Avoidance facilitation in adult mice by prenatal administration of the nootropic drug oxiracetam

Pharmacological

Research

FiDMIbJI

Communications,

STRATION

Vol. 18, No.

C!F

THE

Received

NKITRCG=‘I

in final form

1169

12, 1986

C

DF’UG

3 November

OX1 RACETAM

1986

!~lJMMAR”i I:[)-

1

m i ce

noc~trop

prenatal

i e

drug

p r e g n an c r’ ! and Prenatal I n

reduc

t 0

prenitai

0031-6989/86/l

exh

acqu

i bi

h i gher

dur

for

or

I ng

to

the w h s 1e

t h e

1 ocomotor

ast

two

5 h Ok! e d

ted

ion

ac t 1 I..! i t::,,

i 5. i t. i cn .

of

.a<: t i 11 i t:,

CJ

1 t 5 ,

1 ong-1 ige

sizlut

.

ing

effects.,

months,

mice

a

5.1 lc$lt

t,iJ t

ci t

t he

age

perform~.nces

of

e’..! ldent prenatal 5. igniftcai;t

t h r’ e e

than

1 ,,’

man

t h c. 1

control

rni,:*

i 5 i t i cln .

e5

admi

the

1 ocomotor

an i ma. 1 5

studi

C;t

acqu

produced

ox iracetsm

I n

a~.~0 i d.snce

se ‘., e r- a 1

e

offspviriis.

t i on

t he ce I n

*‘.pc,st,r

drug

e x p CI 5 e d

i dance

i ne

mg/k

adu

when

avo

c.al

.‘.50

tested,

t 1 e-box

mg.ture

t :I’

exposed

oxiracetam

We V e

shut

for

I y

repor

r-1 1 strat

21169-08/$03.00/O

t i Ion

1 ong-1 3 f

ast

i ng

?.Ia. r I 0 u 5

effects

on

1 earn

c e n t r a. 1 1 ‘:

(B 1986

The Italian

acting

i r,Q

3fter drugs.,

Pharmacological

Society

1170

Pharmacological

tncluding

amphe

1’ F i s h m a n

and

tam

i ne

Ya.nai

n eu r 0 1e p t i cs

c Z agon

et

IA,.a E

n e 4.~e r

ayen IGi

al

urqea

PfJr-p05e

,dap

and

Sal

of

t h e admi

compound

CBanf

of

beha,.

i r)r

prenatal

1 :y

tes.ted

far

shuttle-ba-

of

and exposed 1 ucumutor ayordance

lS7Ci,

. , a.zep

a n d i

Communications,

Keener

,

similar

Vol. 18. No.

,

i nes

ba.rbi


I m p r c) v i n g

t cl

72. 1986

tura,tes

/ eder

et

S and

op i ates

experimenta.

k n cw 1 e d g e .1

our

al

. ,

a p p r Ga c h

s.tud:>,

nootrop and

1 earning

i c

memGr

)’

1?77).

pr e 5r n t

et

al

brnxodi

drugs

n i strat 1

,

Hoyt e v e r , t CL

a.ma,

ct

i We r b 0 f f

ted,

class

pr enata!

1 PAS!

1 ‘7 8 2 :I .

. ,

a

t 5,

i.YCla.rk

,

1 y 8 4 ‘1 J

Research

i un

of

i ng

9’; I

i tiori?

0 f

3 t when

two

i gate , Ie w

a

result

3 13 1 u t I 0 n

3.c t i ‘J I t >‘ , .acqui’:

may

a b i 1 i t ..’

5 a 1 i n e

tcs

i r8ves.t

t Cl

0:~ i r a. c e t am ,

1984a,

al., 1 earn

l.rla. 5.

5, t IJ d );

tn

adul t 0

mon

t !-is

three-month-o1

rioutrop

i c

mndifica.tions animals.

t

0 r

whether

Mice,

CI .x i r a c e t am , of

age

, d.

in d

we r e f or

Pharmacological

Research

Communications.

t h a t

t h c

drug

impro~ves

rang

i ng

I3 0 =-.e 5 Sans.one rel

at

i onsh

vctl

ume

for

ml/kg,

trea.ted

dams

12.8

and

res.pect

ively.

