hormone secretion; therefore, a description of the site(s) of action of the benzodiazepines (brain, pituitary, and/or target organ) is necessary. Finally, because benzodiazepine receptors are part of a complex consisting of recognition sites for gamma-aminobutyric acid (GABA) and an associated chloride ionophore with multiple allosteric binding sites (TALLMAN et al., 1980), it is important to review the role of GABA and other neurotransmitters in modulating the effects of benzodiazepines on neuroendocrine function. STRESS

Address correspondence to Errol B. De Souza, Ph.D., Chief, Neurobiology Laboratory, Neuroscience Branch, NIDA Addiction Research Center, P.O. Box 5 180, Baltimore, MD 2 1224, U.S.A. III

liFtt:(“l3 The

Or; HEN%OI~I:\%EI’I~IES OV I’Hf: II\l’t’~~fti;\l.AM~~~-~l’l’l~ll;\li~-~\I~KI:NO~‘O1~1‘1~‘;21,ASIS

mqjor

endocrine

adrenocorticaI (CRF).

response

(HPA)

axis,

atirenocorticolropic

bcn/odia/epines elicits

on HPA

behavioral

to stress

hormone

(ACTI

funcrion

c’t(I/.. 10x5). Rhesus of diarcpam I~SI:I

19X.7:

adrcnocortical

function

increased

CI t/l..

(M.~Rc

corticnsteronu

benzodiazepine

effects

in plasni~i

c’t trl..

c’t trl..

1977:

L!\HrI

of stres\

by stress

studies

in vitro

corticosteronc exposure

significantly

decreased the pla~iia The

abnormal

including

myjor

panic/anxiety Evidence

receptor antagonist 19x5:

MOKVII.L)I.

primarily

Ro

on central-type

on stres\-

M:II<(’ cutt/l..

I IIC 01 t/l..

(S[II’t:KSl

01‘

There

c’t t/l..

g the rise

1977:

I975:

B\KI ()I{’

MoKhlf:l)l,

ct (I/..

7 ~iclriiini\lr3rioii

I%O)

of ;I

are significantI)

correlation

hel\veen the

in plasma a)rticostcroid\

displacement

in radioiigand

ctrcas-induced

to hc attenuated

tha! occur 1973:

(‘I ol..

i\ an excellent

in inhibitin

or drug-induced

Ic)O9: 12.\111.1(21 t/l..

and followin&

lnlr

in ;I doac-related

changes manner

binding

in plasma by prcnarai

(‘I t/l.. I9X4). of the ben/odiazepine\

(Bbwl~ ci c/l.. 19X.3). concentrations.

and

OXil/e[~i~lll

Furthermore.

to insulin-induced that occurs

hypoglycemia in ;I variety

ct ii/., 19X6). s;lcep tii5orders alter HPA

secretion

and beta-carboline

( Mj\ir:U’stii SIZIAIONS

benzodiazepine

10x4:

receptors.

(I~L:zKI)

diaqam

primarily

ct 01.. 19x4) and

through actions in the

which

are found

secretion

of‘ the hen/odia/cpinr

(‘I t/l.,

1’1 t/l..

disorders

ot‘ben/otlia/epines.

administratioii

BIT/I

1972).

c/ (I/..

of psychiatric (.41)>\bl

19x4)

c’f t/l.,

with

on basal and stress-induced

VI cl/.. 19X.5: IIusI-l.

(‘I c/l..

chlordia~~p~,xicle

(GKZM

treatment

was suppres\cd by administration

are reversed by concomitant

I’IX4:

of

dohc\

u ;I> cjb\crvcd after &ronic

glucocorlicoids

Additionally.

01‘ cortisol

IS- 17XX

closes high

19771 basal concentrations

in plasma

IO71;

KRI

that ben/odia/.epines

<‘/ r/l..

19X5:

on haal

while

been observed

at 3H-dia,epan~

1970).

(GK/\rvl

(11 (I/..

of low

1977).

