Bri&J. Psjchiat.

(1978),133,23138

S@Jmposium
Central

Actions of Benzodiazepines:

General

Introduction

By W. E. HAEFELY
SUMMARY

After

a brief

review

of the

characteristic

somatic

and

psychotropic
effects of benzodiazepines
evidence is presented
which
supports a specific facilitatory
action of these drugs on GABA ergic
synapses
within the mammalian
central nervous
system.
Benzo..
diazepines
enhance presynaptic
inhibition
in the spinal cord and
dorsal column nuclei as well as postsynaptic
inhibition
in dorsal
column

nuclei,

bellar

hippocampus,

cortex,

which

inhibition mediated

are

hypothalamus,

all examples

by GABA

cerebral

of recurrent

cortex,

and

cere

collateral

ergic intrinsicneurones. In addition, the

compounds
also enhance
the inhibitory
effect of GABA ergic long
projection neurones in the substantia
nigra and the lateral vestibular
nucleus of Deiters. Several problems remain to be solved, such as the
exact site at which benzodiazepines
initiate their action (pre-synapti
cally

at GABA

ergic

nerve

cells) and the possible

diazepine

receptor.

endings

existence
Some

or postsynaptically

of endogenous

suspected

at the

ligands

implications@

target

for the benzo.

which

studies

benzodiazepine
binding sites could have for a deeper understanding
the mode of action of these drugs are discussed.

system.

As

a general

is the inter

Understanding
the mechanism of action of a
psychotropic drug comprises the knowledge of a
long chain of events (Fig 1) initiated by the
recognition
of its specific receptor molecule
in the CNS by the drug. Binding of the drug may
either activate'the receptor, i.e. alter its

and derivatives with

the central
nervous

introduction

to

this

molecular
pharmacology
of benzodiazepines
I
shall outline the present knowledge
about the
mechanism
of action of this class of drugs and

conformation

attempt to delineate the function of benzo

diazepine receptors within this framework of
present knowledge.
* The

term

benzodiazepines'

is

used

for

the

sake

of

simplicity; it includes derivatives with a hetero-aromatic

5- or 6-membered ring instead of the condensed benzene,
or with 7-membered rings having two nitrogen atoms in
other positionsthan the usual 1,4 or even containing only
one nitrogen. Some of these derivatives produce benzo
diazepir'e-like

actions

of

General mechanisms ofp.@ychotropicdrug action

Introduction

A main topic of this symposium

action of benzodiazepines
specific binding
sites in

on

and displace

5H-cliazepam

from its

specificbindingsites.
231

in such a way that

it will induce

further
changes in adjacent
structures,
or
inactivate'the receptor, i.e. preventing it from
being activated
by other (endogenous
or
exogenous) molecules that are otherwise capable
of activating
it (receptors for psychotropic
agents are not restricted
to receptors for neuro
transmitters).
The activated
receptor
induces,

and the inactivated receptor prevents, changes

in other subcellular elements of the target cell
(e.g. ionophores, enzymes) which regulate its

232

CENTRAL

ACTIONS

OF BENZODIAZEPINES:

characteristic
activity. The altered activity of
target cells modifies the interaction of neurone
populations in one or more areas of the central
nervous system and results directly in somatic
drug effects andin an essentially unknown way
inpsychotropic effects.

recognition + binding
receptor 4
activation or inactivation

changesin subceflular
components

changes in cellular activity

changes in the interactionsof

neurone populations

INTRODUCTION

usually started with the study of multicellular

changes and advanced in the direction of the
initial

receptor

events

and,

as I shall show,

the

benzodiazepines
are no exception to this. In
the future, undoubtedly the opposite approach
will be increasingly used, namely the search for
drug

drug

GENERAL

receptors

in a very

early

phase

of the

pharmacological
investigation of novel drugs. It
would be a great mistake, if neuropsycho
pharmacologists
were discouraged
by this
tendency from studying the biological steps
intermediate
between receptor binding and
eventual pharmacological effect.
Main biologicalproperties of ben@odiazepines
The ultimate goal of studies on the receptor
binding of benzodiazepines and the subsequent
changes that occur in the central nervous
system is to provide an adequate explanation for
some or all of the actions of benzodiazepines
which are listed in Fig 2.
The most characteristic
effect, which these
drugs produce already at the smallest pharma
cologically
active doses, is antianxiety and
disinhibition of certain behavioural
patterns
(Cook and Davidson,
1973; Dantzer,
1977;
Haefely, 1978). The antianxiety effect is seen
in animals as an increase of those behavioural

