027~5846/90

Prog. Neuro-Psychophormacol. 6 Biol. Psychiot. 1990, Vol. 14. pp. 503-523 Printed in Great Britain. All rights reserved

DEPRESSION

AND ANTIDEPRESSANT DYNAMICS FRANK

P. ZEMLANl

$0.00

+

and DAVID

THERAPY:

RECEPTOR

L. CARVER2

1Alzheimer'r Research Center, Department of Psychiatry, School of Medicine, University of Cincinnati, Cincinnati, Ohio, USA 2Department of Psychiatry and Behavioral Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

(Final form December, 1989)

Content8

1. 1.1. 1.2. 2. 2.1. 2.2. 2.2.1 2.2.2 2.2.3 2.3. 2.4. 2.5. 3. 3.1. 3.2. 3.3. 3.4. 4. 4.1. 4.2. 4.3. 4.4

Abstract Introduction Molecular Biology of Monoamine Receptors Challenges to the Classic Theory of Depression 5-HTf Receptor Subsensitivity and Depression S-HTl Receptors - Binding Studies M-IT1 Receptors - Electrophysiology Postsynaptic 5-HTl Receptors Presynaptic 5-HTl Receptors Somatodendritic 5-HTlA Autoreceptors 5-HTl Receptors - Preclinicrd Studies 5-HTl Receptors - Human Studies 5-HTl Receptors - Summary Beta-Adrenergic Receptor Supersensitivity and Depression Beta-Adrenergic Receptors - CAMP Stimulation Beta-Adrenergic Receptors - Binding Studies Beta-Adrenergic Receptors - Human Studies Beta-Adrenergic Receptors - New Antidepressants and Summary 5-HT2 Receptor Supersensitivity and Depression 5-HT2 Receptors - Binding Studies 5-HT’2 Receptors - Preclinical Studies 5-HT2 Receptors - Human Studies 5-HT2 Receptors - Summary References

503 504 504 505 506 506 507 507 508 508 510 510 512 512 512 513 515 515 516 516 517 518 518 519

Zemlan. Frank P. and David L. Garver: Depression and Antidepressant Therapy: Receptor Dynamics. Prog. Neuro-Psychopharmacol. and Bio. Psychiat. 1990. u :503-523 I. 2.

50

@ 1990 Pergamon Press plc

The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments.

503

F. P. Zemlan and D. L. Garvcr

504

3.

Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HTl receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HTl mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HTl receptors. 6. Patient studies, employing a 5-HTl mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HTl receptors; and that chronic antidepressant treatment facilitates 5-HTl receptor responsiveness in depressed patients. 7. New 5-HTl selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HTl receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta- I receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-l agonists. which like clinically proven antidepressants, decrease beta-l receptor responsiveness with chronic treatment. II. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment. Keywords:

antidepressant

drugs, depression,

ECT’. 5-HT receptors,

beta-adrenergic

receptors.

Abbrevlatloos: central nervous system (CNS), cyclic adenosine 3’,5’-monophosphate (CAMP). density of receptors (Bmax), electroconvulsive therapy (ECT). receptor equilibrium dissociation constant (KD), 5hydroxytryptamiae, serotonin (S-HT), monoamine oxidase inhibitor (MAOI). N’-methoxy-N’.N’dimethyltryptamine (5-MeODMT), norepinephrine (NE), phosphoinositide (PI)

1. Introduction The classic monoamine subnormal synapses. related

norepinephrine

hypothesis

of depression

(NE) or serotonin

(5-HT)

suggests

that depressive

disorders

This classic hypothesis has been revised over the past few years to incorporate to the introduction

pharmacology,

of new, atypical

with

antidepressant

recent biochemical data

drugs and a more detailed

knowledge

of the

anatomy and molecular biology of monoamine receptors.

Over the past several years pharmacologists of a magician pulling rabbits out of a hat. traditional

are associated

release at certain critical central nervous system (CNS)

have identified

new monoamine receptor subtypes with the speed

This exciting research explosion has led to a dissatisfaction

with the

method of defining

receptors based on the .receptor’s affinity for transmitters and synthetic ligands. An example of problems resulting from the ligand affinity classification approach was the initial classification of

dopamine receptors into four subtypes (Dl to D4). In reality there turned out to be only two dopamine receptor subtypes (DI and D2) each with a high and low affinity state. The high and low affinity states of the dopamine racrptor are interconvartibla and 0 protein-dependent, In an attempt to avoid ligand based misclassification of receptors,

the present review of antidepressant

and receptor function

will employ the new classification

scheme

based on receptor structure. 1.1 Molecular Biology of Monoamine Receptors. Why should we make the effort

to reclassify

think pure thoughts with dirty receptors. receptor

classification

monoamine

receptors?

In order to identify

As Hartig (1989) suggests - you can’t

similar antidepressant

scheme which does not muddy the waters

may

more

easily

mechanisms illustrate

of action, a

these similarities

Antidepressant

Both functional

and structural

similarities

and differences

biochemical

information

antidepressant

homologies across

may be more difficult

monoamine

will eventually

505

drugs

to detect if our classification

It is anticipated

receptors.

help our understanding

of depression

scheme hides

that incorporation

of this new

and the mechanisms

of action of

drugs.

In the past two years sufficient

cloning

data has become

available

to allow the initial classification

of

monoamine receptors based on protein structure.

For example, comparison of the amino acid sequences of beta-

2 and alpha-2 adrenergic

and 5-HTlC

receptors

with 5-HTlA

from 52 to 80% (Libert et al, 1989). distinct

superfamilies

receptor

of receptors.

superfamily

Classifying

and the ligand-gated

receptors

adrenergic

and dopamine

superfamily

of G protein coupled receptors,

beta-l,

G protein

coupled

demonstrate HTlC

messenger distinct

pathway.

the adenylate

These latter

the superfamily The other

treatment. addition demanded

G protein

Among

cloned

receptors

in the

all these latter receptors are

The second these receptors

coupled receptors

of receptors

coupled

group of cousins

also

include the 5-HT2, 5(PI)

second

consists of two functionally

messenger

system

is the ligand-gated

and their

ion channel

cousins receptors

to the Classic Theory of Detwession. drugs which fail to inhibit neurotransmitter and the identification

and cocaine) which fail to have antidepressant

theories

of depression

(2-3 weeks) was quite different NE or 5-HT.