(11 (I/..

or (I/.. 1972).

and corticosterone

(1~trl..

\timulatictn

(DAN I’/I:K c’t tr/.. 1976).

brain. The actions of henzodiazepines of ACTf-I

CJ~trl..

in “cont1ic.i” procedure\ (I,IPIJ,I

response

depression

suggests

I966:

cortisol

cortisol

(H:\v,IKD

havr

oral adtninialrnti~)ii

hypersccretion

~tdrninistr;ltion

197.5: KI:IVI

r’/ t/l..

afi‘initics

plasma

( M.AII:WS~I

I.\II’II

temayepani

lowered

I5- I7XX

KK~II.IK

Elevation\

in rats (SlhlEvlo~s

196X).

Ro

eO’ects of benrodiazepines

Acute

ben~odiazepincs

human volunteers.

f and ( MAII~WWI c’t r/l.. 19x5 ).

rat\

CRAU’I.IJ>~

I97l:

have been reported

I.l:K VI trl..

including

ct tr/.. 1966; KK~II.I~~ c’tr/l.. 197 I ).

(KK~Y.I~

u c’/ 01..

to dia/epani

In normal (BUI

their

ant1

(LI:Fr

The

administration.

potency of different

are accompanied

peptidea (ACT1

elTccts arc prevcntcd by ~lclillinistratiori

adrcnocorticul

~imphetaniine~

attenuated by ben/odiu/.epine

facto1

The efl’ccta of

of hcta-curholincs

which

vt t/l.. I9X4:

INSH.

I9XO;

c’t al..

I INI:

procedures

including

induced

(II.,

of benzodiazepine\

(‘t c/l., 1070).

ot‘ drugs

relative

ct

Flucocorticoids.

in “avoidance”

variety

( BRIiNI

S[~~‘l~~
I97c): Lt:l,[ll<

19x4).

19x5).

in rats. Sustained

t’ollov. ing application KI:rhl

19x4;

01‘ species

receptor antagonist

Ireatment (SIIPEKS

More consistent elevations

(NIN,\N c’f t/l..

1960;

of ;t variety

of anxiety.

in ;I variety

arc dose-dependent.

decreased

respectively.

of proopiomelanocortin-derived

CK~I\V~.I,Y 01 ~1..

ben/odiarepines

01‘ corticotropin-releasing

Atiministration

charactcri\tic

c’f (:/.. 19X.3). The beta-carbolinc

or the bena)diuapinc

c’f 01..

plamu

effects

and cortisol

monkeys

humans (DOIWW

of the hypothalaniic-pituit~u.~

secretion

I). and glucocorticoid,

arc complex.

concentrations

beta-cndorphin/beta-Iipolropin)

and

stimulation

in coordinated

and physiological

by increa\cs in plasm;t

involves

resulting

IOX4;

Ic)X4).

(‘KAu’I.I.\I.

Ro

c( (I/..