1 ess.)


,

pu p 9

u,e r P

ox i r a.c e t am

1 i tter

died

t h e

an

.an d

f i ve

tcl

s.ex

Lot

omo

i ma1

s

t or

m i ce

b ,:t x e 5.

attached. tmen

op e n i n g

i lvat

sountrr

i ng The

t h e

ac t i v i t:i

the

a. n d

ri 0

electric t t, e
tc”,,

apparatus t6‘s.t.

number recorded

colver5

compar opening

1 amp

‘E.t, ct ‘Z k

,..cja 5

di~r

to

t

in 0n

j rig

30

min.

s.i.;:

one

1 :,

e.:;pos.ed

man

pooled

from T he

orce

least

Can

wh21

e

th

of

age

to

s.al

i ne

was

ng

cage.

mea.sured

in

a.pparatus

us.ed

L ior‘

c Gnc i s t e d

Gf

10

ij

e , gh t electric

i n t r.

t I,., 0

2 0

“.i

10

i t i on

h au i n g

3

3

the gr

floor id

eevent

f!oor

,

recorder

me r e

the

fl

cornpa:

.: : or e s

o b t a

:.

:2

t:,u-s ar,,j

‘

tmer, r, g d

For t

a or,

s,iw i t c h e d oar

cm

le.iel.

,zJbicle,

c c. 1I e r s t 0

pups

at

per

.3. sound-proof

t h e

.and

a.ccordi

eight

the

an

.s. p p 1 1 e d

c r o 3 5 I n ,J ‘5

with

At

.at

ts

t i 1 ted

placed

t he

part

tmen

connected was.

0 f

bl ack

s.a : I n e :O .2

tec.t?.

a

t h e

Iwere

I.5ii th

divided

in

of

z.even

including

3 3.m e

translucent

t h e

through

.3 microswi

.

m0 u s e )

i ng

ta.m

3.c t , ? , + j’

It

a

be 19 i n n i n g

i pace

of

t r a i n i n p .

4.~4i t h

inspected

weaned,

t h e

f ec t

were

from

groups.

w a 5

aose-ef

#cage’?

born

prenata.1 were

1?84a,b;

y,

t h e

i n g :> .

at

taneousl

beha~~tiora.1

taneous

bo.4

a 1 . ,

1 i tters.,

iwe an

in

Spun

ated

connect

c r 0 3 5 i r, g

Ea ch

0 t h er

sepa.r

the

hous.ed

Each

tc.!

for

animak,

s.ubcu

1 i tter-s

ifour

th

ear

o,

only

w I t h

wi

cl

exposed

ox i racetam)

,

a

f r c,$T,

to

before

-

1d

1 ioor

bc

compar

act

kept

and

et

p u ps

ine and

av o i da nc e

t 8c~gg 1 e-f

CIT

to

activity

t h -o

sal

1 i tterc.

treatment

shuttle-box

blJ 1

nine

exposed

and

two-man

of

da.is.

t

i

The

exposed

Three

14

a.m.

a.dul

i Banf

made

of

dams

discarded

t 0

9-11

number

were

11

were

22

six

of

w I t h0 u t

between

me an

1 I ty

mg/kg

ec t i ens

within

The

60

1171

12, 1986 sbi

a,b),

i nj

births

treatment.

to

1985

The

10

1 i v e

10

al.,

i p. of

learning

from

et

Vol. 18, No.

c, f J r; 3.4.. L

to / r,

i.ri* e 3c h

1172

Pharmacological

group

were

of

var

compared

c e

for

behavior

toggl

e-f

training

a

compar

tmen

two-factor

Isex

1 a.pped

K,A j

appl

i ed !).J~.s

animal

avoided

w i t h i n

5

a I..!o i d

the

x

t i nuoucl

30

5..

Vol. 18, No.

treatment)

.a f t e r

72. 1986

a.nalysis

I~Je r e

stat

i ante

i st ?

1 e II e 1 5. ?

i call

t h c and

tra.

i t

being I n i ng

by sex

sess

a (two

i on5

the

compartment fa.iled

to

during

(16

the

males

random1

B.~.:.c.I

100-trial

ev a 1ua t ed

da.rK

y

box

5.

