Prog. Neum-Psychophormocol. 6 Biol. Psychiot. Printed in Great Britain. All rights reserved

027~5646190 $0.00 + SO @ 1990 Pergamon Press plc

1990. Vol. 14. pp. 449-458

FROM PHENOMENON TO MECHANISM: AN INVESTIGATIONAL STRATEGY BTEPEB Department

C. DILBAVRR

of Psychiatry, Ohio Btate Columbus, Ohio, D.B.A. (Final form,

January

University,

1990)

contents

1. 2. 2.1 2.2 2-3 3.

Dilsaver, Bteven C. From Investigational Strategy. Psychal., 1990, u:449-458 1.

Phenomenon to Mechanism: An Prog. Neuro-Psychopharmacol.

450 451 453 453 455 455 456

& Biol.

The author desoribes an investigational strategy useful in the field of pspchopharmacology. This strategy is based on the ability of a multi-disciplinary team first to measure significant changes in a behavioral or variable in physiological response to an experimental manipulation. This initial measurement allOWS investigators to identify a phenomenon but not its underlying meahaniam. study then proceeds to assess the anatomical substratum essential to mediating the physioloqio change and receptology. Finally, changes in second messenger meohanisms are determined. Study of the neurobiologic effects of bright light is used as an illustration.

2.

3. 4. 5. 6.

Revwords:

Investigational

strategy,

1. Inunanuel Kant and It

449 449

Abstract Introduction Behavioral and Phyaiologiaal Paradigms Neurobiology of Bright Light Neuroanatomiaal Bubstratum Mediating the Effect of Bright Light Effect of Bright Light on Becond Messenger neahanisms Conclusions Acknowledgments References

*%oumenon.** is

reality

a term

(1724-1804)

presents

itself

to

research

program

Introduction drew

"Phenomenon~~

referring

paradigm,

the

a distinction

refers way

to the in which

to our senses.

449

between

~~phenomenon~*

appearance an

ultimate

of

a thing. aspect

~INoumenonu is concerned

of

with

450

S. C. Dilsaver

the "thing

in itself"

*@ Phenomenon*t

is

(Copleston,

concerned

with

1964). the

true

~~Nounmnon*~ in contrast

to

nature

of

af

some

aspect

reality. 8aientists

have

is phenomenon the so1

United be

explanations

an

(Dilsaver, 1987a,b;

and

(Dilsaver, 1989:

(Dilsaver

assessing

the

effects

muscarinic

agonist

1989c),

clonidina

lsasa),

or yohimbine

battery

powered

1990b).

heterocyclic and Bnider, and

Alessi,

range

This

and

(Dilsaver is

1987; Dilsaver Dilsaver

and

et al.,

rajchrsak,

Alessi, in

1988,

Dilsaver

et

can

Dilsaver

assessing

chronic

1986).

Z989aLI

to temperature

devices

1988:

et

al.,

A hearing-aid-

and Davidson,

et al., 1987), al.,

al.,

1989).

a

and Davidson,

be

in taore temperature

and

to

1987a:

1987: Dilsaver

2988a;

These

changes

(Dilsaver

et

of

artificial

Davidson,

Dilsaver

sensitive

rats.

mechanisms.

sensitive

and Bnider,

Dilsaver

and

as a means

bright

and

1989a;

198901,

a2-adrenerqic

1989a)

mechanisms

useful

et

1987,

198713: Dilsaver

1989af,

and Davidson,

into

et al.,

agents,

thermosensor

antidepressants

1987;

1989;

to measure

paradigm

Xajohrsak,

Dilsaver

Dilsaver

(Dilsaver

and

on

(Dilsaver,

Hariharan,

and sensitively

physiologiaal

1986:

screen

to

1987a: Dilsaver

in core temperature

stressor

1987a;

paradigms

musaarinic

Dilsaver

pharmacologic

telemetric

us

on

Dilsaver

of

intraperitoneally

noumenon. deceive

manipulations

1988,

change

(Dilsaver

biological

ParadiCImS

and Davidson,

al.,

1988a;

nicotine

lgsoa),

reliably

et

(Dilsaver,

Dilsavrar and

implanted

1987;

forced

and Hajchrzak,

1987,

mechanisms

scientific

and physiological

8nider,

a chronic

or

messenger

The

us to noumenon.