Inhibition

properties; have raised fundamental

illness and our understanding was the realization

The two week time course discrepancy

of the relevant mechanisms of action

fresh approaches

concepts of NE and 5-HT

that the time course of clinical antidepressant

rruptake

between

and mianserin

to both the study of the relevant

increase of

occura within hours after initiation

reuptake inhibition

such aa iprindole

(such

problems for

from the time course of the uptake inhibition-related

of neurotransmitter

to the “atypical” antidepressants

reuptake and do not

of NE and 5-HT reuptake inhibitors

drugs (Charney et al, 1982). Even more disturbing to the traditional

synaptic deficiencies response

1988).

and subtypes of alpha- and beta-

includes the 5-HT3 receptor.

both our concepts of the biology of affective

synaptic

results in two the G protein

employ the phosphoinositide

the CAMP second

superfamily

The advent of a series of new antidepressant

of antidepressant

receptors

similarity different;

Sequence homology between 5-HTlA,

pathway.

of G protein

utilizing

inhibit MAO (such as iprindole or mianserin), as amphetamine

cyclase

homologies within superfamilies;

those receptors

which, among monoamine receptors,

(Lester,

1989).

we find two sets of cousins.

‘receptors.

Therefore,

phosphoinositide.

1.2 Challenges

superfamily

is striking (Libert et al, 1989). Interestingly,

utilizing

adrenergic

by sequence

are functionally

5-HT2 receptors,

(O’Dowd et al, 1989; Hart&

similar structural

sets of relatives,

employing

receptors

receptors

strikingly

and alpha-l

ion channel

include all S-NT1 receptor subtypes,

beta-2 and alpha-2

receptors

These two broad superfamilies

monoamine

receptors

receptors indicates a sequence homology ranging

monoamine

mechanism

of drug

and clinical improvement,

which

do not effect

in

reuptake.

of action of the antidepressants

(Meltrer, et al., 1987). and the study of the biologic nature of depressive illness. A fresh approach from molecular receptors.

to the study of depression

biology

Regulation

described

and antidepressant

mechanism

above; and anatomy such as differential

of action utilizes new concepts effects of pre- and postsynaptic

of neuronal activity is in part by presynaptic receptors, at which the neuron’s own

neurotransmitter inhibits further neuronal activity.

Regulation of postsynaptic neuronal activity, is not only by

release of neurotransmitter onto postsynaptic receptors, but also involves the linkage of the activated receptor with its transmembrane second messenger system (such as adenylate cyclase and phosphoinositide) activity of phosphorylated

kinases which phosphorylate

membrane proteins and functionally

membrane potentials, inhibiting or facilitating neuronal activity.

and the

alter resting

.

F. P. Zemlan and D. L. Garver

506

Table I.

Classification

of monoamine receptors based on DNA structural homologies of receptors and their functional expression systems

G-Protein

Receptor Superfamily

Adenyiate Cyciase Coupled Receptors S-HTI receptor subtypes (1A,lB.lD,iP.iS) Beta- 1 receptors Beta-2 receptors Alpha-2 receptor subtypes Dopamine receptor subtypes

Phosphoinositide

Coupled Receptors

5-HT2 receptors 5-HTiC

receptors

Alpha-2 receptor subtypes

Ligand-gated

Ion Channel Superfamily

S-HT3 receptor subtypes

2. S-HTI 5-HTi

receptors

receptors,

5-HTi

antidepressants,

2.1

5-HTI

are members receptors

Receptor Subreositivity

of the G-protein

are coupled

during chronic treatment,

coupled

to adenylate

and Depression receptor

cyciase

superfamily. (Table

1).

and like beta-i Recent

induce marked changes in postsynaptic

studies

and beta-2 suggest

that

5-HT receptor sensitivity.

Receptors - Binding Studies

Numerous studies have examined the effect of acute and chronic antidepressant in frontal cortex (Table 2). administration

No effect

of chiorimipramine

on the number

(Wirz-Justice

of 5-HTi

receptors

et al. 1978; Bergstrom and Keilar,

ipridole (Peroutka and Snyder,

1980) or mianserin (Blackshear and Sanders-Bush,

treatment

pump blockers such as zimeiadine

with 5-HT reuptake

1982) or fiuoxetine

treatment on 5-HTi

has been observed

receptors

after chronic

1979, Savage et al. 1980);

1982). Interestingly,

(Hail and Ogren.

chronic

1981; Fraxer and Lucki,

(Savage et al., 1979; 1980; Maggi et al., 1980; Peroutka and Snyder, 1980) also have no effect

on 5-HTi

receptors;

reguiatioo.

While there are some reports that chronic desipramioe

although

as a general rule chronic

agonist treatment

usually results in receptor

dowo-

treatment decreases the number of cortical 5-

Antidepressant

HTI receptors 5-HTI

507

drugs

(Segawa et al., 1979; Maggi et al., 1980) most studies have not found any significant

receptor

number (Bergstrom

and Kellar,

decrease in

1979; Peroutka and Snyder, 1980; Koide and Matsushita,

1981;

Tang et al., 1981). Similarly, repeated ECT is without effect on cordcal S-HT1 Bmax values (Kellar et al, 1981; Ventulani et al., 1981). One problem information

with our current

on antidepressant

knowledge

effects

of the effect

HTI receptor subtypes have been identified and 5-HTlS Titeler,

receptors

S-HTlA, treatment

to focus on those subtypes which functional

clinical data, reviewed

below,

particularly

which

predominantly

5-HTlB

The most treatment

5-HTlC,

5-HTlD,

an opposite

on 5-HT

1987; Herrick-Davis

and

on any 5-HT1 receptor

subtypes available for study, it would appear receptors as electrophysiologic. and gepirdne.

effect

of some

5-HTlA

binding

Presynaptic

5-HT1

Cortical

receptors are postsynaptic.

transmission

as postsynaptic

of

behavioral and

may mediate the antidepressant

agotiists, buspirone

as nearly all 5-HTlA

effect

5-

5-HT’lE, 5-HTlp

5-HTlA

receptors.

are

receptors (Murphy and Zemlan, 1988; 1989).

