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Habituation of exploratory activity in rats: Action of N6phenylisopropyladenosine, caffeine and their combination
HABITUATION OF EXPLORATORY ACTIVITY IN RATS: ACTION OF N6PHENYLISOPROPYLADENOSINE, CAFFEINE AND THEIR COMBINATION
LUIGI
MOLINENGO.
MARCO
Istituto
ORSETTI, and
di
BARBARA PASTORELLO. PIERA GHI
Farmacologia Tori no
(Final
form,
e
ISABELLA
SCORDO
Farmacognosia
Italy
June
1995)
Abstract
Molinengo. Luigi, Marco a d Piera Ghi: Habituation N B phenylisopropyladenosine, Neuro-Psychopharmacol.
2.
3.
4.
&
Orsetti, Barbara Pastorello, Isabella Scordo of exploratory activity in rats: Action of Prog caffeine and their combination. Biol. Psychiat. 1995,19(7): 1189-1200.
caffeine (15 mg/kg) and their combination were L-PIA (0.2 mg/kg), field. rats tested in open given subcutaneously to of L-PIA reduced ambulation. Caffeine The acute administration ineffective but increased ambulation in combination alone was with L-PIA. These effects may have been determined by an interaction of L-PIA and caffeine on adenosine receptors. a chronic administration observed after Tolerance to L-PIA was or in The chronic administration of caffeine alone (20 days). with L-PIA increased ambulation. combination redluction of ambulation in the 3 In the habituation test the antasuccessive trials was increased by L-PIA. Caffeine did not same effect. These gonize the L-PIA effect and, in part, had the memory rest Its suggest that L-PIA and. in part, caffeine improve that in open field, and do not support the notion consolidation L-PIA and caffeine action on memory processes is due to an interference on adenosine receptors
Kev--_words :
Memory
conso
Acute 1 idati
administration. Open Field,
on.
Chronic administration, C ffei ne. f? N - (L -phenylisopropyladenosine).
Abbreviations: N6-cyclopentyladenosine adenosine (L-PIA).
(CPA),
1189
N6-(L-phenylisopropyl-
1190
Introdu_cti_op
The
correlations
stimulating tors
locomotor
labelled
the
with
behavioral
of the
adenosine al
of
was
not
modified
Memory
is
by
not
composed
and
maze
by
retrieval).
stered
The
interfered
with
present
experiments
the
same
effects
the
L-PIA
effect
The
rat
fects were
behavior
of
caffeine
evaluated
provides Plate1
a et
Experiments tions
of
the
strations test. effects
were
of The
the
L-PIA,
also
results
interfered
et
so
obtained
with
the
L-PIA
al
this
storage
drugs,but
storage
by
1989). displays
it
drugs
admini-
that
the
The
purpose
on
drug of
consolidation
al.
1994)
and
if
caffeine. and
field
immediately
after
exploratory
the
the
activity,
(Plate1
and
ef-
trials, which
Porsolt
1982,
1990). in
order
caused or may
rat
caused
by
its
(L-PIA)
by
et
to
with
consolidation,
open
processes
activity of
due
memory
indicate
Hall’s
of
performed
doses
altered
antagonized
given
memory
Izquierdo
be
(Molinengo
habituation of
1994).
L-PIA
storage
evaluated
exploratory the
if
in
model
1984,
verify
was
on
concluded
not
of
the
caffeine
agreement
(Izquierdo
is
of
of and
are
al
acquisition
1987). of
doses
improvement
behavior
1984,
Harvey
alone
In
can
of
on
at
(acquisition,
consolidation
and
valid al
to
Spealman
and
caffeine
et
consolidation
observed on
the
with
attenuation
only
of
that
memory
was
the
blockage
L-phenylisopropyladenosine
processes
memory
that
(Molinengo
after
Winsky
a
that
consistent
and
administered
by
modifications
immediately
1984,
receptors.
entity
variuos
are
(Glowa
recep-
suggested
involve
reports
obtained
that
caused
simple
al
in
adenosine
rnethylxantines
adenosine
caffeine
a
1981).
effects
observation
staircase
et
when
rates
on
(Snyder
observed was
rnethylxantines
on
Carney
stimulant
the
is
and
of
competing
hypothesis
analogs
action
series
Several
(1988)
psychomotor
conclusion the
al
response
antagonistic
in
Logan
a
in
of
blockage
adenosine
increased the
analogs
receptors
et
of
and
effects
1985,
Katz
effects
that
potent
receptor
et
However,
that
activity
adenosine
Goldberg
potencies
stimulant
central
is
between
by
to acute
caffeine be
behavior
used in
verify and
used to the
in
verify memory
the
rnodifica-
chronic the if
adrnini-
habituation direct
test.
drugs
L-PL4 and caffeine on exploratory Materials
Animals
and
all
In
ad
I191
Methods
Apparatus
experiments
strain,
and
activity
weighing
naive
male
ZOO-220
gr)
albino
wet-e
rats
used.
(Morini,
They
Wistar
received
derived
food
and
water
lib. The
open
bounded cm
field
by
60
squares.
open the
100
of
in
the
field
circular floor
hanging
base the
field
200
cm
above
The
recorded
200
of
i 1 lumination and
of
a
The
lamp
the
3 minutes
of
walls.
watt
provided
edge
versed
cm high
A
field
consisted
the
cm was
in
center
sat
number
diameter
divided
the
observer
total
in
at
of
30
of a
the
desk
squares
at tra-
experiment.
Druqs
0.2 of
mg/kg
of
caffeine
were
distilled HCl. water.