l.s- I7XX

in signif’icantly

act\

higher

NEUROENDOCRINEEFFECTS OFBENZODIAZWINES

II3

concentrations in the brain when compared to the pituitary gland or the adrenal cortex. More recently. direct effects of benzodiazepines have been demonstrated on CRF secretion from rat hypothalamic organ cultures (CALOGEROer al., 1988: BERNARDINIet al., 1987). In these studies, diazepam inhibited serotonin induced CRF secretion; the effect was reversed by the benzodiazepine receptor antagonist Ro 15-l 788 (CALOGEROet al., 1988). Furthermore, the benzodiazepine inverse agonist beta-carboline-3-carboxylic acid methylester was a potent stimulator of hypothalamic CRF secretion in 11it~1and its effects were antagonized by diazepam (CALOGEROet ~1.. 1988). The mechanisms of action by which the benzodiazepines produce their effects on CRF release are complex. GABAergic inhibition of the release of CRF and ACTH is well established (RACAC;NI ~‘f al., 1982). The benzodiazepines may act at GABA-coupled benzodiazepine receptors in hypothalamus or other brain regions to potentiate the effects of endogenous GABA. Brain monoamines have been postulated as potential modulators of the effects of benzodiazepines on stress induced HPA function. Acute (KEIM cl ul., 1977) or chronic prenatal (SIMMONS Pt N/., 1984) administration of diazepam in rats attenuated the reduction in hypothalamic norepinephrine evoked by stress, and in turn, inhibited the corticosterone responses to stress, suggesting that some of the effects of benzodiazepines may be mediated by catecholamines. Very recently, platelet activatin g factor has been reported to stimulate hypothalamic CRF secretion it? ,itw; this effect was inhibited by the triazolobenzodiazepine alprazolam (BERNARDINIet ml., 1987). In summary, the benzodiazepines probably alter HPA function through inhibition of hypothalamic release of CRF. EFFECTSOF BENZODIAZEPINESON THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Thyrotropin releasing hormone (TRH) is the primary regulator of thyroid stimulating hormone (TSH) release from the anterior pituitary. TSH enters the systemic circulation and stimulates the release of T3 and T4 hormone secretion from the thyroid gland. While diazepam does not alter basal secretion of TSH in rats, benzodiazepines, including diazepam and clonazepam, block the threefold to fivefold increase in TSH induced by exposure to cold (GRANDISONet u/., 1983: CAMORATTOet ul., 1983). The benzodiazepine receptor antagonist Ro IS-1788 was effective in reversing the clonaxepam inhibition of cold-induced TSH release (CAMORATTOet (~1.. 1983). Compelling evidence suggests that the increase in TSH release following exposure to cold is regulated primarily by a norepinephrine input that acts at the hypothalamic level (MORLEY, 1981). Thus, it is conceivable that the effects of benzodiazepines on cold induced TSH secretion may be regulated through indirect actions on norepinephrine secretion. Alternatively, benzodiazepines could act within the hypothalamus to potentiate the effects of GABA: GABA. as well as GABA agonists. inhibit the release of TSH following exposure to cold (MATTILA et al.. 1980). Since diazepam does not affect the ability of TRH to increase TSH secretion in \!it~-o (CAMORATTOet al., 1983), it is unlikely that the effects of benzodiazepines are mediated through actions on benzodiazepine receptors in the pituitary gland. Low concentrations (nanomolar) of a variety of benzodiazepines. including diazepam, flurazepam, chlordiazepoxide, midazolam and medazepam. have been reported to inhibit TRH induced TSH secretion from perifused rat pituitaries (ROIJSSEL et al.. 1986). The

antagonism

of the

diazepam actions

of

pituitary

diazepam from

(micromolar)

at GABA

the

inhibit.

c’t ul..

been

anterior

The

pituitary

pituitary

clonal

hormone

(DKLIMMO~U.

tumor

are

ct t/l..

cell

line

Basal

secretion

In addition,

at very

high

effective

of

doses

pharmacological

prolactin

lYX.3:

secretion

which

diazcpam

by

of

receptors.

\ince

and since

the relative

these

correspond

ben/odiaLepine

(BE/\KY

actions

nanomolar

stimulated

ben/odiazepine\ diazepam

and growth

from

at peripheral-type

of

dose

>>

addition.

is induced

by

Ro

a

precursor

S-

of‘ henLodiazepines

on

hen/odia/epine

15-178X

(Lore,

to produce

their

compounds

19X3)

inhibitory

at central-type

prolactin

secretion inhibited and

rank

from

order

clonazepam)

half-life. volunteer\

did

not alter

1979). arc evident.

secretion, basal primary for

i\

women

of prolactin

prolactin

(DoKo~.

a short

diazepam

sol\i C/ (I/..

affect

receptors.

secretion

with

in normal

(WII

pituitary

The

that

and

In

serotonin

symptoms.