/ @S%%S%%\
responses

that

are

suppressed

experimentally

by

punishment, or which are absent or infrequent

spontaneously
because of innate aversion or
influence of environmental
factors, such as
novelty. In some experimental situations, benzo
diazepines
impair the animal's capacity to
withhold a certain behavioural response, e.g.
the capacity to avoid punishment
by with
holding a certain behavioural response, which is
FIG 1.The cascade of events induced by psychotropic
agents at the subcellular (receptor, ionophores, enzymes, called passive avoidance.
The induction
of
etc.),
cellular
(excitability),
and multicellular
(brain aggressive feelings and acts in animals as well as
regions, whole central nervous system) levels resulting in
in manoften described as paradoxical
re
somatic and psychotropic
effects. The interrupted
arrow
results
indicates that psychotropic effectscan be correlated with, action to a sedative anxiolyticprobably
from the release of a behavioural response which
but not explained'
by, changes in neuronal activity.
would be meaningful in given circumstances but
which is suppressed by fear or conditioning.
This banal general scheme of the steps
The reverse, namely taming of some animals in
involved in a neuropsychotropic
effect is not
non-sedative
doses, is probably
rather
an
unnecessary because the recent success in drug
effect than
a true antiaggressive
receptor identification tends to produce the false anxiolytic
action.
impression that the main mystery of psycho
The most impressive effect of benzodiazepines
tropic drug action has now been solved. In the
on somatic functions is the result of their
past, elucidation
of mechanisms
of action

somatic psychotropic
effects
effects

233

W. E. HAEFELY

Characteristic biological properties

of

leptics

; a decrease

doses

anticonvulsant
sedative

and

special

psychomotorand emotionalreactions
facilitationof Sleepbehaviour,
.enti-aggresslve'.

potentiatlonof central depressants,

anterograde amnesia

musclerelaxant
virtuallack of direct peripheraleffects
very low toxicity

Fio 2.Characteristicbiological properties of benzo

diazepines.

anticonvulsant property. These drugs are most

potent against chemically induced epileptiform
activities; the effect of convulsants, which in one
way or another depress GABA ergic synaptic
transmission, is particularly sensitive to benzo
diazepines. At higher doses most, but not all,
benzodiazepines
also prevent seizures induced
by electric shock.
The sedative action of benzodiazepines
has
aspects:

the

normalization

of excessive

alertness and responsiveness to normal stimuli

and the damping
of normal responses to
excessive stressful factors result in the thera
peutically desired calming effect, while de
pression of a normal behavioural responsiveness
in physiological
conditions
is the basis of
sedative
sideeffects.
The depression
of normal
alertness and psychomotor activities is much less

for example,
experimental

locomotor

requires

high

conditions.

Normal sleep is little augmented

or even
decreased by benzodiazepines in several animal
species. Only when sleep is disrupted by drugs or
environmental factors do these drugs shorten the
latency to onset and the amount of sleep (Poic
and Haefely, 1975). The rather high doses of
benzodiazepines that are required to block most
of the experimentally

reductionofexcessiveor normal

than after neuro

of the spontaneous

activity of rodents,

anti-anxiety
andbehavioral
disinhibition

two

intense after benzodiazepines

induced

forms of aggres

sive behaviour, e.g. shock-induced fighting in

mice, suggest that the so-called antiaggressive
action is in fact but one expression of marked
sedation. Benzodiazepines and other centrally
depressant agents usually potentiate each other
in their various sedative effects. The antero
grade amnesia which is observed after high
doses of benzodiazepines
is due to a reduced
engram formation during the presence of high
concentrations
of the drugs in the central
nervous syste'@nand is observed with appropriate
doses of all sedatives.
The muscle relaxant effect of benzodiazepines
usually occurs in sedative doses and is not
easily differentiated
from sedation
in the
conscious intact animal. The cat is particularly
sensitive to the muscle relaxant action and shows
marked ataxia after relatively low doses.
Any mechanism which provides a satisfactory
biological basis of the characteristic profile of
action of benzodiazepines
must also explain a
peculiar property of these drugs, namely to
produce interesting specific neurotropic
and
psychotropic effects at very low doses, but to
lead to a general depression of central nervous
functions only at the very high lethal doses. In
particular, general anaesthesia is not obtained in
animals with benzodiazepines alone.
Early studies on the mechanism of action of benzo
diazepines
The search for specific changes of neuronal
activity that could underly the actions of
benzodiazepines
started early after their dis
covery. The biochemical approach (see Costa and
Greengard, 1975) was essentially- negative until
a few years ago. Thus, the drugs were found to
lack any effect on the levels of biogenic amines.