L-PIA
was
These of
subcutaneously. was
dissolved
corrected
doses Logan
of
(L-PIA)
to
caffeine
and
Carney
in
a
5.5
and
and
L-PIA
and
Caffeine
was
minimal
quantity
then
diluted
were
15
mg/kg
dissolved of
with
selected
in 0.1
N
distilled
according
to
(1984).
Analyses
Mean
and
Dunnett’s te
pH
report
Data
injected
water. The
the
N6-(L-phenylisopropyladenosine)
test
the
value
standard for
significance of
error the
was
evaluated.
comparison
of
PcO.05
were
the
with
a
differences
considered
to
Analysis control
were
between
be
of
the
variance used
groups
and
to
evalua-
of
data.
A
significant.
Resu 1ts -__.
Acute
administration
L-PIA
(0.2
combination the
open
mg/kg, (IO
field
of
rats) test.
10
LzPIA,
rats),
Caffeine ___-.
caffeine
were
administered
Another
group
of
and
(15
Their
mg/kg.
Combination
10
subcutaneously 10
rats
(controls)
rats) 20
their
and min
before
received
1
I,. Molincngo
1192
al rd.
N.S.
T
co.05
1
_!I
C
L
L.PIA
Caff
L.PIA Caf f
Fig 1. The number of squares traversed in open field are given in controls (10 rats) and after the administration 20 minutes before the of caffeine 15 mg/kg (10 rats), trial of L-PIA 0.2 mg/kg (IO rats), and of their combination (10 rats). Dunnett’s test was applied to evaluate the significance of the differences to the controls.
of
ml
solvent.
containing terba
5
lanced
The are
given
and in
differences
Dunnett’s (0.2
and
that
test
All
the Fig
1.
mg/kg) the
The
analysis squares
the
caused
a
combination
caused
an
increase
caused
no
modification
in
f.
of
into
the
of
number
(0.2 of
number
half-groups
tested
in
a
coun-
mg/kg) squares of
travesed
the
4
that
the
experimental
P<(O.OOl).
a
the
squares
indicated by
F=25.28
in
two
of
variance
with
reduction
number
were
traversed
comparison
the
divided
1 p.m..
of
3/36;
L-PIA the
and
errors
the (d.
for
was
half-groups
9 a.m.
standard
significant test
group
different
between
between
were
PIA
rats.
order,
means
groups
Each
control
number plus
indicated of
squares
caffeine
traversed.
squares
traversed.
that
L-
traversed (15
Caffeine
mg/kg) alone
I,-PIA and caffeine on exploratory
activity
I193
c 0.05
T
r
N.S.
T-
‘1 _-_I-L-
Caf f
L. PIA
C
L. P IA Caff
Fig 2. The number of squares traversed in open field are given in controls (10 rats) and after the administration 20 minutes before the of caffeine 15 mg/kg (10 rats), trial of L-PIA 0.2 mg/kg (10 rats). The acute administrations were and of their combination (IO rats). preceded by a chronic administration (20 days) of the same doses of Dunnett’s test was apL-PIA. of caffeine and of their combination. plied to evaluate the significance of the differences to the controls.
Chronic
Administration
L-PIA
0.2
mg/kg
combination given
test
rats)
group
different
between The
(10
(IO
subcutaneously
Each All
of
3
means
a.m. and
rats), and
each was
-groups
and
1 p.m.. standard
Caffeine
caffeine 1
day
divided
half
the
L-PIA,
ml
of
in
the
into were 20
min
errors
and
15 solvent
of
(10
for
20
half-groups
tested from
mg/kg
in the the
Combination
(controls
morning
two
Their
a last
nllmber
rats). 10
their
rats)
were
days. containing
5
counterbalanced drug of
rats. order
administration. squares
traver.sed
I>. Mol~nerlgo (‘I tel.
1194
are
in
given
Fig
2.
of
test
squares
indicated
versed
of
open
be
test
and
by
plus
L-PIA
and
modifications
F= of
rats
were
successive
Their
14.83;
the
of
caffeine
the
Dunnett’s squares
was
_____on
the
in
PcO.001)
number
Combination
used.
They
days.By
were
measuring
possibility
group
in
a
was
of
divided
into
tra-
significant.
Habituation
tested rat
finding
given
3
times
behavior
in
relatively
on
the
evaluate the
trials, versed
in
between
15
mg/kg,
the per
the
the
first
and
of
in
the
a
small
third
effects
their
first
and
2
second
day.
squares
the
min
by
between
the
trial the
in
a.m.
the
p.m.
1
ml
of
of
the
L-PIA solvent trials
repetition
number the
first
2
end
the
and
rats. were
and
and
ft-om
caused
second
traversed
8
9
half-groups
combination
within
differences
containing
different
between
modifications
cent
half-groups all
order,
subcutaneously
performed
two
effects,
counterbalanced caffeine
mg/kg,
To
3/36;
increase
order-of-testing
tested
were
3
18
trial.the
avoid
0.2
f.
that
increased.
Each To
indicated
significant
the
Caffeine
of
in
habituation may
caffeine
variance
Act ivitvz
groups field
(d.
only
L-PIA,
Exp_l_oya.t KY_
Four
by
of
caused
traversed that
caused
Action
analysis
treatment
pharmacological number
The
of
per
and
of squares
cent
the
the tra-
differences
third
trial
were
calculated. The
values
obtained
give
the
squares
traversed
in
the
second
squares
traversed
in
the
first
results
These med
to
check
are
the
squares
and
traversed
P<(O.OOl).The significant Dunnett’s
(d. test
_ It
f.