’ glands

1YX.i).

ot

prolactin

thioridazine. 19X2).

centra-type

diazepam

dependently

hemipituitaq

henzodiazepine

of

anxiety

not

inhibition

I YX2).

secretion did

> diazapam

these

in

proestrus

inhibited

the

analogs

of prolactin

on anterior

(GRANDISON.

by

are and

increase

during

induced

secretion and

7 142 stimulates

with

induced

LOTZ.

I,~\,c) effects

product

prolactin

diazepam

S-4864

i/l

LOV.

FG

diarepam

release

19X2;

observed

physiological

occur\

bulpiride.

potencie\

1082:

of patients

stimulated

cells (Ro

of

benLodiazepinex

of

stress

by the antagonixt

concentrations

of ben/odia/rpincs

prolactin

The

hrcakdown

plasma

concentrations, pituitary

diazepam

in an anterior

benzodiazepines

to diar.epam

to be mediated

ligand

a major

concentrations.

micromolar anterior

order

ct c/I., t YX3). In a study

Direct

and

receptor

suppression

of henzodia/epine\

of the hen/.odia/.epine

rank

the

normally

fluoxetine

can he inhibited

beta-carboline

increased

that

of‘ prolactin

lYX2).

by

slight

However.

bloched

regard

hlockcr

(GK;\UUISON.

basal or metoclopramide At

and

prolactin

to a variety

GK:\CL)ISOU.

appear

potencies

Temazepam,

significantly

effects

to the

the

both

only

(haloperidol,

uptake

secretion

receptors

In humans, I YX3).

at its own

Sld‘RETiON

19X2).

a variety

19X3:

(GKANI)ISON. prolactin

With

stimulation

serotonin

hydroxytryptopharl inhibition

concentrations

receptors

unaffected with

dia/.epam

IY82).

potent

relatively

in prolactin

neuroleptics

the

OF the

of TRH

secretes

in response

of prolactin.

(GK.,Z“II)IsoN.

inhibited

i\

(GKA>UUISOV.

increase

GR:\NIIISON.

induced

metoclopramide)

in rat on TSH

diazepam,

of TRH

ON f’ROLAC1‘IN

LOT%, 1982)

example.

the

stimulation

combination

rats

\ecrction

For

prevented

(GR,INDISOY,

in

I YX?:

of benzodiazepines

stimuli.

and

pharmacological

effect\

prolactin

in blocking

prolactin

higher

chlordiazepoxide

antagonists

as GH3.

receptors

1YX.S).

GKNL)ISON.

19X3:

binding

of the

and specific

benLodiazepines

chlordiar.epoxide.

receptor

EFFEC‘TS OF HEN%OI>IA%EPlh’ES

(GKANDISON.

of

reversal

of direct

since

including

lYX4).

and the

benzodiaLepine effects

controversial

competitive

known

iS-17X8

are suggestive

irl \,if~~

fashion,

to act as specific

Ro

central-type

direct

of ben/.odiazepines

1YX-C: SIMASKO

by

by picrotoxin

coupled,

in a competitive

shown

effects

response

c’t ul.. 1986).

of a variety

t’lurazepam (SHARII;

benaodiazepine

of the TSH

(Ror~ss~t.

secretion

have

irl ~itr’o

inhibition

the

indicative

Peripheral-type

whereas

and

at

secretagogue cultures

latter of

of rat

effects

ot

actions

of

henzodiazepine

receptors are found in significantly higher concentrations in the anterior pituitary when compared to central-type benzodiazepine receptors (GKANDISON, 19X3; DESOUZA et al., 1985). In other studies, however, nanomolar concentrations of diazepam (SCHETTINIet al., 1984) and clonazepam (ANDERSON et ul., 1984) enhanced the prolactin-inhibitory effect of muscimol, a GABA receptor agonist. The potentiating effects of GABA on prolactin secretion may be mediated via the GABA coupled, central-type benzodiazepine receptors. Thus, both the central-type and peripheral-type benzodiazepine receptors in the pituitary may mediate the direct effects of benzodiazepines on anterior pituitary prolactin secretion. As discussed above, the ijr IV~Weffects of benzodiazepines in rodents on stress induced and drug induced prolactin secretion appear to be mediated primarily by actions on central-type benzodiazepine receptors. Since GABA and GABA agonists can act at both the hypothalamus and pituitary to alter prolactin release (RAC‘AC;NI et u/..1982; GRANDISON et al..1979), potentiating actions of benzodiazepines on GABAergic systems at both sites may account for the irr ~+\YIeffects of benzodiazepines. EFFECTSOFBENZODIAZEPINESON