S-HT1 Rectptvs

- Electrophysiology

extensive

antidepressant

easy to interpret

have

is that no

data suggest as possibly involved in the mechanism

suggest that 5-HT1A receptors

the newer 5-HT1A

receptors

At present, seven different

has not been determined

The first candidate would be 5-HTlA

data would be particularly receptors,

5-HTlB.

With this wealth of 5-HT1 receptor

action of antidepressants.

2.2

including

1988). The effect of chronic antidepressant

antidepressants,

on S-HTl

(Zemlan et al, 1988; Zemlan et al, 1989; Huering and Peroutka,

subtype to our knowledge. reasonable

of antidepressants

on 5-HT’l receptor subtypes is available.

evidence

treatment

is a reported

that

neural

transmission

comes from electrophysiologic facilitation

5-HT

at 5-HT1 studies.

transmission.

receptors

is facilitated

The net effect

This facilitation

of chronic

can occur

by chronic antidepressant

by any one of three

mechanisms.

S-HTl

2.2.1 Postsynaptic First,

tricyclic

iontophoretically treatment

Receptors.

antidepressants

administered

1980; de Montigny and Aghajanian.

5-HTl

the postsynaptic

single unit response

to

argued that the enhanced to iontophoretically

5-HTI

response in the ventral and dorsal lateral 8!eniculate. (Menkes et al.

1978) hippocampus,

1981) amygdala (Wang and Aghajanian.

(de Montigny and Aghajanian,

1978; de Montigny et al.

1980) and the nucleus of VII (Menkes et al. 1980).

sensitization.

(Hall and Ogren,

methoxydimethyltryptamine process. (Ross and Renyi, is typically

First. chronic treatment 1981) also enhances

(5-MeODMT)

5-H?

with iprindole, sensitivity.

1969; Horn, 1973) is seen after chronic antidepressant

seen after both acute and chronic treatment.

effect by chronic tricyclic

on the postsynaptic

treatment

to long term treatments

antidepressant

Therefore,

the enhanced

increased

sensitivity

for the high affinity treatment.

treatment,

to 5-

reuptake

Third, the reuptake

while the enhanced

5-HT

5-HT response appears to reflect an

5-HT receptor complex.

which alleviate depression.

three facts argue

which has little or no ability to

Second,

and LSD, which are not substrates

response is only seen after chronic seems to be specific

While it may be

receptor mediated response might be due to prolonged exposure of the receptor

applied 5-HT. caused by 5-HT uptake blockade by some antidepressants,

in favor of postsynaptic

blockade

enhance

applied 5-HT in several regions of the CNS (Figure 1). Chronic, but not acute antidepressant

sensitizes the postsynaptic

block reuptake,

chronically

The enhanced 5-HT response

Acute or chronic treatment

with the

F. P. Zemlan and D. L. Carver

508

antipsychotic

chlorpromazine

Montigny and Aghajanian. 5-HT sensitivity

does not enhance

and clinical antidepressant

the sensitivity of iontophoretically

2.2.2.

Presyaaptic

Facilitation

5-HTI

of 5-HT

antidepressants

5-HT

1978; Wang and Aghajanian.

response is strengthened

receptors.

transmission

at postsynaptic

5-HTl

released per action potential. rates.

Chronic

presynaptic inhibition

treatment

receptors

5-HTl

at 5-HTl

it binds

A

5-HT

!I-HTlA

disinhibition

5-HTl

receptors

facilitates

S-I-IT1

activity.

amiflamine

by blocking

by blocking presynaptic

Similarly, clinically

clorgyline,

thereby facilitating

at high firing

5-HT transmission effective

monoamine

and phenelzine,

5-HT oxidase

block presynaptic

quanta1 release of 5-HT (Blier et al, 1987).

can facilitate postsynaptic

autoreceptors

(Figure

autoreceptors

5-HT activity is by disinhibition

located on their somata or dendrites.

buspirone and gepirone suggest that these two drugs may possess significant

antidepressant

treatment (Schweizer et al, 1986; Amsterdam et al, 1987). In electrophysiological Therefore,

autoreceptors

These 5-

the cell and therefore

Initial clinical trials with the selective 5-HT1A agonists

decreasing the number of action potentials generated.

raphe 5-HTlA

of 5-HT

5-HT cell bodies located in midline raphe

1).

serve as a break on the 5-HT neuron’s firing rate by hyperpolarizing

receptors.

(Figure I). As 5-HT

and presynaptic

release of 5-HT by deceasing the amount of 5-I-IT

such as fluoxetine

structures inhibit their own activity via S-HTlA

postsynaptic

by

fluoxetine,

Autoreceptors.

with somatodendritic

gepirone desensitizes

differently

such as zimeladine.

receptor serves as a brake on neural transmission

receptor

third method by which antidepressants

HT1A autoreceptors

is accomplished

of 5-HT release (Blier, et al, 1988). Antidepressants,

with chronic treatment

activity associated

receptors

receptor complex (de Montigny et al, 1981; Blier et

decrease subsequent

The presynaptic

postsynaptic

2.2.3. Somrtodcndrltlc

1980).

antidepressants

receptors by presynaptic

inhibitors such as the type A selective MAO inhibitors 5-HT inhibition

1981; de

between enhanced

by the report that repeated ECT enhances

to both postsynaptic

with antidepressants

5-HT inhibition facilitate

cleft

5-HTl

Several clinically effective

5-I-IT transmission

into the synaptic Presynaptic

and Aghajanian,

the relationship

Receptors.