3/139; indicated
3.
reduction third
showed
by 18.65:
that
of
of
the
the
that the
significant
caused F=
of
trials
Analysis between
trials
were
variation
the
Fig
third
the
and
variation
treatments
second
cent
the
number
compared
of
to
the
trial.
in
probable
pharmacological the
given
per
per
was
successive
the
(d. the
variance
trials
differences
cent f.
perfor-
between
reduction l/139;
pharmacological
and
of
the
F=60.02; treatment
was
P
of
L-PIA
after
the
L-PL4 and caffeine on exploratory
activity
1195
loo-
C
< 0.05
0 90
co.05
_” 80. : E 70. m ‘;; 60 E 50, ._ I; 40 : Q 30 G
20, 10
L-PIA
C
L-PIA Caff
Caff
Fig 3. The percent reduction between the first and the secondVTd trials and between the first and the third trialsl] of the number in controls (18 rats) and after the of squares traversed are given administration within 2 minutes from the end of the first and second trials of L-PIA 0.2 mg/kg (18 rats ).of caffeine 15 mg/kg (18 rats) and of their combination (18 rats). Dunnett’s test was applied to evaluate the significance of the differences to the controls.
first
and
second
of
squares
number result
was
nett’s
test
traversed, third
trials
caused
traversed
obtained
caused
in
for
indicated
the
that by
an the
increase second
in and
combination the
caffeine
the
third
L-PIA
reduction alone,
of was
reduction
of
trials. plus
the
A
similar
caffeine.
number
significant
of only
the
Dunsquares in
the
trial.
D>scussion
in
Ambulation experiment
is
the
considered
open an
field aspect
during of
the
the
first
exploratory
few
minutes
activity
of of
the
animal,
and
has
been
the
study
the
habituation
considered
Porsolt
of
drugs
the
present
behaviour
in
the It
number may
1983.
al
of
L-PIA,
the
open
of
be
of
activity
memory
with
et
of
processes
memory
1984,1zquierdo
Logan
et
these
al
al
the
animal
suitable
processes
for
(Plate1
and
1990).
after
during
which
activity
a
ment
with
with
in
present
of
a
a
L-PIA
by
apparently was
thus
by
they
unmasking
are
no
rat effect
the
is
of
by
stimulant
60
per-
minutes locomotor
several in
hours.In the
first in
(1982).
the
data
the
exploratory to
But
data
3
agree-
obtained activity obtained
introduced.
the
L-PIA
to
Therefore,
ambulation,
squares
observations of
5
comparable
al
acute
was
successive
increased
reduction
the
activity
to
et
activity.
evaluated
of
not
after
of
period. al
1988,Katims
animal
minutes was
L-PIA
blockage the
30
et
period
effect a
and
evaluation
similar
stimulating
determined
sites
and
had
locomotor
period
Plate1
an
al
the the
activity
are
a
reported
of
from
with
caused
of
recorded
of
combination
(1983)
al.
increase
habituation
itself
observed
al
habituation
observations
environment
in
1981)
locomotor
experiments
Caffeine
et
lasted
presession
presession
et
not
acute
modified
caffeine
(Choi
habituation
period
no
that
the
(ambulation).
evaluation
was
the
the
new
when
the
presession
testing
minutes
an
how
combination
authors
Snyder
caffeine
examined
their
showed
traversed
activity
experiments
It
other
first
and
field.
1986,
experiments
authors
caffeine
that
of
formed
the
squares
noted
administration
et
model
research,
administration
our
et
exploratory
Administration
In
in
valid
the
interfering
1982,Platel
Acute
on
a
of
traversed.
and
in
suggested
combination
with
methylxanthines
of
effect
at
of
L-PIA
resulted
in
although
lower higher
Katims that
the
caffeine affinity affinity
sites. Chronic The
Administration chronic
tolerance (1986)
administration
analogous in
operant
to
of the
conditioned
L-PIA
tolerance behavior.
observed The
the by
developement
Coffin
desensitization
of
and
Carney
of
adeno-
L-PL4 and caffeirw on exploratory
sine
receptors
by
neurochemical The
et
an
al
a
basis
chronic
caused
increase
or
menta
1
30
caffeine
and
with
in
results
increased
the
a
rat
be
the
of
was
the
exploratory
measured
not
the period
recorded.In
period
3
caused
habituation
and
minutes.
In
exploratory
that
caffeine
authors
presession
first
caffeine
(1986).Nikodijevic
habituation
the
suggest
may
plus
with
These
activity
evaluation
1988)
L-PIA
of
treatment
presession
measured
al
Holtzman
activity.
which
no
or
chronic
minutes
was
was
our
the
during
situation,an
Therefore
caffeine
locomotor
minutes
activity
of
et
tolerance.
ambulation.Finn
the
there
(Porter
behavioral
that
for
10
experiments motor
of
of
activity
5
the
reported
reduction
of
of
agonists
administration
(1993)
animal
adenosine
1197
actiW
the
this
locoexperi-
activity
chronic
our
prevai
1s
administration
activity
of
the
new
of environ-
ment There
are
phylline
(Fredholm
1984,
Wells adenosine
and
These
of
crease
of
Fredholm
which
caffeine
administration
we
of
systems
may
be
al
observed or
implied
et
the
open
L-PIA
in
this
central 1983,
an
plus
do
nervous
Marangos
et and
up-regulation to
not
the
after
caffeine.
a
Other
effect
of
behavioral
explain
field
behavioral
theo-
(Zhang
tolerance
the
or
periphery
shown
but
of
the al
the
1985), in
caffeine
in
in
explain
et
caffeine
and
generally
may
(Chou
chronic
Boulenger
1990) have
of
receptors
1980,
studies
motility
effects
adenosine
Hedqvist
receptors,
effect
of
on
and
Fastbom
1990).
mica1
reports
administration
system al
several
in-
chronic
neuroche-
of
L-PIA
and
caffeine. Habituation
With
the
reduction
of
repetition of
the
Exploratory
the
ved
in
the
habituation
of
repetition.