GROWTH

HORMONESECRETION

Several studies have reported that acute oral administration of diazepam results in potent stimulation of growth hormone secretion in man (KOULU et ~1.. 1979; KOHLU e’t u/., 1982: KANNAN. I98 I ). Tolerance to the benzodiazepine effects to stimulate growth hormone occurred following repeated administration of benzodiazepines (PETCJRSSON et al.. 198 I), whereas the normal stimulatory response was observed following withdrawal from longterm benzodiazepine treatment (PEWRSSON Pt ul., 1981). In one study, the beta-carboline ligand FG 7142 was reported to stimulate growth hormone secretion in two volunteers (DOROW et ~1.. 1983). Diazepam consistently induced growth hormone secretion in acromegalic sub.jects and produced a much smaller but significant increase in plasma concentrations of growth hormone in hypopituitary subjects ( KANNAh. 1% I ). The stimulatory effects of diuzepam on growth hormone secretion in man appear to involve both dopaminergic and GABAergic mechanisms. Treatment with pimozide. the selective dopamine receptor blocking agent. reduced the growth hormone response to diazepam by SO%, and sodium valproate, a GABA transaminase inhibitor, also inhibited diarepam-induced growth hormone secretion (KOULC:ct ~1.. 1979). In contrast, the serotonin antagonist methysergide had no effect on diazepam stimulated growth hormone secretion (KOLU_L~ it ill., 1979). Diazepam has been reported to alter the turnover rates of dopamine (LIDRRINK et (11.. 1973) and has been demonstrated to potentiate GABA-mediated transmission: thus, it is conceivable that both neurotransmitters may be involved in the actions of benzodiazepines on growth hormone secretion. EFFECTS OF BENZODIAZEPINES ONTHEl-1YPOTHAL.AMIC~PITllIT.4KY-(;ONAD.4L,4XIS No consistent effects of benzodiazepines have been reported on the hypothalamic-pituitarygonadal axis. Increased levels of plasma testosterone have been reported in men aged 35 to 55 years with minor complaints of nervousness and mental tension (AKGt.r:Lr_Es rf ~1.. 1975). Male rats chronically treated with high doses of diazepam failed to exhibit any

changes in testicular concentrations have

been

reported

(ARTHAUD mediated

et al..

A summary have

response

to alter

in the interstitial

of the effects effects

to stressful

glucocorticoid hypersecretion

the

tissue

inhibition

and cortisol.

These

p:ttients

In contrast

doses

cells latter

(DtzSouz,~

and

which

ACTH,

effects cortisol.

stimuli.

psychiatric inhibitory

t .b

are found

function

on busal and

Furthermore,

with

tubules

of diazepam

may

in very

be high

pt t/l., 1985).

TYH,

to the

hormone

of benLodiaL.epines

seminiferous

effects

on neuroendocrinc

inconsistent of

and luteinizing

high

receptors

of the testis

pharmacological in

Leydig’s

lY82).

of benzodiuLepinos

Tecretion of

of

testosterone

studies,

benzodiazepine

produce on

and serum In other

histology PI trl..

peripheral-type

ben,&iazepine\

potent

weights,

et ul.. 1980).

19X 1: Mr:.ANs

through

concentrations

1. While

and prostate

(WILKINSON

secretion

benLodiazepincs of

in Inblc

accretion.

prolactin

disorders effects

is listed

hormone

as\c)ci;tted ben~odialepine\

the) in

biunt M ith on

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