An EEG investigation on nabilone, a synthetic cannabinoid, in rabbits

Pharmacological

Research

Communications,

AN EEG INVESTIGATION S. Sagratella, Laboratorio Viale

Vol. 18. No.

ON NABILONE, IN RABBITS

A. Pkzzola

A SYNTHETIC CANNABINOID,

and A.

Scotti

de Carolis

Istituto Superiore di ‘299 - 00161 Roma, Italy

dl Farmacologia, Regina Elena,

Received

653

7, 1986

in final form

24 April

Sanitl

1986

SUMMARY

In this paper, the electroencephalographic (EEG) and behavioural effects of nabilone, a derivative compound from d9-tetrahydrocannabinol (A 9-THC), are studied in comparison with those of A 8-tetrahydrocannabinol (A 8-THC) in rabbits. The results show that nabilone requires lower doses than A8-THC to elicit cortical spike-and-wave complexes, but higher doses to disrupt hippocampal theta rhythm. These data are discussed in connection with the clinical actions of nabilone in man.

INTRODUCTION Recent logical

studies

effects

degree

from

on synthetic (both

their

Nabilone

potential

beneficial

countries

for

chemotherapy Stark

euphorigenic

represents

separates

the

cannabinoids

from therapy

of

synthetic

undesiderable of

severe

Correspondence and reprints Dr. A. Scotti de Carolis Laboratorio di Farmacologia Istituto Superiore di Sanitl Viale Regina Elena, 299 00161 Roma - Italy 0031-6989/86/070653-l

O/SO3.00/0

out

the

can be separated cannabinoid

effects nausea

1979; Steele et al., --et al., and Dews (1980) found in a comparative carried

that

psychoto

some

action. the

(Herman

and chlordiazepoxide,

demonstrated

and psychotogenic)

therapeutic one

have

in mice,

rats,

and

and

compounds

is

registered

vomiting

induced

which in

by

some cancer

1980). study dogs,

between

nabi.lone,dg-THC

and Rhesus

monkeys,

clear

to:

0 1986

The Italian

Pharmacological

Society

654

Pharmacological

evidence also

of

a qualitative

between

nabilone

administration, --et

al,

that

nabilone

some anxyolytic dose

might

of

3.0

as the In

previous

were

examined

(Lipparini

rats

(-)A9-THC

and

the

EEG record,

complex

abuse

Vol. 18, No.

nabilone

man,

after

1984).

and

This

(1978,

last

1981)

relieves

d 9-THC but or

euphoria

than

suggests

nabilone

seems to

demonstrated

some symptoms

oral

d 9-THC

finding

In addition,

al.,

7, 1986

intravenous

and less

liability.

--et significantly

induced

by

by

this

natural

laboratory,

of

and

alterations

synthetic

that,

at

anxiety

as

disruption

of

the

behavioural

syndrome block

ataxia,

theta

These which of

waves

of

al.,

1973).

they

induced

the

cornel

brain

elec-

of

reflex,

were

(THCS)

In

hippocampus

EEG modifications consisted

of

tetrahydrocannabinols

1969; Willinsky --et al., --et (->A,-THC had similar effects:

spike-and-waves.

depression:

In

and Mello,

investigations

activity

voltage

between

tachycardia

Fabre

OS, it

Communications,

of depression.

trical

high

less

a lower

effects:

mg per

only

chlordiazepoxide.

Mendelson

have

feeling

not

induces

1982;

have the

and

nabilone

(Lemberger

well

similarity

Research

rabbits

and

flattening

of

and trains

of

accompanied

a mixture

of

jacksonian

by

excitement

episodes

a and

and

motor

paralysis. Willinsky theta

et

hippocampal

administration this In

put

particular

activity

observed

in

other

hallucinogenic

of

mescaline

(Longo,

(1973)

1962,

EEG change

activity

al.,

Baran

could

be

and

an

emphasis rabbits,

which

drugs, Longo,

is

such

1965),

electrical

on the as

of

also

observed

LSD,

psylocibin

the

hypothesis

the

psychodysleptic

advancing

counterpart

disruption

of

the

after and that

in man.

the

present

the

paper,

in comparison

with

those

EEG and behavioural ofd8-THC

effects

of

nabilone

were

studied

in rabbits.

METHODS Electroencephalographic preparations des.

and from

Implantation

under

ether

1962).