A
in
observations
ments
the
in
caffeine
the
combination
had
it of
L-PIA
open and
caused
a
repetition
the
L--PIA may
the
second
third
of
But,
in
alone
the
persistence
these
trials
Caffeine
only with
the
ambulation
controls.
combination
Activity
same or
be plus
field
third
caffeine
noted caffeine
that
significant
trials
was
significant and
effect
a
increase
L-PIA also
alone in
effects in caused
the
obser-
the
of or
second
might
explain
acute
experi-
an
in
increase
of
1198
L. Molinengo et al.
motility
while
reduction and
of
third
caused
an
of the
as
these
The of
increase
spatial
learning
Barraco
Cl991 CPA
rats
were
administration. tested
possibility
at
that test
30
a
cannot
be
[Von
must
plus
it
improvement
of
be
from
be
action
of
CPA
attribuinterprewith
memory
storage
(CPA)improved
al
1993
1.
avoidance
that CPA
admini-
agreement
of
passive
noted
the
test.
be
can
In
et
L-PIA to
session cannot
and
Lubitz
minutes
direct
post
the second
habituation
consolidation. an
the
correspond
the
effects
impairment
It
caffeine
modify
in
N6-cyclopentyladenosine
memory an
of
combination
direct
and
L-PIA
not
in
not
by
after
their
caused
reported
does
observed
memory
1994) and/or
]
drug
L-PIA al
which
and
of
caused
habituation
L-PIA
conclusions,
after
in
of
did
administration
activity
facilitation
et
activity
motility
persistence
a
test.caffeine
chronic
caffeine,
(Molinengo
memory
exploratory
the
stration
habituation
exploratory
Therefore
ted
the
increase of
to
the
trials.
reduction
ted
in
in
their
Normile retention experiments,
administration had
and
and
interfered
the
with
the
excluded.
Conclusion
observation
The effect
on
consolidation
antagonism that
the
that
between observed
consolidation
are
caffeine
has,
displayed
by
and
L-PIA.
caffeine behavioral due
to
effects their
at
least
L-PI A, does of
and not
L-PIA
interference
in
that
the
caffeine
adenosine
the there
support
and
on
part,
on
same is
no
notion memory
receptors.
Achnowledqement
This
work
was
supported
by
MURST
(60%
-
40%
1991)
References
BOULENGER J_ P . , PATEL J _, (1983) Chronic Caffeine Adenosine Receptors. Life CHOI
O.H.,SHAMIM
M.T..PADGETT
POST R. M., PARMA A. Consumption Increases Sci. 32: 1135-1142. W.L
and
DALY
J.W.
M and MARANGOS P-J. the Number of Brain
(1988)
Caffeine
and
L-PL4 and caffeine
Theophylline vity
on exploraton,
Analogues:Correlation
as
Adenosine
Inhibitors.
Life
Receptor Sci.
of
L.
CARNEY J. and on Schedule-Controlled 1141-1147.
M.
and
HIRSH
CHOU D. T.. KHAN S.. FORDE J. and rance: Behavioral, Electrophysiological Life Sci _3_: 2347-2358. COFFIN V. Adenosine gy 255:
Behavioral
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43:
K.
(1986) Effects Behavior
FREDHOLM sion by 1635-1643.
B. B Purine
and HEDQVIST Nucleotides
GLO A J.R. and N ! -(L-phenylisopropyl) Squirrel Monkey. GOLDBERG vioral Caffeine. IZQUIERDO stic. IZQUIERDO Receptor genous Behav.
S.G. (1986) Activity
P. and
R.
I. lo:
R.D. (1984) Adenos i ne Pharmacol. Exp.
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Caffeine
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of
of Rat and
J.
of
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H.S.
Effects of Combination 665-670.
Scopolamine
LOGAN L. and CARNEY J. M. of L-phenylisopropyladenosine tes. Pharmacol. Biochem.
(1984) Behav.
LOGAN L.,SEALE Sensitivity chem.Behav.24:
to
MARANGOS P. J.. nic Caffeine Studies. Life
BOULENGER J. P. on Brain Adenosine Sci. 34: 899-907.
T.W.and CARNEY Methylxanthines 1281-1286.
Effects in
Antagonism of the (L-PIA) by Caffeine cl_: 375-379. J.M.
as
(1986) among
Inherent Inbred
and PATEL J. (1984) Receptors:Regional
29:
Caffeine, in
Stereoselective and Antagonism
an
to
Ther.
NeurotransmisPharmacol.
the
Behaby
Amne-
Benzodiazepine of an EndoReceptors.
(1983) Interactions and Adenosine Derivatives.