10.2

when

animals

toggle-floor

5

intertrial

crossing

,

CS

by

shock

recorded

mice

two

The

~.lJC;!

The

If by

the

CCS).

the

CS.

treatment)

daily

fa.ctors

the

t 1 e-box

in

floor.

i nto

above

shut

electric

was

escape

for

five y

an

three-month-old

tested to

was

i ng of

p r e n a. t a 1

pr e v i 0 u5 1y subjected

onset

I n

c,t imuluc.

grad

runn

i bed

a.1 ternately

response

could

descr

stimulus

US

dance

the

on

the

t, y

they

each

The to

avoi

we r e

f or

tched

unconditioned s.

US

that

a c t r I..! i ? y .

swi

the

y

An

was

a. conditioned

25

con

5. h cs ,: K

1:~e r e

of for

rubjects

females.

U.J~.S af

the

s

The

W!

t it

a.pparatuc,

1 ocomotor

used

once

over

those

110

an d

and

The

box

1 ~ght

the

i n t e r v a. 1

-

1 oor

tr.

preceded

l.?ar

a

Communications.

i ante,

Au o i Jan

us .

b,:z

Research

and

taken

from

actiuitr. oris..

16

Mice

The

reE.ul

anal

y5.i

ts

three-fat

tor

levels),

ox i ra.cetam

< two

measures;

f i I...$e

(repeated

s

of

level:.).

RESULTS a c t i ~1 i t v

Locomotor carried

test) 1 . Imar

These

res.ul

=

4 . 12 ;

a c t I ‘..2i t y :F

=

i n

ts,

4.&&a;

df

decrements df

lFl~j;;

The

two-man

results th-ol

e v a 1 u a. t e d

indicated

i ante,

,F

out

-

h i g h er

d b;v

in

mice

p’;Ij.[15‘j.

mi ce , a

prenatal

are

two-f

1 ocomotor

p ; [I . 0 5 )

1,102.

the

of

act arl d 1 :g

t oggl

e-f

repor-ted

1 oar in

box Table

an a 1 :..~5 i 5

ac t or i v i tr

i n

5.1 i ght

but

treated

wi

femal

e

of mi cc

significant th

ox

i racetam

Pharmacological

Research

Communications,

Vol. 18, No.

[9--.L-fIl

SRL

-

ox

MflLES _

75

12, 1986

1173

FEMFILES

25

I

:

12

:

:

,

3

4

5

Dai

sessions

ly

- Shuttle-box avoidance acquisition FIG. 1 i n three-man th-ol~d representing the offspring of damstreated daily, during mice, pregnancy r with saline ISAL) or oxira.ceta.m (0.X; 50 mg/kg). The a.r e results presented as mean per cent a.voi dance responses, for each of the five daily 100-trial sessions, in gro?lp~. of 16 animal 3. Vertical bars indicate S.E.M. Aster i sKs 5 i gn i f i cant difference l,p’-O .D5) betr+~een i n d i c a. t e a trea.tmen ts.

TABLE LOCOMOTOR

ACTIVITY

P r e n a. t a. 1 treatment

Mean< Number

tam

lr. of

S.E.) mice

OFFSPRING

be hav

u I r t u a 11y

n o

acqut5ition

+

4.48

ISO,

85.37

2

I~.‘~:~

(I,?,)

65.58

+

3.29

12q;>

Xl.45

+

3.46

c:31s~

cros.:.ings.

-

escape

Mice fai

learned 1 ure

avoidance the

durtng

30

min.

brackets.

i or

of 5 h ow 5

Females

71.06

activity in

A 1.)o i da n c e

figure

TWO-MONTH-OLD

Ma 1 e 5

Sa 1 i n e Ox i race

IN

1

mea.n

was

behavior per

cent

to

ec.ca.pr

observed

z’er;. dur

/ ng

i c. preserlted avoida.nce

ra.pldi train 1n

response-:

. J

and

i ne. Fi

mg, 1. exh

i bl

The ih ted,

i E-

1174

i

Pharmacological

n

f i ve

and

100-trial

fema.1

r‘ e c e 1 a.,~i

e

ox

mice,

n g tar

0.11;

sessi dance

i mprouemen

as

training p

so

controls

female

from

oxiracetam Intertrial

i spon )