The

recording

(EEG) 4 chronically

of

superficial

anaesthesia animals sessions

Histological

recordings implanted

obtained rabbits

and concentric

according

acutely which

were

to

prepared started

examinations

l-2 post

were

placed

hr after mortem

10

bearing

deep

a technique

from

cortical

electrodes described

in

confirmed

rabbit electro-

was carried elsewhere

a restraining

discontinuation

acute

box

out (Longo,

for

the

of ether. the

location

of

deep

electrodes. Both

nabilone

and

A8-THC

were

dissolved

in

polyethylenglycol

300

and

Pharmacological

Research

administered solvent

Communications,

by slow

which,

intravenous

up to

0.6

655

Vol. 18, No. 7. 1986

Controls

route.

ml total

dose,

had

were

done

by administering

no influence

on the

the

EEG and beha-

vior. One drug cal

experiment

implanted

per week was carried

electrodes,

to avoid

out

tolerance

in rabbits

bearing

and cumulative

the

chroni-

doses

varying

effects.

RESULTS Nabilone from

In

6 acute

0.05-5.0

after

or

mydriasis

total and

after

the

doses

exophtalmus,

te

the

ataxically.

After of

alternated

$_8-THC

Doses

6 rabbits only

at

ranging

d8-THC theta

the

slight

reducing

and-waves; but

more

Exitations lity

disruption

mydriasis,

played

hind

EEG; doses

the

a few

Two mg/kg

(flattening)

(Fig.

1).

mydriasis, agitation

they general

and a compleshort

were

mg/kg)

first

epochs after

periods

of

in

was partially

blocked

observed

and partial

of

At

spike were

had a more

inducing

the This

with

of with

Behaviourally, excited

and dis-

pronounced

appearance dose

cornea1

1.0 mg/kg and waves

effect of

spike-

produced

similar

lasted

3-4 hr.

alterations,which alternated

to

a slight

injection.

disrupted.

behavioural

administered

produced

hour.

animals

of A8-THC

and

were

compound response

the

was markedly

movements

dose,

pronounced

exhophtalmus

10 minutes

aforementioned

the

by the

leg

rhythm

a more

(0.1-0.25

mydriasis,

decreased,

ataxia.

of

demonstrated

arousal

and arreflexia,

and ataxic

of

doses

had disappeared

was

observed hyperpnea,

periods

on a

higher

2-3 hr.

2.0 mg/kg

exophtalmus

theta

pronounced

the

Low

appeared

EEG voltage the

to

these but

the

of depression.

cortical

At

present

EEG voltage

waves

besides in

mgfkg.

were

0.1

Ten minutes

of spike-and-waves

Animals

throughout

from the

episodes

appeared.

preparations). of

0.25

frequent

a short

superimposed

with

was also

mglkg)

and a

time

observed.

showed

during

(3-5

this

complexes

and

and

doses

periods

persisted

(acute

synchronization

highest

At

and then,

excited

arreflexia

waves with

effects

arreflexia

in

a synchronization

were

in EEG voltage

were

more

theta

arreflexia

isolated

decrease

the

mg/kg appeared.

spike-and-wave

first

animals

in EEG voltage,

disruption These

mg/kg)

cornea1

0.05-0.1

cornea1

at

a slight

complete

excitation

was injected

EEG "arousal"

complete

(0.25-1.0

continuous;

of

the

EEG appeared,

Behaviourally,

decrease

of

an almost

higher

moved

nabilone

administration

blockade

desynchronized almost

preparations,

mg/kg.

A few minutes partial

rabbit

periods

of immobi-

and headnodding. After

the

highest

doses

(up

to

a total

of

10 mg/kg)

of

nabilone

like

Pharmacological

First

and third

tired

non

Second

record:

accompanied Fourth

acccompanied

nabilone

tonic seizure.

(consisting was

(1.0 (5.0

seen

under

the of

elicited

voltage

i.v.)

mg/kg,

of

cortical

cortex;

cortical

or clonic

convulsions

After

high

the

of head drop

concomitantly

alterations was 4-5 hr. The onset of drug-induced

(4 mglkg)

and flaccidity

with

The

ataxia.

effects

waves.

levels. P = posterior

hippocampus.

nor

appeared,

doses

applied.

spike-and-waves,

cortex;

= dorsal

unanaestheis

hippocampal

and hippocampal

Hipp

7, 1986

spike-and-waves

theta

F = anterior-sensorimotor

0 = optic

in the stimulus

the

elicited

at cortical

Vol. 18, No.

conditions

an acoustic

i.v.> the

Communications,

basic

arrows,

mg/kg,

record

L = left;

cortex;

neither

paralysis

At

by a flattened

sensorimotor

"grand-mal"

recorded

reduction

nabilone

R = right;

L\8-THC,

were rabbits.

by a slight

record:

Leads:

back)

records

curarized

Research

did

of both

of the duration

was shortened

the

tracing

compounds,

show a muscular

postural muscles of the of these behavioural

as the

dose

of both

drugs

increased. DISCUSSION On the the

cerebral

basis

of the

electrical

present activity

results of

rabbits

the

influence is

basically

of

nabilone similar

and A8-THC and is

charac-

on

Pharmacological

Research

10 min after

RO - I.0

Communications,

A8 THC 2 mglkg

657

Vol. 18. No. 7, 1986

i.v.

dp

RFP LPO

Fig.