KATZ J.L..PRADA J.A.and GOLBERG S.R. (1988) Analogs Alone and in Combination with Caffeine key. Pharmacol.Biochem.Behav. 29: 429-432.
of
Long-Term TheophylBrain:AutoradiograAltered Coupling
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Acti-
of Selected Analogs Rats. Neuropharmacolo-
in
S. R.. PRADA J. A. and KATZ J.L.(1985) Effects of N6-phenylisopropyl-adenosine Psychopharmacology 87: 272-277.
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(1985)
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in
Effects with Phosphodiesterase
as
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1199
acli~‘i&
the
in
the .I.
of Adenosine Squirrel Mon-
Behavioral and its
Effects Metaboli-
Differences Mice.Pharmacol.Bio-
Effects and
of ChroOntogenetic
in
1200
L. Molinengo
MOLINENGO L-PIA
L..
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and their 5Q: 1247-1250.
Sci.
I
_
PASTORELLO B. (1994) on Memory Retention
Combination
NIKODIJEVIC O..JACOBSON in Mice during Chronic macol.Biochem.Behav. NORMILE pairs tors.
and
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(1982) Test
J.W.(1993) Caffeine
Action in
of the
Locomotor Activity and Withdrawal.Phar-
N6-cyclopentyladenosine Action
Selective
Habituation for Memory
Caffeine, Rat. Life
Imat
A,
of Exploratory Enhancing Drugs.
Recep-
ActiviPsycho-
_
JALFRE M., PAWELEC C.. ROUX S. and PORSOLT R. 0. (1984) PLATEL A., Habituation of Exploratory activity in Mice:Effects of Combination of Piracetam and Choline on Memory Processes. Pharmacol. Biochem. Behav _ 21: 209-212. PORTER N. M., RADULOVACKI M. and GREEN of Adenosine and Dopamine Receptors Adenosine Analogs. J. Pharmacol. Exp. SNYDER S. H., KATIMS J.J.. Recepiors Adenosine (Caffeine/Theophylline/ Adenosine). Proc. Nat.
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with
ANNAU 2.. BRUNS R.F. and DALY J.W. (1981) Behavioral Action of Methylxanthines “S” N cyclohexyladenosine/N6-(phenylisopropyl) Acad _ Sci 78: 3260-3264.
VON LUBITZ D. K. J. E.. PAUL I. A., BARTUS R. T. and JACOBSON K. A. (1993) Effects of Chronic Administration of Adenosine Al Receptor Learning and Memory. Eur. J. Agonist and Antagonist on Spatial Pharmacol. 249: 271-280. WINSKY
L.
ZHANG Y. nistration Ther .
Inquiries
HARVEY
and
Adenosine, Conditioned of 241: 223-229. and
254:
Caffeine,
J. A. (1987) Theophylline Responses in the
WELLS J. (1990) on Peripheral 757-763.
and
reprint
Dr. Luigi Molinengo Istituto di Farmacologia Via Giuria 9 10125 Torino (Italy)
requests
e
Effects of N6-(phenylisopropyl) and Rolipram on the Acquisition Rabbit. J. Pharmacol. Exp. Ther.
Effects of Chronic The Adenosine Receptors. J.
should
Farmacognosia
be
addressed
Caffeine Pharmacol.
to:
AdmiExp.
LUIGI
MOLINENGO.
MARCO
Istituto
ORSETTI, and
di
BARBARA PASTORELLO. PIERA GHI
Farmacologia Tori no
(Final
form,
e
ISABELLA
SCORDO
Farmacognosia
Italy
June
1995)
Abstract
Molinengo. Luigi, Marco a d Piera Ghi: Habituation N B phenylisopropyladenosine, Neuro-Psychopharmacol.
2.
3.
4.
&
Orsetti, Barbara Pastorello, Isabella Scordo of exploratory activity in rats: Action of Prog caffeine and their combination. Biol. Psychiat. 1995,19(7): 1189-1200.
caffeine (15 mg/kg) and their combination were L-PIA (0.2 mg/kg), field. rats tested in open given subcutaneously to of L-PIA reduced ambulation. Caffeine The acute administration ineffective but increased ambulation in combination alone was with L-PIA. These effects may have been determined by an interaction of L-PIA and caffeine on adenosine receptors. a chronic administration observed after Tolerance to L-PIA was or in The chronic administration of caffeine alone (20 days). with L-PIA increased ambulation. combination redluction of ambulation in the 3 In the habituation test the antasuccessive trials was increased by L-PIA. Caffeine did not same effect. These gonize the L-PIA effect and, in part, had the memory rest Its suggest that L-PIA and. in part, caffeine improve that in open field, and do not support the notion consolidation L-PIA and caffeine action on memory processes is due to an interference on adenosine receptors
Kev--_words :
Memory
conso
Acute 1 idati
administration. Open Field,
on.
Chronic administration, C ffei ne. f? N - (L -phenylisopropyladenosine).
Abbreviations: N6-cyclopentyladenosine adenosine (L-PIA).
(CPA),
1189
N6-(L-phenylisopropyl-
1190
Introdu_cti_op
The
correlations
stimulating tors
locomotor
labelled
the
with
behavioral
of the
adenosine al
of
was
not
modified
Memory
is
by
not
composed
and
maze
by
retrieval).
stered
The
interfered
with
present
experiments
the
same
effects
the
L-PIA
effect
The
rat
fects were
behavior
of
caffeine
evaluated
provides Plate1
a et
Experiments tions
of
the
strations test. effects
were
of The
the
L-PIA,
also
results
interfered
et
so
obtained
with
the
L-PIA
al
this
storage
drugs,but
storage
by
1989). displays
it
drugs
admini-
that
the
The
purpose
on
drug of
consolidation
al.