and indalpine do not directly affect the postsynaptic is released

(Menkes

applied 5-I-IT or 5-MeODMT (de Montigny.

that are not tricyclics.

al, 1984) but facilitate

responsiveness

1980). Conversely,

activity with chronic

studies, chronic treatment

(Blier, et al, 1987) which would facilitate

there is a good correlation

between

the facilitation

with

5-HT release onto of 5-HT release by

gepirone and its delayed clinical efficacy as an antidepressant. In summary,

chronic

treatment

Although antidepressants directly

facilitate

such as

the postsynaptic

indirectly via presynaptic antidepressant (presynaptic

with tricyclic

MAO inhibitors, 5-HTl

antidepressants

receptor

One problem

effect. effect,

It appears requiring

5-HT

transmission.

they do facilitate

5-HT

neural

transmission

elegant theory of

with the theory is that it relies on a facilitation

of 5-HT release

5-HT receptors and 5-HT1A autoreceptors).

antidepressant

to facilitate

This is an anatomically

is to increase 5-HT release onto postsynaptic antidepressant

complex,

5-HT receptors and 5-HT1A autoreceptors.

drug action.

appears

5-HT reuptake pump blockers and 5-HT1A agonists do not

receptors,

that 5-HT1A chronic-long

If the effect of MAO inhibitors

and 5-HTlA

agonists

then 5-HTl agonists should have a direct and immediate

agonists,

such as buspirone

term treatment

for clinical

and gepirone,

efficacy

have a delayed

(Schweizer

et al, 1986;

S~~ATO~~~DRfTrC S-BTlA A~OREC~PTOR~ - ~stsynaptic S-HT ~aosmission is facilitated by chronic S-WTIA agonists, busprione and gepirone, by downregulating inhibitory S-HTlA autoreceptors.