1 ight

compartment

were

always

at

present

mice

to

t h-01

s.1 ight

(50

i oral d

mice

ml ce,

pun

:

ma1

df

evident

F =

7.42;

compar

i son in

e

(sex

group

4,240;

b;.’

df

session

the x

p
from

i shed

1 e-box

the

electric

dark

to

shock

admi

ability

of i c

12’

at

of

the

t avoi

mature ly

exposed

i ng

to

and

oxi

ox

exhi

iracetam i s

a

nootrop

an i ma1

s

regardless

dance

s I tuat

ion,

to

ic

drug of

of

pregnancy’>

showed

three bi

ted

task:

rather

whether

improves the

of

improved is

say

a

months

effect

impossible

of

e

racetam, At

is.

i on

who1

activity.

Th

exposure

i ng.

to

tion. i t

the

offspr

exposed

acquis.i present

n i strat adul

in

prenatal

dur

1 ocomotor

avoidance but

that

mg/kglday,

prena.tal in

prenatal

euant,

if

r e

changes

reduction

prenatal

spec

the

crossings

demonstrate

oxira.cetam behau

5.h IJ t t

ens

The

leuels.

findings

produced

ageI

we

and

ON

The

rel

low

taneous

for

more

i n

‘3.42;

=

iF

effects.

was

second

in

A

p c0 .0 g 1 ! .

s.essi

e

muthers

pc0.001~

4,240;

session F

main

1 ,a;

the

ma1

difference

differences.,

from

:

responses

ica.nt

x

icant

third

sex

ox iracetam

i racetam

appeared

sessions

the

b:y

signif

the

X

Two-man

that

CFig.11,

and

01 SCUSSI

produced

of

12, 1986

pregnancy.

no

df

d

i ng

i ng

df

87.35;

lox

s.pr

dur

15.65;

=

proceeded

4,240; w i t h

t

off

signif

Vol. 18, No.

three-month-o1

showed but

=

CF

ens

the

~variance

(F

Communications, by

5 a 1 in e

.05),

treatment

training avoi

or

p“.O

ons,

t 0

of

1 ,.a;

tam

s.essi

belonging

analysis

df

i race

n i ng

ox i r 3.c e tam

three-fat =

trai

Research

the learning

or

of

i t

is

Pharmacological

Research

Communications,

Vol. 18, No.

12, 1986

1175

1176

PharmacologicalResearch

Communications,

Vol. 18, No.

12, 1986

~CKNUWLEDGEMENTS The

authors

are

technical

assi

Dorigotti

CISF;

gra.teful

Sitarice. Trezzano-Mi

to Ox i race 1 a.n,

Mario tam

was

Bat kind1

tag1

i a 2;

for

dona.ted

the by

expert Dr.

L.

Italy),

REFERENCES Ranfi,

S.,

L. Dorigotti, M.P. Abbra,cchio, W. Balduini, E. C. Raguca a.nd F. Cattabeni . Pharmacol . Res. Comm. 67-83, 1?84a. 16, Banf i , s., W . Fan i o , E. Al 1 ievi, M. Pinza and L. Doriqotti. 11 Farmaco (Ed. Sc1.1 39 ) 16-22, 1984b. Cl arK, C.V.H. I D. Gorma.n a.nd A. Vernadak is. Devel . Psychobi 01 . 1?70. 2 I 225-235, Cum i n , R., E.F. Bandle, E. Gamz u and W . E . Haefely. Psychopharmacol ooy 78 104-111, 1982. F i shman , 1 , R.H.R. and J. 7?ni.i. Neurosc i . B i obehalv . R e 5.j . 19-28, 1983. Frieder, P., S. Epstein and V.E. Grimm, Psychopharmacol oqy a3 51-55, 1984. GiuEel, C.E. Druo Devel . Res. .3 441-446, 1982. Gi urgea, c. and M. Sal ama. Pro: Aeuro-Psychopharmac. 1 , 235-247, 1977. Peda.ta, F., F. Moroni and G.C. Pepeu. Cl in. Neuropharmacol . z