1994)
and
if
caffeine. and
field
immediately
after
exploratory
the
the
activity,
(Plate1
and
ef-
trials, which
Porsolt
1982,
1990). in
order
caused or may
rat
caused
by
its
(L-PIA)
by
et
to
with
consolidation,
open
processes
activity of
due
memory
indicate
Hall’s
of
performed
doses
altered
antagonized
given
memory
Izquierdo
be
(Molinengo
habituation of
1994).
L-PIA
storage
evaluated
exploratory the
if
in
model
1984,
verify
was
on
concluded
not
of
the
caffeine
agreement
(Izquierdo
is
of
of and
are
al
acquisition
1987). of
doses
improvement
behavior
1984,
Harvey
alone
In
can
of
on
at
(acquisition,
consolidation
and
valid al
to
Spealman
and
caffeine
et
consolidation
observed on
the
with
attenuation
only
of
that
memory
was
the
blockage
L-phenylisopropyladenosine
processes
memory
that
(Molinengo
after
Winsky
a
that
consistent
and
administered
by
modifications
immediately
1984,
receptors.
entity
variuos
are
(Glowa
recep-
suggested
involve
reports
obtained
that
caused
simple
al
in
adenosine
rnethylxantines
adenosine
caffeine
a
1981).
effects
observation
staircase
et
when
rates
on
(Snyder
observed was
rnethylxantines
on
Carney
stimulant
the
is
and
of
competing
hypothesis
analogs
action
series
Several
(1988)
psychomotor
conclusion the
al
response
antagonistic
in
Logan
a
in
of
blockage
adenosine
increased the
analogs
receptors
et
of
and
effects
1985,
Katz
effects
that
potent
receptor
et
However,
that
activity
adenosine
Goldberg
potencies
stimulant
central
is
between
by
to acute
caffeine be
behavior
used in
verify and
used to the
in
verify memory
the
rnodifica-
chronic the if
adrnini-
habituation direct
test.
drugs
L-PL4 and caffeine on exploratory Materials
Animals
and
all
In
ad
I191
Methods
Apparatus
experiments
strain,
and
activity
weighing
naive
male
ZOO-220
gr)
albino
wet-e
rats
used.
(Morini,
They
Wistar
received
derived
food
and
water
lib. The
open
bounded cm
field
by
60
squares.
open the
100
of
in
the
field
circular floor
hanging
base the
field
200
cm
above
The
recorded
200
of
i 1 lumination and
of
a
The
lamp
the
3 minutes
of
walls.
watt
provided
edge
versed
cm high
A
field
consisted
the
cm was
in
center
sat
number
diameter
divided
the
observer
total
in
at
of
30
of a
the
desk
squares
at tra-
experiment.
Druqs
0.2 of
mg/kg
of
caffeine
were
distilled HCl. water.
L-PIA
was
These of
subcutaneously. was
dissolved
corrected
doses Logan
of
(L-PIA)
to
caffeine
and
Carney
in
a
5.5
and
and
L-PIA
and
Caffeine
was
minimal
quantity
then
diluted
were
15
mg/kg
dissolved of
with
selected
in 0.1
N
distilled
according
to
(1984).
Analyses
Mean
and
Dunnett’s te
pH
report
Data
injected
water. The
the
N6-(L-phenylisopropyladenosine)
test
the
value
standard for
significance of
error the
was
evaluated.
comparison
of
PcO.05
were
the
with
a
differences
considered
to
Analysis control
were
between
be
of
the
variance used
groups
and
to
evalua-
of
data.
A
significant.
Resu 1ts -__.
Acute
administration
L-PIA
(0.2
combination the
open
mg/kg, (IO
field
of
rats) test.
10
LzPIA,
rats),
Caffeine ___-.
caffeine
were
administered
Another
group
of
and
(15
Their
mg/kg.
Combination
10
subcutaneously 10
rats
(controls)
rats) 20
their
and min
before
received
1
I,. Molincngo
1192
al rd.
N.S.
T
co.05
1
_!I
C
L
L.PIA
Caff
L.PIA Caf f
Fig 1. The number of squares traversed in open field are given in controls (10 rats) and after the administration 20 minutes before the of caffeine 15 mg/kg (10 rats), trial of L-PIA 0.2 mg/kg (IO rats), and of their combination (10 rats). Dunnett’s test was applied to evaluate the significance of the differences to the controls.
of
ml
solvent.
containing terba
5
lanced
The are
given
and in
differences
Dunnett’s (0.2
and
that
test
All
the Fig
1.
mg/kg) the
The
analysis squares
the
caused
a
combination
caused
an
increase
caused
no
modification
in
f.
of
into
the
of
number
(0.2 of
number
half-groups
tested
in
a
coun-
mg/kg) squares of
travesed
the
4
that
the
experimental
P<(O.OOl).
a
the
squares
indicated by
F=25.28
in
two
of
variance
with
reduction
number
were
traversed
comparison
the
divided
1 p.m..
of
3/36;
L-PIA the
and
errors
the (d.
for
was
half-groups
9 a.m.
standard
significant test
group
different
between
between
were
PIA
rats.
order,
means
groups
Each
control
number plus
indicated of
squares
caffeine
traversed.
squares
traversed.
that
L-
traversed (15
Caffeine
mg/kg) alone
I,-PIA and caffeine on exploratory
activity
I193
c 0.05
T
r
N.S.
T-
‘1 _-_I-L-
Caf f
L. PIA
C
L. P IA Caff
Fig 2. The number of squares traversed in open field are given in controls (10 rats) and after the administration 20 minutes before the of caffeine 15 mg/kg (10 rats), trial of L-PIA 0.2 mg/kg (10 rats). The acute administrations were and of their combination (IO rats). preceded by a chronic administration (20 days) of the same doses of Dunnett’s test was apL-PIA. of caffeine and of their combination. plied to evaluate the significance of the differences to the controls.