PRRsY~APTrc S-HT1#$ RECEPTOR - ~s~y~apt~c HI’ tampion is facii~mted by ronic reuptake pump blockade or MACH’s ~~uoxetine, ~~y~~~e~ by inhibitory Sdown-regulating mlR ~UtQr~~pta~.

~~~yoaptic S-NT t~~rn~io~ is facilitated by chronic tricyclics, like ~~p~rnjoe by scting on postreceptor eoupiing mechanisms &% G protein, adeoy~~t~cyclue) ATP

cAMP

F. P. Zemlan and D. L. Garver

510

Amsterdam et al, 1987).

Further,

m-chJorophenyJpiperine

(mCPP), a rebtively

(Murphy and ZemJan, 1990). is anxiogenic in both panic disorderid While this aspect

al, 1987). indicating

that tricyclic

accurate explanation

of the theory

antidepressants

of the mechanism

large number of antidepressant different

transmitters

appears

facilitate

further

receptor

receptors

of several transmitter

and the mechanism of action of antidepressants.

The enhanced 5-HT sensitivity is clearly

reflected

behavioral syndrome

observed following chronic antidepressant

in animal

(Friedman

models

activity,

Various

of depression. which are regulated

desipramine

treatment behaviors

regarding

the

or mianserin

treatment.

seen in electrophysiologic including

sleep. the 5-HT

by S-HT. can be reliably elicited by S-HT

and DaJlob. 1979; Mogilnicka and Klimek,

the behavioral responses elicited by S-HT agonist administration amitriptyline,

classes of antidepressants.

system will provide only limited information

Studies

and locomotor

agonist administration

data

it seems logical to assume that

of different

biologic basis of depression

studies

the electrophysiological

is sound and may prove to be an

systems,

may underlie the efficacy

on a single transmitter

S-HTJ Receptors - Preclinical

S-HTJ agonist

In view of the complex action of a

It appears that information

2.3

study,

function

of action of some antidepressants.

on the function

and different

to require

S-HTl

non-selective

patients and healthy volunteers (Charney et

1979). These studies indicate that

are uniformly

Additionally,

repeated

enhanced

by chronic itnipramine,

ECT enhances

the 5-HT

syndrome

elicited by S-HT agonists, which has been shown to be mediated by S-HTJ receptors (Green at al, 1977; Green and Deakin. 1980; Grahame-Smith selective

drugs indicate

depression.

et al, 1978; Lucki et al, 1984).

that 5-HTlA

The selective

agonists possess significant

5-HTJA

agonists,

II-OH-DPAT,

More specifically,

antidepressant buspirone.

studies with 5-HTJA

activity

gepirone

antidepressant-like

effects

antidepressant-like

effect appeared specific for selective 5-HTJA agonists, as non-selective

as mCPP. benzodiaxepines specific effects

such as diazepam

antidepressant

(1987).

tricyclic antidepressants

particularly

agonists demonstrate

screening

transmission

antidepressant

some aSPeCt of increased

and stimulants

antidepressant

on another preclinical of depression,

produce

in the forced swim test (Cervo and Samanin. 1987; Wieland and Lucki, 1989). This

on this preclinical

In summary,

in animal models of

and ipsapirone

screening

such as d-amphetamine

agonists such

test. Similar results with selective 5-HTJA

in preclinical

5-HT transmission

behavioral

Consistent

screening

et al.

in animal models

with these data, 5-HTJA

tests.

may be associated with the biochemical

any

agonists

test, acute unavoidable stress has been reported by Kennett and ECT appear to increase 5-HT transmission

associated with 5-HTJ receptors.

activity

S-HTJ

did not demonstrate

These data suggest that effects

of antidepressant

drugs.

2.4

5-HTJ

Receptors

The best developed is 5-HT agonist-induced tryptophan

- Human Studies neuroendocrine

model for studying central 5-HTJ receptor systems in depressed

release of prolactin.

or 5-hydroxytryptophan

In normal volunteers,

i.v. infusion

patients

of the 5-HT precuron

L-

results in a robust increase in plasma prolactin (Cowen et al. 198% Winokur

et al, 1986; Price et al. 1988). Consistent with these human data, inhibition of 5-HT synthesis or neurochemical

,

lesions of the 5-HT system reduced plasma prolactin levels in rata (Chen and Meites. 1975; Willoughby et al. 1982).

In depressed patients, basal prolactin levels were found to be decreased when compared to normal

controls (Sachar et al, 1980).

Further, L-tryptophan

infusion

in depressed patients resulted in a blunted

Antidepressant

prolactin response when compared central 5-HT system in depression. mediated by S-HTl tryptophan enhanced tryptophan

receptors.

Administration

did not block the L-tryptophan the prolactin

of the centrally acting 5-HT2 antagonist,

prolactin

prolactin

release.

blockade of 5-HT2 receptors

levels by stimulating The blunted

prolactin

5:HTl

receptors

response

prior to Lsignificantly

not only does not block the L-

while 5-HT2 receptors

observed

in depressed

deficit at 5-HT1 receptors and possibly an excess of transmitter increases

ritanserin,

induced increase in plasma prolactin; rather, ritanserin

Therefore.

response.

stimulated prolactin response appears to be predominantly

induced increase in plasma prolactin but actually enhances the response suggesting that L-tryptophan

increases

Chronic

et al., 1984). These data suggest a subsensitive

to normal controls (Heninger The L-tryptophan

511

drugs

treatment

with the tricyclic

the L-tryptophan

monoamine oxidase. inhibitor (Price et al. 1985). induced prolactin an antidepressant

induced

antidepressants

prolactin

tranylcypromine

in treatment

increases the L-tryptophan

(Charney

treatment

depression.

induced prolactin

ream

Interestingly,

in depressed

et al, 1984) as does treatment

patients with the

enhances

both acute and chronic

receptors, and that this decreased

Table 2.

The Effect of Chronic Antidepressant Treatments on the Number (Bmax) of Cortical 5-HT1 and 5-HT2 Receptors

Antidepressant amitriptyline imipramine desipramine iprindole mianserin traxodone

5-I-IT] 0 0 0

N/A WA

MAO1 pargyline tranylcypromine

lithium

These data suuest

antidepressants.

5-HT2

the L-tryptophan

lithium is often used in conjunction

(Glue et al, 1986).

may be associated with decreased activity at certain 5-HTl

by certain clinically effective

inhibit

5-HT2 receptors.

or desipramine

in normal volunteers

and Cowen, 1986). Clinically,

resistant

appear to tonically

would suggest a transmitter

when the prolactin response is measured as area-under-the-curve

Similarly, chronic desipramine

response (Anderson

release at inhibitory

amitriptyline

response

patients

WA WA

Neuroleptic chlorpromazine haloperidol

8

8

ECT

+

0

Decrease in Bmax(-), increase in Bmax(+). no effect on Bmax(0). data not available (NA)

with

treatment

that depression

activity is reversed

F. P. Zemlan and D. L. Garver

512

Receptors - Summary

2.5 S-HTI

In summary, deficiency

clinical,

behavioral

theory of depression.

HT receptor

complex

antidepressant

studies can be marshalled

The data suggest that depression

deficiency

treatment

and ebctrophysiological

condition

or ECT.

which

is reversed