and Davidson,

average

phenomenon.

or molecular

and Phvsioloaical

Dilsaver

In

(and rightfully

does not necessarily

1989a: Dilsaver

employs

second

experimental

and Majchrsak,

One paradigm

1987bt

of

to

to

a contemporary

uses behavioral

Dilsaver

Hariharan,

al.,

direct

effects

in

manipulation

phenomenon

1986; Dilsaver

nicotinfc

Dilsaver

that

Behavioral

Our laboratory

for possible

change

tends

devoted

discipline

of

it just might

2.

light,

a

What

and noumenon.

may not be to another.

pharmacology

to approximate

suggests

of phenomenon

to one scientist

experimental

seem

author

and that

as

account to

sense

behavioral

regafded

consequent

own

or noumenon

States,

quantitative

The

their

the

stressors

ethanol

in the et

effects

1987a:

is used

al., of

Dilsaver (Dilsaver

(Majchrsak

and

From phenomenon

Dilsaver,

1989b),

1988a,b:

Dilsaver,

regulation

technical

how

data

light

a recent

variable

concerned

with

parameter

can

in which

used

to

data

consequent

and

the

and

or causal

paradigm

article used.

in core

a

is The

temperature

was the topic

This

article

is

measured

multidisciplinary

in conveying

manipulation

some

on

University,

rapidly

of

study

of the neurobiology

2.1.

Neurobioloav research

Our

of bright

of Briqht group

group's

as

can

be

pharmacologic

paradigm

in which the independent

intensity

or

duration

of exposure

dependent

variable

to a muscarinic, a dose-effect

pharmacologic

strategies

The utilization neurobiology

theoretically bright

mechanism

or

of

to bright

nicotinic, curve

1987b:

interesting

illustrative

8tate

Program)

illustration.

is

a

pharmacologic

studied

variable

using

light.

change

the

in

agonist.

in principle,

a

(dose) is the

artificial

or aminergic

can be,

and physiological

light

conclusions: light

Dilsaver,

allowed

1989b;

finding

us

such as:

subsensitizes

in the regulation

Majchrzak,

Ohio

of a

The

thermic

In either

constructed

and

applied.

bright

important

organism

response)

of behavioral

artificial

involved

an

light

Its

instance,

on

bright

treatment.

(effect

effects

(The

is a good

the

a quick and

Light

regards

effect

However,

can provide

Psychopharmacology

light

and

about basic processes

for the possible

Psychiatry,

and

simplistic

are reasonable.

screening

changes

Behavioral

relatively

strategies

mechanism.

Department

in receptor

biochemical

information

These viewpoints

of

interested

basic

manipulations.

and physiological

means

of

are often considered

mechanisms.

inexpensive

with

be

inexpensively of

are particularly

experimental

to

use of behavioral

the

can

1988).

aspects

measurement

regarded as ineffective

response

in the

research

Alessi,

a simply

direct

1987b,

involved

program.

physiological

Our

and

Majchrzak,

of this brief

paradigm

in psychopharmacologic

Neuropsychopharmacologists binding

this

the use of change

(Dilsaver

the way be

and

mechanism

The purpose

using

governing

article

451

(Dilsaver

on a muscarinic

derived

principles

as a dependent

research

bright

1989b)

of core temperature.