Chronic
Administration
L-PIA
0.2
mg/kg
combination given
test
rats)
group
different
between The
(10
(IO
subcutaneously
Each All
of
3
means
a.m. and
rats), and
each was
-groups
and
1 p.m.. standard
Caffeine
caffeine 1
day
divided
half
the
L-PIA,
ml
of
in
the
into were 20
min
errors
and
15 solvent
of
(10
for
20
half-groups
tested from
mg/kg
in the the
Combination
(controls
morning
two
Their
a last
nllmber
rats). 10
their
rats)
were
days. containing
5
counterbalanced drug of
rats. order
administration. squares
traver.sed
I>. Mol~nerlgo (‘I tel.
1194
are
in
given
Fig
2.
of
test
squares
indicated
versed
of
open
be
test
and
by
plus
L-PIA
and
modifications
F= of
rats
were
successive
Their
14.83;
the
of
caffeine
the
Dunnett’s squares
was
_____on
the
in
PcO.001)
number
Combination
used.
They
days.By
were
measuring
possibility
group
in
a
was
of
divided
into
tra-
significant.
Habituation
tested rat
finding
given
3
times
behavior
in
relatively
on
the
evaluate the
trials, versed
in
between
15
mg/kg,
the per
the
the
first
and
of
in
the
a
small
third
effects
their
first
and
2
second
day.
squares
the
min
by
between
the
trial the
in
a.m.
the
p.m.
1
ml
of
of
the
L-PIA solvent trials
repetition
number the
first
2
end
the
and
rats. were
and
and
ft-om
caused
second
traversed
8
9
half-groups
combination
within
differences
containing
different
between
modifications
cent
half-groups all
order,
subcutaneously
performed
two
effects,
counterbalanced caffeine
mg/kg,
To
3/36;
increase
order-of-testing
tested
were
3
18
trial.the
avoid
0.2
f.
that
increased.
Each To
indicated
significant
the
Caffeine
of
in
habituation may
caffeine
variance
Act ivitvz
groups field
(d.
only
L-PIA,
Exp_l_oya.t KY_
Four
by
of
caused
traversed that
caused
Action
analysis
treatment
pharmacological number
The
of
per
and
of squares
cent
the
the tra-
differences
third
trial
were
calculated. The
values
obtained
give
the
squares
traversed
in
the
second
squares
traversed
in
the
first
results
These med
to
check
are
the
squares
and
traversed
P<(O.OOl).The significant Dunnett’s
(d. test
_ It
f.
3/139; indicated
3.
reduction third
showed
by 18.65:
that
of
of
the
the
that the
significant
caused F=
of
trials
Analysis between
trials
were
variation
the
Fig
third
the
and
variation
treatments
second
cent
the
number
compared
of
to
the
trial.
in
probable
pharmacological the
given
per
per
was
successive
the
(d. the
variance
trials
differences
cent f.
perfor-
between
reduction l/139;
pharmacological
and
of
the
F=60.02; treatment
was
P
of
L-PIA
after
the
L-PL4 and caffeine on exploratory
activity
1195
loo-
C
< 0.05
0 90
co.05
_” 80. : E 70. m ‘;; 60 E 50, ._ I; 40 : Q 30 G
20, 10
L-PIA
C
L-PIA Caff
Caff
Fig 3. The percent reduction between the first and the secondVTd trials and between the first and the third trialsl] of the number in controls (18 rats) and after the of squares traversed are given administration within 2 minutes from the end of the first and second trials of L-PIA 0.2 mg/kg (18 rats ).of caffeine 15 mg/kg (18 rats) and of their combination (18 rats). Dunnett’s test was applied to evaluate the significance of the differences to the controls.
first
and
second
of
squares
number result
was
nett’s
test
traversed, third
trials
caused
traversed
obtained
caused
in
for
indicated
the
that by
an the
increase second
in and
combination the
caffeine
the
third
L-PIA
reduction alone,
of was
reduction
of
trials. plus
the
A
similar
caffeine.
number
significant
of only
the
Dunsquares in
the
trial.
D>scussion
in
Ambulation experiment
is
the
considered
open an
field aspect
during of
the
the
first
exploratory
few
minutes
activity
of of
the
animal,
and
has
been
the
study
the
habituation
considered
Porsolt
of
drugs
the
present
behaviour
in
the It
number may
1983.
al
of
L-PIA,
the
open
of
be
of
activity
memory
with
et
of
processes
memory
1984,1zquierdo
Logan
et
these
al
al
the
animal
suitable
processes
for
(Plate1
and
1990).
after
during
which
activity
a
ment
with
with
in
present
of
a
a
L-PIA
by
apparently was
thus
by
they
unmasking
are
no
rat effect
the
is
of
by
stimulant
60
per-
minutes locomotor
several in
hours.In the
first in
(1982).
the
data
the
exploratory to
But
data
3
agree-
obtained activity obtained
introduced.
the
L-PIA
to
Therefore,
ambulation,
squares
observations of
5
comparable
al
acute
was
successive
increased
reduction
the
activity
to
et
activity.
evaluated
of
not
after
of
period. al
1988,Katims
animal
minutes was
L-PIA
blockage the
30
et
period
effect a
and
evaluation
similar
stimulating
determined
sites
and
had
locomotor
period
Plate1
an
al
the the
activity
are
a
reported
of
from
with
caused
of
recorded
of
combination
(1983)
al.
increase
habituation
itself
observed
al
habituation
observations
environment
in
1981)
locomotor
experiments
Caffeine
et
lasted
presession
presession
et
not
acute
modified
caffeine
(Choi
habituation
period
no
that
the
(ambulation).
evaluation
was
the
the
new
when
the
presession
testing
minutes
an
how
combination
authors
Snyder
caffeine
examined
their
showed
traversed
activity
experiments
It
other
first
and
field.