234

CENTRAL

ACTIONS

OF BENZODIAZEPINES:

Even the turnover of catecholamines was later

found to be unaffected or only slightly reduced;
the effect on the turnover of 5-HT is still
controversial.

reduced

turnover

of

acetyl

GENERAL

dence indicated

INTRODUCTION

the role of y-aminobutyric

(GABA)

in

mediate

presynaptic

afferent

the

endings

axo-axonal

(see

synapses

inhibition
Levy,

1977),

of

acid
that

primary

we reinvesti

choline has been found recently. Since all these

transmitter systems are profoundly affected by
neuroleptics and antidepressants,
the minimal
effects of even very high doses of benzodiaze
pines on them did not provide any convincing
explanation
for their specific neuropsycho
pharmacological
actions. An enormous amount
of data from electrophysiological investigations of
benzodiazepines
have
been
accumulated.
Studies of spontaneous electrical activities, of
evoked responses, and of single cell activities
have shown that the limbic system (amygdala,

gated the effects of diazepam on the cat spinal

cord (Polc et ci, 1974). Diazepam and other
active benzodiazepines increased the amplitude
and the duration of the dorsal root potential
(DRP), which is the expression of the synap
tically induced depolarization of primary afferent
endings, and enhanced the presynaptic inhibi
tion of the monosynaptic
excitation of spinal
motoneurones
(ventral
root reflex, VRR).
GABA antagonists,
such as picrotoxin
and

hippocampus),

synaptic inhibition. After depletion of endo

genous GABA by the synthesis
inhibitor
thiosemicarbazide,
presynaptic
inhibition was
abolished and could no longer be restored by

the

thalamus,

and

the

spinal

cord are particularly sensitive to the action of

benzodiazepines (Schallek et al, 1972; Chou and
Wang, 1977). This view is further supported by
the finding that anxiolytics differ quite markedly
from other psychotropic agents in their effect on
hippocampal

activity,

e.g.

on

the

amygdalo

hippocampal
evoked potentials (Jalfre et ci,
1971). However, one should not overlook that
benzodiazepines

affect

most

central

nervous

structures investigated so far. Therefore, the

identification
of those synapses that are pri
marily affected by benzodiazepines,
required
the study of distinct pathways with known
functions and/or transmitters.
The GABA ergzc .@ynapseas the primaiy site of action
of benzodiazepines
Schmidt et al (1967) were the first to observe
the potentiation
by diazepam of presynaptic
inhibition
in the cat spinal cord, and they
suggested that this might contribute
to the
central muscle relaxant effect of this drug;
postsynaptic inhibition in the spinal cord was
found to be unaffected by diazepam. The sig
nificance of these findings for the mechanism of
action of benzodiazepines
was not recognized
for several years, first, because at that time the
phenomenon of presynaptic inhibition was still
a matter of debate amongst physiologists and
virtually
unknown
to pharmacologists
and,
second, because the transmitter mediating this
type of inhibition was not known.
When in the early seventies increasing cvi

bicuculline,
and benzodiazepines
behaved
as
mutual antagonists
in their influence on pre

benzodiazepines.
By themselves
they
did not
produce
a depolarization
of primary
afferents,

which
action
The
allow
were

means that they have no GABA-mimetic

(Polc and Haefely, 1977).
experiments on the spinal cord did not
us to decide whether benzodiazepines
acting specifically on the mechanisms

underlying

primary

afferent

depolarization

or

whether they modulated in a general way the

synaptic transmission mediated by GABA. In
order to distinguish between these two possi
bilities we had to study the effect of benzo
diazepines

on

pathway

for

postsynaptic

inhibition in which GABA is involved.

The dorsal column nuclei appeared to us to be
the ideal structure
to perform this crucial
experiment,
because here GABA had been
shown to be the mediator of both presynaptic
and postsynaptic
inhibition.
We found that
benzodiazepines enhanced both types of synap
tic inhibition in the cuneate nucleus and had no
effect on synaptic excitation of cuneothalamic
relay cells (Polc and Haefely, 1976). As already
seen in the spinal cord, benzodiazepines
and
GABA

antagonists

were

mutually

antagonistic

in their effect on synaptic inhibition; and again

the depletion of endogenous GABA by thio
semicarbazide
abolished any effect of benzo
diazepines. The results in the cuneate nucleus,
therefore, strongly suggested that these drugs

235

W. E. HAEFELY

might affect similarly all GABA ergic synapses

in the CNS (Haefely ci al, 1975).
The neuronal circuit which mediates post
synaptic
inhibition
of cuneothalamic
relay
cells by impulses in primary afferents of the
dorsal columns is an example of so-called
collateral inhibition. Collaterals of the afferent

increase

of the

inhibitory

influence

of basket

cells. The direct evidence for such an action was

recently provided by Geller ci al (1978). Costa
and collaborators (Costa ci al, 1975; Guidotti,
1978) have used the level of cyclic guanosine
monophosphate
as an index of cerebellar
Purkinje

cell activity.