2:

cally

Comparative

implanted

Similar

frontoparietal

dence 2.0

EEG effects

(6-9

Leads/

i.v.

of

See Fig.

terized

by

in

anterior

the

(lower

following

sting

of

and

mgfkg

i.v.

are of

elicited

chroni-

nabilone

at

the

(upper

same inci-

record)

and by

record).

a) appearance

of

spike-and-wave

posterior

cortex

leads

superimposed

b) disruption

of

hippocampal

theta

however,

in

is

inducing the

the

amplitude

a mixture following higher

cornea1

arreflexia

activity

of

the

at

least

complexes

EEG changes

described The

with

complexes

on a desynchronized rhythm,

c)

a generalized

active

than

in EEG voltage.

decreasing The

complexes

alterations:

spike-and-wave

A 8-THC

and A 8-THC in rabbits

1.

the

Nabilone eliciting

by 0.25

6.8-THC

electrocorticogram, decreased

nabilone

spike-and-wave

complexes/min)

mgfkg

of

electrodes.

disruption of the

are of the

potency in synthetic

5-10

, while of

more

the

2-3 times

hippocampal

A8-THC

less

effective

theta

rhythm

in than

and

in

EEG tracing.

accompanied

excitation

by a complex and depression

administration of

times appears

of

nabilone

rabbits, cannabinoid

in in

the

in respect

syndrome

qualitatively natural

eliciting

respect

behavioural

similar

THC derivatives cortical

to

&j 8-THC, to the

consito

(Table

spike-and-waves confirms

natural

the

that 1). and

higher

tetrahydrocanna-

658

Pharmacological

TABLE 1. Behavioural

and EEG effects

Research

of nabilone

Communications,

(NAB)

Vol. 18, No.

and

7, 1986

8-THC in the

rabbit.

Drug

Dose

Cornea1

mg/kg

arreflexia

0.1 11

+

0.25 II

+ +

+

1.0 11

+ +

+ +

3-5

+ +

+ +

+ +

NAB 8-THC NAB 8-THC NAB 8-THC NAB B-THC

+

-

complexes; binol

D.H.T.W.

nabilone

ataxia

by

i.v.

or

monkeys

in

our

the

previous

disruption

lower

disruptive

marjhuana

oral

Biochemical

to

+

+ +

+ +

+ +

+ +

+

=

cortical

spike-and-wave

waves.

reported more

administration muricide

(Lipparini, of

reduce

active dogs

and Dews (1980),

than

or

in

d 9-THC

fixed-ratio nabilone

in

decreasing

or in reducing

compounds

on hippocampal (Revuelta

by Stark

the the

theta

and perceptual

in

man. waves alterations

rate schedule.

hypothesis,

In

fact,

and

is

advanced 1973), test

nabilone less

of

of responding

fixed-interval

support

who

producing

the

rate

1969; Willinski --et al., --et al., theta waves can be used as a predictive

these

euphoria

in

in rats, with

and among them nabilone,

+

times

a multiple

data

+

those

under

effect

+ +

theta

results

effect

+

hippocampal

working paper

+ +

C.S.W.C.

present

in inducing

of

EEG voltage

effect;

2-4

of hippocampal

psychodysleptic

Reduction

CNS functions.

comparable

and the

In addition,

Slight

approximately

self-stimulation in Rhesus

+

several are

D.H.T.W.

+ + -

= disruption

in affecting

C.S.W.C.

exophtalmus

Absent;

Our results found

Mydriasis

+

2

Present;

Ataxia

that for

a

shows

a

effective

than

in man.

1982) indicate that et -- al., the turnover rate of GABA in

some cannabinoids, the

septum

of rats.