to explain

of

and

to mechanism

paradigms to

several

(1) Treatment

of rats

central

of core temperature Dilsaver

to study

to

a

come

et

is that treatment

al., with

muscarinic (Dilsaver 1989b). bright

and An

light

S. C. Dilsaver

452

1

Tab10

RESULTS

geoendent

OF PRTSIOLOQICAL

PARADIGMS

Hypothermic Resnonse

Variables

Oxotrexorine

X

(0X0) challenge

Amitryptyline

treatment

Bright Light Amitriptyline swim

stress

Bright stress

Light Treatment & OX0 challenge

Inescapable

X

c OX0 challenge

Treatment with concurrent treatment C OX0 challenge

Forced

X X

& OX0 challenge

Footshock

Constant Dark OX0 challenge

Enhanced Hvnothermia

with

forced

swim X X

61 0x0 challenge

Environment

6 X

I

I

Table 1: The rats' baseline temperatures were measured before challenge with oxotremorine. The rats* were subsequently challenged with oxotremorine an& their temperatures measured. The rats' normal response to oxotremorine is hypothermia.

for six hours to produce (Dilsaver

et al.,

Dilsaver

et

hypothermic spectrum a.m.

daily

completely

supersensitivity

3:30

supersensitize (Dilsaver,

artificial p.m.) rats

1989b).

to

the hypothermic

effects

constantly

to

darkened

SUperSenSitiVity 1989b). the exact

environment

to

the

effect

of

bright

and Snider,

supersensitivity

of

enhance

of

of

7:30

stress

to

oxotremorine 1986)

of rats to

and Alessi,

1987).

rats

in

a

in a profound

oxotremorine

(Dilsaver,

light and darkness

(Table 1)

the

full-

et al.,

placing

days results

artificial

on the rat.

of

the sensitivity

light,

1987; to

(between

swim

(Dilsaver

(Dilsaver

bright

effect

daily

forced

effects

stress

for seven

thermic

Thus, full-spectrum opposite

swim

of oxotremorine effect

of oxotremorine

(2) The administration

Capacity

potently

the

(Dilsaver

hypothermic

forced

of amitriptyline

effects

for eight hours

the

the

Both

capacity

produces

light

blocks

footshock

contrast

potently

of this agonist.

and inescapable

(3) In

the

Rmitriptyline

1987)

effects

bright

and

1989b).

al.,

blocks

to the hypothermic

have

From phenomenon to mechanism

2.2.

.1: Neu

oanatom

Physiologic

al

data

at at

derived

steps of a protracted

in our

project.

study of the neuroanatomical light

in a collaborative

neuropathologist. selectively

Iesioned

full-spectrum

effectiveness

the

of

(Ehlert

autoradioqraphy first

assess

2.3.

method

the

anatomic

et

(Rainbow

al.,

sensitive,

of an experimental

distribution

the

locus

light

The

to exert The

using

and

brain

quantitative

second

manipulation

the

rat.

studies.

simultaneously

but the

be

is determined

variables

1983) are

and

system

to mediating in

initial

binding

1982)

visual

of bright

our

of bright

assessed.

allows

on changes

us to

in the

of receptors.

fof

The

strategy

neuroanatomy treatment

eventually

and

calls

receptoloqy

to

(in this case, bright

in a collaborative

study with

and

chemists.

physiological

particular affected

interest by bright

are

Irvine,

1984,

et al, 1985),

Bnider

et

Irvine,

1984).

agonists Cyclic

Renterqhem measuring strategy.

1982,

IMP

assessment

The

those

1984;

1984), These

in given

changes

and

of

to

the

1985:

and Wolfe,

cyolic

GNP

flux

the

Davis,

1985: Yoshimura

effects

1985;

mediate

mechanisms.

mechanisms

and

of

include

Bartus,

effects

1984;

(Berridqe

and

of musaarinic

in the generation et

al.,

1985) provides Piqure

and

1985;

and Crews,

Richelson,

ions

Buqden

a

systems

These

Oonsales and

of changes

1985;

of

mechanisms

1985; Berridqe

Fisher

of

pharmacologists

studies.

Calcium

et al.,

study

neurotransmitter

(Ranba

of

Measurement

in adrenerqic

the

second-messenger

linked

three measenqers

1986;

from

(Batty and Nahorski,

Gill of

tissues.