With

this elegant

model

they provided strong biochemical evidence for

the facilitatory action of benzodiazepines
on
same or adjacent relay cells. A slightly different
GABA ergic synapses in the cerebellar cortex.
circuit is responsible for the so-called recurrent
The findings in four different areas of the
inhibition;
in this case, the inhibitory inter
central nervous system which I have mentioned
neurone is not activated by a collateral of the so far, are convincing evidence that benzo
diazepines enhance ongoing transmission medi
excitatory input neurone, but by a recurrent
collateral
of the principal
neurone
itself@ ated by GABA ergic interneurones.
Logically,
Whereas the most intensively
investigated
type
the question then arises whether the same
of recurrent inhibition, the Renshaw inhibition
effects are found on the synapses formed by
of spinal motoneurones,
probably uses glycine
GABA ergic long projection output neurones.
as the inhibitory transmitter and is resistant to
Such a GABA ergic pathway connects the
the action of benzodiazepines,
GABA ergic neostriatum with the substaniia nigra, mediating
recurrent inhibition occurs frequently in other
monosynaptic (postsynaptic) inhibition of nigral
dopamine neurones. Evoked potentials recorded
structures
of the CNS, e.g. in the hippocampus,
in the pars compacta of the substantia nigra in
the cerebral cortex and the hypothalamus.
response to single electrical stimuli in the
Wolf and Haas (1977) found that diazepam
caudate nucleus of the cat were abolished by the
enhanced
recurrent
inhibition
of hippocampal
GABA antagonists, picrotoxin and bicuculline,
pyramidal cells in the cat and Raabe and Gumnit
but not by the glycine antagonist strychnine
(1977) reported a similar effect on recurrent
inhibition
of pyramidal
cells in the cerebral (Schaffner and Haefely, 1975; Haefely ci al,
1978). Benzodi zepines did not affect the
cortex. Zakusov ci al (1975) had already observed
evoked potentials, however, they were very
a facilitating effect of diazepam on inhibitory
potent in preventing or reversing the depressant
processes in the rabbit cerebral cortex. GABA
mediated
recurrent
inhibition
in neurones
of effect of GABA antagonists. Biochemical studies
tuberal hypothalamic cultures was enhanced by also support the view that benzodiazepines
enhance GABA ergic inhibition of dopamine
diazepam (Geller ci al, 1978).
The only output cell of the cerebellarcortex, the neurones. The drugs slightly decrease the level
of homovanillic
acid, a main metabolite of
Purkinje cell, and one of the input fibres to the
cerebellar
cortex,the climbingfibre,form a dopamine, and strongly antagonize the increase
of homovanillic acid induced by neuroleptics
neuronal circuit which combines the two types
(Keller ci al, 1976), which are thought to
of collateral
and recurrent
inhibition,
the
activate dopamine neurones reflexly by blocking
basket cell serving as the inhibitory
intrinsic
dopamine receptors. In line with this assump
neurone.
The spontaneous
firing rate of single
tion is the potentiation by benzodiazepines
of
cerebellarPurkinje cellsin rats and cats was
the cataleptic effect of neuroleptics (Keller ci al,
found to be consistently depressed by various
1976), and the prevention by benzodiazepines
benzodiazepines
(Pieri
and Haefely,
1976).
Although the neuronal connectionsin the of the change of kinetic properties of striatal
cerebellar
cortexarefurther
complicatedby the tyrosine hydroxylase induced by neuroleptics
(Guidotti, 1978).
existence of an additional
excitatory
input and
Results similar to those obtained in the
of three other inhibitory interneurones, the
substantia nigra were seen in studies of the
reduction of Purkinje cell firing by benzo
picrotoxin-sensitive
component of the potential
diazepines
is consistent
with a drug-induced
fibres
which
interneurones

excite
relay
cells
also
with inhibitory
influence

activate
on the

236

CENTRAL

ACTIONS OF BENZODIAZEPINES:

evoked in the lateral vestibular nucleus of Deiters by

single stimuli to the GABA ergic cerebellar
Purkinje cell axons (Haefely et al, 1978).
Open questions on the molecular mechanism of
benzodiazepine action
While it can now be considered as established
that benzodiazepines
very selectively enhance
GABA ergic transmission throughout the central
nervous system, and that they neither activate
directly GABA receptors nor inhibit the uptake
and metabolic inactivation of GABA, several
questions remain to be answered.
(a) Molecular mechanism of action of ben@o
diazepines. A yet unsolved problem is the nature
of the molecular events that result in an enhance
ment of GABA ergic transmission.
(1) One possibility is a priori unlikely, al
thought the direct proof is lacking. Benzodiaze
pines could increase the excitability of GABA
ergic interneurones leading to an increase of the
number of action potentials fired in response to a
given excitatory
input. This possibility can
probably be dismissed, because an enhanced
GABA

ergic

transmission

was also found

when

stimulating
directly axons of GABA ergic
neurones, provided that transmission was re
duced by GABA antagonists.
(2) A second possibility is an increase of the
amount
of GABA released at the axonal
endings of GABA ergic neurones in response to
an action potential, in other words, an improved
excitation-secretion
coupling in GABA ergic
terminals. The effect of benzodiazepines on the
evoked release of GABA in vivo has not yet
been investigated. Studies of the in vitro release
of GABA from brain homogenates revealed no
specific effects of diazepam (Olsen et ci, 1978).
(3) The third possibility would be an action
on the subsynaptic membrane of GABA ergic
synapses

which

increases

the

effectiveness

of

GABA. Such an action could consist in an

increase of the affinity of the GABA receptor
for GABA

or in improved

coupling

between

GABA receptor activation and the increase of

the chloride conductance
of the subsynaptic
membrane.
While some recent electrophysio
logical studies indicate that benzodiazepines
enhance the effect of exogenous GABA on the
membrane
chloride conductance
of various

GENERAL

INTRODUCTION

neurones (Choi et al, 1977 ; Geller et al, 1978;

Kozhechkin
and Ostrovskaya,
1977 ; Mac
Donald and Barker, 1978), other investigations
were negative
(Bowery and Dray,
1978).
Dr Costa will report on experiments which
demonstrate
an effect of diazepam
on the
binding of GABA to its receptor.
(b) Potentiation of GABA ergic transmission by
benzodiazepines and other agents. Benzodiazepines
are not the only agents that enhance GA.BA
ergic transmission. Barbiturates were found very
early to prolong presynaptic inhibition. Despite
certain similarities in the effects of barbiturates
and benzodiazepines,
clarcut differences also
exist (Bowery and Dray, 1978; Haefely, 1977;
Nicoll,
1978). Ethanol
also enhances
GABA
ergic transmission
(unpublished
results) and a
systematic
study might well detect
similar
effects of other agents. Potentiation
of GABA

ergic transmission by different agents does not

imply that they all act by an identical molecular
mechanism.
Moreover, an enhanced
GABA
ergic transmission may be the only or pre
dominant action of certain drugs on the central
nervous system, as seems to be the case with
benzodiazepines, or just one of many effects on
neuronal elements, as is probably the case with
barbiturates.
(c) Can the polenliation of GABA ergic trans
mission explain all the pharmacological action of
benzodiazepines? An increased
efficiency
of
physiological synaptic inhibitory mechanisms
(recurrent
and collateral inhibition)
is very
likely to account for the somatic effects of
benzodiazepines.
It would be surprising if the
anxiolytic and sedative effects of benzodiaze
pines were independent
from their specific
action on GABA ergic inhibition. The crucial
experiments
to prove or disprove a causal
connection between psychotropic benzodiaze
pine effects and enhanced GABA ergic trans
mission have yet to be performed.
(d) Prospects of benzodiazepine receptor studies.
Recent and future studies on the specific
benzodiazepine
binding sites should be helpful
in clarifying some of the problems mentioned
above. Localization
of the benzodiazepine
receptors perhaps may permit one to decide
whether the drugs act presynaptically
or post
synaptically at GABA ergic synapses. Possible

237

W. E. HAEFELY

interactions between, on the one hand, benzo

diazepine

receptors

and,

on

the

other

GABA receptors or chloride ionophores can be

studied, and a separation
of the primary
structures
affected by different agents that
produce similar effects on the GABA ergic
synapse will be possible. In vitro binding assays
are

virtually

indispensable

methods

search for possible endogenous

benzodiazepine

receptors;

in

the

ligands for the

personally,

I do not

think that all psychotropic drugs have to act on

sites which bind endogenous molecules under
physiological
or pathological
conditions.
A
remote goal of these studies is the chemical
identification
of the specific binding sites for
benzodiazepines.
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