is related to a functional at the postsynaptic

The receptor binding studies fail to document

of 5-HTl

postsynaptic

receptors.

function,

at least in systems related to depression

This may make a very important

of changes in receptor number or affinity.

to support

point.

and antidepressant

a S-HT

postsynaptic

receptor

5-

complex

by

an increase in the number

Changes in postsynaptic

receptor

drugs, may be relatively independent

The implication for our clinical understanding

action is that receptor function

is the most important parameter to keep in mind.

for ail their technical elegance,

have several limitations in explaining

of antidepressant

Receptor binding studies,

how antidepressant

therapies produce

their clinical response.

3. Beta-Adrenergic Beta-Adrenergic receptors

receptors,

coupled to adenyiate

function is down-regulated

like 5-HTi

receptors,

cyclase (Table 1).

by chronic antidepressant

The classical NE deficiency

hypothesis

of the G-protein

regulated

superfamily

below suggest that beta-adrenergic

of

receptor

treatment.

of depression

and Suiser in 1975 that chronic,

(including tricyciics,

MAOi’s and iprindoie.

was turned “upside down” in the seminal discovery

but not acute treatment

with a variety of antidepressant

as well as ECT) caused a down-regulation

induced CAMP response in iimbic forebrain drug treatment

are members Data reviewed

and Bepressioo

Receptors - CAMP Stimulation

3.1 Beta-Adrenerglc Ventuiani

Receptor Supersensitivity

of

agent

of the postsynaptic

NE-

tissue (Ventuiani and Suiser, 1975). Although acute antidepressant

has no effect on NE-stimulated

CAMP production;

following

IO-20 days of treatment

a blunted

CAMP response to NE agonist stimulation occurred. Reduction

of NE-stimulated

CAMP has now been reported

typical and atypical antidepressant et al, 1974; Sugrue, 1983; Garattini and ciomipramine

following

long term treatment

with a variety of

agents, as well as for MAOI’s and ECT by a variety of investigators. and Samanin, 1988). Selective 5-HT uptake inhibitors

are identical to NE uptake inhibitors

in producing

(Frazer

such as zimelidine

such postsynaptic beta adrenergic down-

regulation (Table 3).

The subtype Isoproterenol, stimulation,

of adrenergic

receptor

which is a beta-adrenergic suggesting

that a non-beta

tissues (Piic and Enna, 1985 & 1986).

at which

NE, causes CAMP generation

is not fully understood.

agonist, causes only half of the CAMP production component

of NE induced CAMP generation

Only the non-beta

component

seen with NE

is present

in most

appears to be decreased by chronic

mianserin or ximelidine treatment (Mishra et al. 1980; Gandolfi et al, i9g3).

513

Antidepressant drugs

Table 3. The Effect of Chronic Antidepressant Treatment on Cyclic AMP Generation by Norepinephrine or Isoproterenol

Antidepressant

Treatment

“atypical”

0 0

____-_-of individual

Receptors-Blndlng

The above data indicating (a functional

N/A N/A

pargyline

ECT

treatment

N/A

iprindole mianserin ximelidine

MAOI

3.2 Beta-Adrenerglc

Isoproterenol

imipramine desipramine clomipramine amitriptyline

tricyclic

See text for description available(N/A).

NE

Drug

treatment

inhibition(-),

no effect(O),

prompted

CAMP generation

the examination

was blunted by chronic antidepressant

of drug effects

on adrenergic

Utilixing a ligand which specifically binds to beta-adrenergic receptors (3H-DHA), without

a change

regulation

in receptor

in the number

antidepressant antidepressants

affinity

et al, 1977).

receptors

such as iprindole,

traxodone and buproprion,

the non-beta

component

binding.

As noted in Table 4, such down-

(B max) has been reported

fail to reduce beta-adrenergic

receptor

Banerjee et al. reported

in multiple brain areas with a variety of antidepressants,

Only mianserin and zimeladine in down-regulating

(KD) (Banerjee

of beta-adrenergic

drug treatment

data not

Studies

that NE-stimulated

effect)

effects;

following

chronic

including atypical

and with MAOI’s as well as following

ECT.

receptor binding, however, both are effective

of NE induced CAMP generation

(Table 3).

The possibility

that beta-receptor binding decrements are related to antidepressant effects clinically is suggested by the observation

that Only long term, not acute, treatment with antidepressant drugs, is associated

with

antidepressant response clinically and down-regulation of beta-receptor number.

The mechanism CAMP production

by which antidepressant is not known.

drugs down-regulate

beta-receptor

number and NE-stimulated

An initial hypothesis suggested that down-regulation of postsynaptic beta-

adrenergic systems occurs secondary to the antidepressant induced increase in NE within the synaptic cleft. Many receptor systems are known to homeostatically

down-regulate

both their receptor number and

functional sensitivity in response to increased transmitter availability. The prolonged increase of synaptic NE caused by reuptake inhibition, of degradative

by blockade at presynaptic

alpha2 receptors (mianserin),

or by inhibition

enzymes (MAOIs) could conceivably result in the secondary down-regulation of postsynaptic

F. P. Zemlan and D. L. Garver

514

Table 4. The Effect of Three Types of Chronic Antidepressant Treatment on the Number (Bmax) of Beta-Adrenoceptors

Antidepressant

Treatment

Drug

Beta-Adrenocepton

tricyclics

imipramine amitriptyline chlominpramine doxeprine nortriptyline desipramine

“atypical”

mianserin iprindole ximeladine traxndone buproprion

MAOIs

0 0

phenelzine tranylcypromine clorgyline paragyline nialamide ___-_

ECT Decrease in Bmax(-). no effect(O).

beta-receptor

number and sensitivity.

stimulated CAMP production

However, it is difficult to account for the down-regulation

and/or down-regulation

of the number of beta receptors by drugs which have

little or no effect on either NE reuptake or MAO inhibition, as drugs like amitriptyline. Other

speculations

postsynaptic

possibility generalized

of’

effects

major changes

transmembrane

bilayer,

by which

antidepressant

systems concern more generalized.

receptors and receptor coupling processes.

during

chronic,

in membrane

changes may effect

outer membrane

the mechanism(s)

or NE-stimulated

changes effecting

or receptor-associated

or even on presynaptic

alpha2 blockade, such

traxodone. and especially. by iprindole and buproprion.

concerning

beta-adrenergic

membrane-related

of NE-

but not acute antidepressant

properties

including

composition

not only the number of identifiable

but also the movement

catalytic units, thus potentially

drugs

down-regulate

but as yet poorly defined

The multiplicity

of receptor

drug treatment

suggest the

and fluidity/viscosity.

beta-adrenergic

Such

binding sites on the

of the bilayers which permit the linkage of receptors

effecting

a variety of neuronal systems (Sulser and Mobley, 1981).

both receptor number and functional

sensitivity

to of

Antidepressant

3.3 Betr-Adreaergic

Peripheral

receptor function