(Clark,

et al.,

shift

biochemically-oriented

cycle

generation

al.,

a

Iiqht) on second messenger

Fisher and Aqranoff,

1984;

Fisher

for

light in our physiological

the polyphosphoinositide

of

in

1980,

et al.,

is the more

impact

the capacity

receptor

on

light

at a particular

described

subsequent

psycholoqiat

the

integral

artificial

a lesion

light

an experimental that

the

have led us to plan the effect

mediating

of a site(s)

bright

effects

bright

homogenates

The

in search

determines

findings

requires

that it blocks

physiological

effects

substratum

study

of placing

by demonstrating

studies

Positive

study with

This

effects

of

453

1985; a means

1 illustrates

Van of

our

Fig

1.

i

OR

structures

effects

a~toradiography)

using

systems)

of the exper-

PARADIGM mental manipuiat~on on 2nd messenger

of the effects

B~~C~E~~CAL (Assessment

BASIC

and quantitative

binding parameters

STUDY

on receptor

brain homogenates

(Assess

RECEPTOLOGI~ CAL

to medi-

manipulation)

essental

of ph armacologic

central

ating effects

(Identify

STUDY

challenge)

ANATOMICAL

to a pharmacologic

of change in core temp

~ARA~IG

Investigational strategy

in response

~~easufem~nt

PWY SIOLOGICAL

From phenomenon

our

Thus,

strategy

(measurement

of

microscopic variable

(study

is used

effective

to

Psychiatric techniques way

treatment

be

a

paradigm

effects

molecular

the changes

which

in second

the

methods

confluent

must

themselves

are

the methods to assume

causes

of

that

at the level

illustrates

pharmacologists,

neuropharmacologists,

the effects

mechanisms

have

have

discussed

full-

in the rat

be determined.

using

One would

a

neuroanatomioal

on second-messenger

behavioral

with

Eventually

mechanisms

be asked.

whether mechanism.

treatment

and costly

indicated.

The strategy of

that

of the reviews

pharmacologic

assess

or adrenergic

to investigation

messengers

expression.

and

these mechanisms

intensive

light

amenable

to the use

This article

variable

affects

be costexpensive

studies.

moving

indicated

labor

might

and

nicotinic,

are now

of bright

intensive

inexpensively

on second-messenger

questions

neuroanatomists,

and

the

physiological

it might

biochemists.

physiologic

light

More

biologists

of genomic

increasingly

to guickly

studies

of this treatment the

are

of basic

repeatedly

1989b).

illuminated,

Conclusions

artificial

A

whether

and biochemical

a muscarinic,

has

bright

receptologic

Once

labor

to

changes)

systems).

3.

simple

used

affects

(Dilsaver, and

messenger in assessing

receptological,

which

can

physiological

more

perform

researchers

in

spectrum

second

and strategies

paradigm

This

of

from the level of the macroscopic

or

as a probe

neuroanatomical,

the

is to proceed

behavioral

455

to mechanism

the way in

physiologists,

and

basic

biochemists

his

gratitude

are

and complimentary. Acknowledaements

The

author

Malatynska, Monigue

and Jason

work

Peck

to

for their

described upon

Neuroscience

empress

Pharmacologist,

Mark Majchrzak,

Physician-Bcientist Ohio

like

Research

Giroux,

the project The

would

contributions

in this

which Career

and his students

Dr. Stuart

this

B. Miller,

to Duane

Dr.

Ewa

Flemmer,

Gail Nakamura,

to the various

components

of

supported

by

article. article

Development

based

is Award

Program , and the Bremer

was

MROO5530-3,

Foundation.

the state of

S. C. Dilsaver

456

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Antimuscarinic

effects

Chronic EAJCHREAK, M.J. and DILSAVER, B.C. (1990) ethanol produces supersensitivity to oxotremorine. Psychopharm. 8 Biol. Psychiat. (in press).

of lithium.

treatment with Prog. Neuro-

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