1986,
experiments
authors
caffeine
that
of
formed
the
squares
noted
administration
et
model
research,
administration
our
et
exploratory
Administration
In
in
valid
the
interfering
1982,Platel
Acute
on
a
of
traversed.
and
in
suggested
combination
with
methylxanthines
of
effect
at
of
L-PIA
resulted
in
although
lower higher
Katims that
the
caffeine affinity affinity
sites. Chronic The
Administration chronic
tolerance (1986)
administration
analogous in
operant
to
of the
conditioned
L-PIA
tolerance behavior.
observed The
the by
developement
Coffin
desensitization
of
and
Carney
of
adeno-
L-PL4 and caffeirw on exploratory
sine
receptors
by
neurochemical The
et
an
al
a
basis
chronic
caused
increase
or
menta
1
30
caffeine
and
with
in
results
increased
the
a
rat
be
the
of
was
the
exploratory
measured
not
the period
recorded.In
period
3
caused
habituation
and
minutes.
In
exploratory
that
caffeine
authors
presession
first
caffeine
(1986).Nikodijevic
habituation
the
suggest
may
plus
with
These
activity
evaluation
1988)
L-PIA
of
treatment
presession
measured
al
Holtzman
activity.
which
no
or
chronic
minutes
was
was
our
the
during
situation,an
Therefore
caffeine
locomotor
minutes
activity
of
et
tolerance.
ambulation.Finn
the
there
(Porter
behavioral
that
for
10
experiments motor
of
of
activity
5
the
reported
reduction
of
of
agonists
administration
(1993)
animal
adenosine
1197
actiW
the
this
locoexperi-
activity
chronic
our
prevai
1s
administration
activity
of
the
new
of environ-
ment There
are
phylline
(Fredholm
1984,
Wells adenosine
and
These
of
crease
of
Fredholm
which
caffeine
administration
we
of
systems
may
be
al
observed or
implied
et
the
open
L-PIA
in
this
central 1983,
an
plus
do
nervous
Marangos
et and
up-regulation to
not
the
after
caffeine.
a
Other
effect
of
behavioral
explain
field
behavioral
theo-
(Zhang
tolerance
the
or
periphery
shown
but
of
the al
the
1985), in
caffeine
in
in
explain
et
caffeine
and
generally
may
(Chou
chronic
Boulenger
1990) have
of
receptors
1980,
studies
motility
effects
adenosine
Hedqvist
receptors,
effect
of
on
and
Fastbom
1990).
mica1
reports
administration
system al
several
in-
chronic
neuroche-
of
L-PIA
and
caffeine. Habituation
With
the
reduction
of
repetition of
the
Exploratory
the
ved
in
the
habituation
of
repetition.
A
in
observations
ments
the
in
caffeine
the
combination
had
it of
L-PIA
open and
caused
a
repetition
the
L--PIA may
the
second
third
of
But,
in
alone
the
persistence
these
trials
Caffeine
only with
the
ambulation
controls.
combination
Activity
same or
be plus
field
third
caffeine
noted caffeine
that
significant
trials
was
significant and
effect
a
increase
L-PIA also
alone in
effects in caused
the
obser-
the
of or
second
might
explain
acute
experi-
an
in
increase
of
1198
L. Molinengo et al.
motility
while
reduction and
of
third
caused
an
of the
as
these
The of
increase
spatial
learning
Barraco
Cl991 CPA
rats
were
administration. tested
possibility
at
that test
30
a
cannot
be
[Von
must
plus
it
improvement
of
be
from
be
action
of
CPA
attribuinterprewith
memory
storage
(CPA)improved
al
1993
1.
avoidance
that CPA
admini-
agreement
of
passive
noted
the
test.
be
can
In
et
L-PIA to
session cannot
and
Lubitz
minutes
direct
post
the second
habituation
consolidation. an
the
correspond
the
effects
impairment
It
caffeine
modify
in
N6-cyclopentyladenosine
memory an
of
combination
direct
and
L-PIA
not
in
not
by
after
their
caused
reported
does
observed
memory
1994) and/or
]
drug
L-PIA al
which
and
of
caused
habituation
L-PIA
conclusions,
after
in
of
did
administration
activity
facilitation
et
activity
motility
persistence
a
test.caffeine
chronic
caffeine,
(Molinengo
memory
exploratory
the
stration
habituation
exploratory
Therefore
ted
the
increase of
to
the
trials.
reduction
ted
in
in
their
Normile retention experiments,
administration had
and
and
interfered
the
with
the
excluded.
Conclusion
observation
The effect
on
consolidation
antagonism that
the
that
between observed
consolidation
are
caffeine
has,
displayed
by
and
L-PIA.
caffeine behavioral due
to
effects their
at
least
L-PI A, does of
and not
L-PIA
interference
in
that
the
caffeine
adenosine
the there
support
and
on
part,
on
same is
no
notion memory
receptors.
Achnowledqement
This
work
was
supported
by
MURST
(60%
-
40%
1991)
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