Pharmacological

Research

a similar

Moreover, the

hippocampus

last

effect the

connected

et

al.,

rate

anxiety

(as

(Stark

et

our

has

man

and

and

in

could

in

-et 2'al the

same

If

this

hippocampal the

these of

in

disrupcompounds

acethylcholine (Brunello

alteration

in

and

hippocampal

1969). that

animals.

a taming

and an antianxiety

effect

On the

demostrate

1979).

muscimol

literature

experimental

1978).

for

found

the

with

reduction

described

been

explain

treated

The similar

has

do not

firing

the

has

-et al L' rate of

this

rabbit

been

made

McLendon,

1978)

the

de Carolis been

the

induced

chlordiazepoxide) 1980),

al.,

in

data).

study

has

in

does

(Fabre

(Nakano

present

(Scotti

and Dews,

man

of suggest,

waves

rate

(Revuelta

authors

mention

property

nabilone

b9-THC

a reduction

in

activity

Repeated

turnover

with

hippocampus

which

1981),

electrical

in

the

acetylcholine with

theta

659

7, 1986

as these 1969,

in

of

treated

hippocampal

(Lipparini turnover Chey,

rats

neurones,

of

Vol. 18, No.

decrease of

is

cholinergic tion

Communications,

has

It

has

effect

in

septal-lesioned

at

a dosage

contrary,

a clear

nabilone been of

other

anxiolytic

anti-

shown

that rats

3.0

mg per

clinical

OS

studies

effects

of

nabilone

in man. We should

stress

nabilone.

The

after relevant

doses

reaction

(25-50

described

hand,

the

compared

,ug/kg),

after

with

the

nection, ineffective

blind

antidepressant of

anxiety.

This

feeling

that

and do not

and hilarity Pertwee,

are 1973),

marjhuana results) and 1.0

or

elicit known

or any

often

other

(Chopra hand,

relief to occurr

and Smith, in

In

particular

preliminary

they

doses

block

EEG arousal

--et

al.

anxiolitic

drug

probably

such

of anxiety. together effect

In

found the

with

occurr

to

of

unreality

previous

research the

smokers after

be

under

existing

post-smoking

in marjhuana often

con-

same authors

accentuate Moreover,

be such

this

A 9-THC

as feelings

agrees

can

administered

contrary,

EEG other

drugs,

(Fig.3). when

the

mg/kg)

anxiogenic

(1973)

On the

effects,

with On the

(0.5-1.0 of

clinically

the

same animal.

tetrahydrocannabinols

that both nabilone andA8-THC, mg/kg), are able to antagonize

drugs.

Kotin

side

finding

marjhuana

the

observed

at of

p carbolines

patients.

adverse

EEG patterns elicits,

doses

small

and psychotic-anxiogenic

abusers

On the

that

the

many similarities

in

higher

after

to depressed

prominence

increased

demonstrating

presents drugs

and several

as

of nabilone

or no impairment

after

elicited

be mentioned

the

a slight

sedative

should an

that

observed

pattern

conditions

described

features

stimulation,

pentylentetrazol,

it

double

certain with

many

spike-and-waves

as picrotoxin,

lytic

present

to vibroacoustical

pattern

and

at

EEG synchronization

anxiety (Paton

high

and

doses

in

1974). experiments at

we demonstrated

intermediate

doses

some EEG effects

of

the

slowing

of

the

(unpublished

(respectively sedative

frequency

0.2

and anxioand increase

660

Pharmacological 2 min after

PENTAMETHYLENTETRAZOL

5min

NABILONE

Research

10 mglkg

Communications,

Vol. 18, No.

7. 1986

i.v.

RF- L.F. RF

R.l?

Ls?- LO

Fig.

3:

after

Effects

of

3 mg/kg

i.v.

pentamethylentetrazol

(PTZ)

and nabilone

on the

EEG of

the

rabbit. Upper

record:

theta

hippocampal

Lower

record:

the

theta

Leads:

the

PTZ elicited

See Fig.

in

trazol)

(Sagratella

an

rabbits,

(excitant reported

and activated

by

data

anxiogenic and anxiolytic

cortical

spike-and-wave

complexes

and disrupted

diazepam

and/or

excitant may

anxiogenic

drugs)

at

drugs

the

level

of

do (picrotoxin,

the

are

support

the

hypothesis

further

and

the

anxiolytic

or anxiogenic

indebted

red

pentylente-

1985).

However, sedative

pentobarbital

studies interactions drugs activity

that

nabilone

including

other

between

nabilone

must

be carried

out

could drug or to

to Prof.

V.G.

tetrahyelucidate

of nabilone.

Longo

for

guidance

have classes

ACKNOWLEDGEMENTS The authors

the

waves.

like

effect.

drocannabinols the

elicited

and Longo,

preliminary

anxiogenic

complexes

1.

induced

nucleus These

spike-and-wave

rhythm. nabilone

hippocampal

voltage

cortical

and advice.

Pharmacological

Research

Communications,

661

Vol. 18, No. 7, 1986

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