estimates of the numbers of beta-adrenergic

increased,

(Pandey

leukocytes

3H-DHA binding (41 + 14 fmole/mg)

major

isoproterenol-induced abnormality

depressive

CAMP generation

other body tissues.

in

(Extein et al, 1979).

No evidence

antidepressants

in leukocytes sensitivity

on leukocyte

down-regulate

Decreased is the opposite

from

Bmax and decreased

of what would be expected

drug treatment with desipramine binding or isoproterenol

can yet be marshalled hypothesis

beta-adrenergic

CAMP production

beta-receptor

if an

were not only present in the brain, but also generalized

3H-DHA

hypersensitivity

both Extein (Extein et al, 1979) and

isoprotere_nol-induced

patients.

Chronic antidepressant

effect

a beta-adrenergic

decreased

disordered

of increased beta-adrenergic

to have a significant

support

disorders have been limited to

as compared to both controls (52 + 16) and

period (53 2 18). Moreover,

et al, 1979) have reported

from

throughout

in the affective

receptors and their function (in terms of CAMP generation)

Extein et al (1979) found that leukocytes from patients with major depressive disorders had not but &creased

to the same patients during a euthymic Pandey

515

Receptors - Human Studies

measures of beta-adrenergic

leukocytes.

drugs

from peripheral of depression

or lithium also fails

stimulated

CAMP generation

studies in depressed

or to support

patients to

the hypothesis

systems in tissue devoid of adrenergic innervation

that

(Schweizer

et al, 1979). The hypothesis beta-adrenergic

that depression function--a

could be related to an excess of CNS beta-adrenergic

beta-supersensitivity

are achieved by down-regulating

hypothesis

such beta-adrenergic

of depression--and

supersensitivity,

on beta-adrenergic

beta-adrenergic Alternatively,

sensitivity monitoring

receptor in affective

activity and,may disordered

of central beta-adrenergic

eventually

patients function

activity.

by the significant

contribution

provide a means of comparing control

by means of neuroendocrine

of alpha-adrenergic

effects

to test clinically

Pineal melatonin release

to that of other

as the growth hormone response to insulin (which is known to be facilitated is complicated

that antidepressant

has been difficult

owing to the lack of clear cut clinical markers of central beta-adrenergic is dependent

receptors and excess

the

populations. responses,

by beta-adrenergic

such

receptors)

and 5-HT systems to the regulation

of

growth hormone release.

3.4

Beta-Adrewrslc

As discussed

Rtcepton

above,

(CAMP production)

chronic

- New Aotldeweuantr

antidepressant

and Sumrrry

treatment

reduces

cortical

beta-adrenergic

responsiveness

often accompanied by a reduction in the number of cortical beta-receptors.

group at the University

Frarcr’s

of Pennsylvania has utilized the pharmacology of antidepressants to determine

whether a new class of clinically effective antidepressants might be developed. beta agonists, similar to chronic antidepressant

treatment,

As chronic treatment with

reduce beta-adrenergic

responsiveness

and

receptor density, Frazer has explored whether centrally acting beta agonists possess a pharmacologic profile similar to clinically proven antidepressants (O’Donnell and Fraxer, 1985). Frazer’s group has extensively

studied two drugs. clenbuterol and prenalterol which are both centrally

acting beta adrenergic agonists (Tondo et al, 1985; Conway et al, 1987). Chronic clenbuterol treatment, like antidepressants, decreases the responsiveness of cortical beta receptors.

There are two subtypes of beta

516

F. P. Zemlan and D. L. Garvcr

receptors in cortex.

Beto-l

receptors comprise about 80% of all cortical beta

mce~ton.

whii

beta-2

receptors represent the remaining 20% (Roiabow et ol. 1984). Clenbutcrol bin& to both cortical beta-l and beta-2 receptors equally well (Ordway et al, 1987) but has different pharmacologic actions at these two receptor subtypes. by beta-2

Clenbuterol is an agonist at beta-2 receptors as it stimulates CAMP production mediated

receptors and, as would be expected, down-regulates

treatment (Davenport et al, 1986; O’Donnell ad

cortical beta-2 receptors after chronic

Fraxer. 1985, Vos et al. 1987). Clenbuterol appears to be

an antagonist at cortical beta-l receptors. Clenbuterol does not increase beta-l mediated CAMP production, rather it blocks the effect of isoproteronol on beta-l mediated CAMP and has no effect on the density of cortical beta- 1 receptors.

While clenbuterol’s agonist properties are limited to beta-2 receptors, it appears

that antidepressants have little effect on beta-2 receptors. Chronic treatment with antidepressants results in decreased beta-l

receptor density

in cortex with little effect on beta-2 receptors.

different from clenbuterol possessing beta-l effective antidepressant.

Therefore, a drug

agonist properties would more likely prove to be a clinically

However, in humans, there is one study suggesting that clenbuterol possess some

clinical efficacy as an antidepressant (Simon et al, 1984). Prenalterol is a selective beta-l acting.

agonist in the periphery (Co&son et al. 1977) which is also centrally

Chronic treatment with prenalterol resulted in a small, but significant decrease in isoproterenol

stimulated CAMP production, however. no effect was observed on the density of cortical beta-l (Ordway and Frazer, 1988).

receptors

While chronic prenalterol treatment did appear to mimic some of the

properties of chronic antidepressant treatment, it appears unlikely that prenalteral will prove an effective antidepressant.

Substantial doses of prenalteral are required in order for this drug to be centrally acting;

doses which would most likely produce tachycardio.

What is currently needed to bring this innovative

antidepressant drug development approach to clinical trials is the identification of a potent, centrally acting beta-l agonist that is relatively devoid of cardiovascular side effects. In summary, there is convincing biochemical and receptor binding data suggesting that beta-l receptors are down-regulated by chronic antidepressant treatment. The novel approach to antidepressant development taken by Fraxer (O’Donnell and Frazer. 1985; Ordway et al, 1987; Ordway and Frazer, 1988) should provide a rigorous test of the beta-l down-regulation

4.

hypothesis of antidepressant clinical efficacy.

S-HT2 Receptor Superseosltlvlty lod Dsprcssloo

5-HT2 receptors are members of the G-protein

receptor superfamily,

receptors, am coupled to the phosphoinositide second messenger system.

but unlike S-HTI and beta-

Only limited information on the

role of 5-HT2 receptors in depression is available although 5-HT2 receptor binding data suggests a possible role for these receptors in the biochemical action of clinically effective antidepressants. 4.1 S-HTs Receptors - Bindlox Studles. Ligond binding studies demonstrate that chronic antidepressant treatment decreases the number of 5-HT2 receptors in cerebral cortex (Peroutko and Snyder, 198% Blockshear et al. 1980; Kellar et al. 1981; Mann

Antidepressant

and Enna.

1980; Enna and Kendall.

Kendall and Nahorski. 2H-ketansetin.

to be consistently

and MAOI’s.

of the antidepressant trazodone

1981; Biackrhru

and !bden-Bush.

and amitriptyiine

receptors.

which

demonstrating

down-regulate

5-I-IT2 receptors.

receptor down-regulation

reduced

For example,

demonstrate

little or no affinity A problem

is an ubiquitous

a high affinity

decrease

function

for

with interpreting

S-HT2

treatment

of the affinity

receptors,

is ECT data.

administration

such as

as well as and pargyline), that S-HT2

While Kellar et

decreased the density

are promising,

data on PI turnover

of 5-HT2 receptor systems.

available.

Similarly,

increased the density of cortical 5-HT2 receptors.

data and initial biochemical the responsiveness

(reviewed

below) suggest

There currently

is no central

Although initial studies of antidepressant

more extensive

or

atypical

antidepressants

the above data as indicating

ipridole or amitriptyiine

model for 5-HT2 receptors

5-HT2 receptor

effective

repeated ECT increased the number of cortical 5-HT2 binding sites.

iigand binding

neuroendocrine

including

for these binding sites (tranyicypromine

Ventuiani et al (1981) found that repeated ECT treatment In summary,

by antidepressants,

clinically

feature of antidepressant

al. (1981) found that chronic tranylcypromine, of cortical S-HT2 receptors,

in number

198s;

by 8%spiroperidoi

The decrease in S-HT2 receptor density appears independent

for 5-HT2

antidepressants

that antidepressants

198% Luttin~er et d.,

1985). The S-HT2 receptors (Table 2). labeled preferentially

are found

antidepressants

517

drugs

studies of chronic antidepressant

action on

treatment

on 5-

I-IT2 receptor coupled function are needed to assess the potential role of 5-HT2 receptors in depression.

4.2 S-HT? Receutors Although receptors branches

both

- Preciinical

5-HT1

Studies.

and 5-HT2

and demonstrate

receptors belong to the same superfamily

substantial

of this family.

structural

5-HT1 receptors

homologies;

Although

these data are consistent

with the above binding data.

decreased

(Kendall and Nahorski, in radioligand

limited data on the effect of antidepressants

the number

to two separate

employ the adenyiate cyciase pathway

utilized the PI pathway.

and imipramine

they belong

of G-protein

and distinct

while 5-HT2 receptors

on PI turnover is available,

Chronic treatment with the antidepressants

of 8H-ketanserin

coupled

labeled 5-I-fl-2 binding

ipridoie

sites and PI turnover

1985). These data Suggest that the decrease in the number of 5-HT2 receptors seen

binding experiments

are functionally

significant

in that they are related to decreased activity

in the second messenger system. Pharmacologic treatment.

studies

have identified

The ability of antagonists

in rats and mice induced

two different

types of behaviors

observed

by several different

5-HT agonists is related to antagonist

receptors (Lucki et al, 1984). While the head shake response appears 5-HT2 receptor syndrome

is preferentially

associated

with 5-HTi

receptor binding data, Blackshear and Sanders-Bush produced

receptors

behavior was paralleled by a decrease in the B,,, treatment was to down-regulate

as described

above.

affinity

for 5-HT2

mediated,

Consistent

(1982) reported that chronic treatment

a decrease in the head shake response in mice.

antidepressant

after 5-HT agonist

to block the head shake response (“wet dog shakes” or head twitches)

the 5-H-I

with 5-HT2

with mianserin

The observed decrease in this 5-HT2 mediated

of 5-HT2 receptors suggesting that the chronic effect of

5-HT2 receptors.

518

F. P. Zemlan and D. L. Garver

4.3 5-HT2 Receptors - Human Studies In humans, the primary neuroendocrine prolactin

response.

facilitated

if the distinction

Interpretation

model for studying

of the effects

between 5-HTl

and MAOIs. mianserin and trazodone

properties

of antidepressants

higher affinities

1981; Luttinger

by these two clinically effective

demonstrated

in several functional

consistent

L-tryptophan effective

patients,

models of 5-HTl

unlike

this response

than for other S-

et al, 1985). The high affinity is reflected

5-HT2 receptor

in their 5-HT antagonist

response induced by quipazine in rats is

with the data of Meltzer et al (1981).

For example, neither trazodone

in depressed

in enhancing

model is

tests (Fuller et al, 1984; Hingtgen et al, 1984). For example,

effect in human and animal neuroendocrine 1981; Price et al, 1988).

induced

Unlike tricyclic antidepressants

for S-HT2 receptors

antidepressants

Fuller et al. found that the S-HT2 receptor mediated corticosterone blocked by trazodone;

is the L-tryptophan

on this neuroendocrine

and S-HT2 receptors is made.

demonstrate

HT receptor subtypes (Enna and Kendall, binding demonstrated

S-HT function

tricyclic

In contrast,

trazodone

is without

receptors (Fuller et al, 1984; Meltzer et al.

nor mianse.rin augment the prolactin

antidepressants

(Cowen and Anderson,

and MAOIs which

1986; Price et al, 1988).

response to

appear

to be

The lack of a

mianserin or trazodone effect on the prolactin response may be related to the fact that this neuroendocrine model primarily receptors.

reflects activity at 5-HTl

These data help illustrate

receptors

Rather than assuming that clinical efficacy transmitter

while mianserin and trazodone

a shift in thinking

of all antidepressants

system, it appears more likely that clinical efficacy

and even multiple subtypes within that system (e.g. 5-HTl

4.4

s-HI’2

of a neuroendocrine

makes it difficult

and function. suggest

model for studying

to assess the effect of antidepressants

studies of 5-HT2 receptor

trazodone

primary affect 5-HT2

antidepressant

mechanism

is related to a single effect

of action. on one CNS

is associated with several transmitter

systems

and 5-HT2 receptors).

Receptors-Summary

The absence

number

regarding

coupled PI turnover The identification

that increased

attention

5-HT2 receptor

on this system.

function

to 5-HT2

5-HT2

receptor

patients

5-HT2 receptor binding and initial

both suggest that antidepressants

of high potency

in depressed

compounds

function

decrease

5-IiT2

receptor

such as mianserin

in relation

and

to antidepressant

mechanism of action is warranted.

Acknowledgements We wish to thank Cindy

manuscript.

Becker and Karen Parker for their expert assistance in the preparation

This research was supported

by grants from the National Institutes

of this

of Health (NS-18326 to

F.P.Z.), The National Institute of Mental Health (MH40293 to F.P.Z. and MH-326602 to D.L.G.) and a Center grant from the Ohio Department

of Aging (ODA1371).

Antidepressant

drugs

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Inquiries and reprint requests should be addressed to: Dr. Frank P. Zemlan Department University

of Psychiatry of Cincinnati

School of Medicine Cincinnati,

Ohio 45267-0559 USA