Nr ur ophar macolog~
Vol.
20.
pp.
587
to
591.
1981
0028-3908/ 81/ 060587-05802.00/ 0
Printed m Great Britain. All nghts reserved
Copynght
0
1981 Perpamon Press Ltd
zyxwvut
CHRONIC LITHIUM ADM INISTRATION ALTERS THE
INTERACTION BETW EEN OPIATE ANTAGONISTS AND
OPIATE RECEPTORS IN VII/O
S. AMIR and R. SIMANTOV
Departments of Isotope Research and Genetics, Weizmann Institute of Science, Rehovot, Israel
(Accepted 5 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPON
January 1981)
Summary-Chronic
administration of lithium suppressed the jumping response of saline treated mice in
the hot plate test but had no effect on rearing and grooming behaviour. Naloxone (0.15640 mg/kg) or
naltrexone (0.15640 mg/kg) elevated by up to 130”,/,the frequency of the jumping response of mice fed
with lithium but had little effect on the control animals. The same treatment with the opiate antagonists
decreased, in a dose-dependent fashion, the rearing and grooming episodes. Large doses of naltrexone
suppressed the jumping response of both normal mice and mice fed with lithium. Mice fed for 5-40 days
with lithium showed a complete development of the increased jumping response to naloxone within 10
days. and somewhat less pronounced response after 40 days. Lithium levels in brain also reached a
maximum after 10 days of lithium feeding. The increased in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHG
uiuo sensitivity to opiate antagonists of
lithium-treated mice was not reflected by changes in either the affinity or the total number of opiate
receptors as tested by the binding of [3H]na10xone to crude membrane preparations of whole brain. The
data suggest that chronic administration of lithium alters the in oioo interaction between opiate antagonists. and possibly the endogenous opioid peptides, and the opiate receptors.
The growing awareness in the last several years that
endogenous
opioids (enkephalins,
endorphins)
may
play a role in the pathogenesis of psychotic states (e.g.
Terenius,
WahlstrGm,
Lindstriim
and Widerlow,
1976; Watson,
Akil, Berger and Barchas,
1979,
Ananth and Callanan, 1979) has prompted investigators to use opiate antagonists in the treatment of psychotic symptoms (Davis, Bunney, De Fraites. Kleinman,
Van
Kammen,
Post
and
Wyatt,
1977;
Emrich, Cording, PirCe, Kalling, Zerssen and Herz,
1977). It is of importance, therefore. to determine the
nature and extent of the interaction
between these
agents and commonly used antipsychotic
drugs.
An interaction between endogenous opioids, opiate
antagonists and the antipsychotic
agents, haloperidol
and chlorpromazine,
has been demonstrated
in
several recent studies. For example, small doses of
naloxone and haloperidol were found to act synergistically in blocking the apomophine-induced
stereotyped behavior in rats (Moon, Feigenbaum,
Carson
and Klawans, 1980). Similarly, small doses of naloxone were found to potentiate the rate-decreasing
effect
of chlorpromazine
on schedule controlled behaviour
in the pigeon (McMillan, 1971). The chronic administration of haloperidol and chlorpromazine
has been
reported to increase the met-enkephalin
content of
the rat striatum (Hong, Yang, Gillin, Di Giulio.
Fratta and Costa, 1979; Hong, Yang, Fratta and
Costa, 1978). Finally, some neuroleptics
have been
Key words: psychoticism, enkephalin, naloxone, opiate
dependence, lithium.
587
shown to possess binding affinity for brain opiate
receptors (Clay and Brougham,
1975; Creese, Feinberg and Snyder, 1976; Somoza, 1978).
Lithium salts are widely accepted as drugs of first
choice in the treatment of most forms of recurrent
endogenous affective disorders (Shou and Thomsen,
1975). Like haloperidol and chlorpromazine,
the chronic administration
of lithium chloride (LiCl) has been
reported to result in an increase in the met-enkephalin content of rat striatum (Gillin, Hong, Yang and
Costa, 1978). Furthermore,
lithium has been shown to
decrease the binding affinity of opiate agonists to
brain opiate receptors in vitro (Pert and Snyder, 1974),
to block the morphine-induced
motor activation in
mice (Carroll and Sharp, 1971) and to reduce morphine self-administration
in dependent
rats (Tomkiewicz and Steinberg, 1974). The effects of lithium on
the zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPON
in uiuo
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSR
actions of opiate antagonists have not been
investigated.
Opiate antagonists have been reported to facilitate
the jumping response of mice in the hot plate test by
interacting stereospecifically
with opiate receptors in
the brain (Jacob and Ramabadran,
1977, 1978; Ramabadran and Jacob. 1979). Furthermore,
lithium has
been reported to increase the binding affinity of
opiate antagonists
to brain opiate receptors under
specific in vitro conditions (i.e. Pert and Snyder, 1974).
In the present study the effects of chronic lithium administratioh
on the pharmacological
actions of the
opiate antagonists
naloxone
and naltrexone
were
investigated in mice using a modified hot plate test.
Alteration in the sensitivity to these antagonists in the
chronically treated mice prompted the study in vitro
588
S. AMIRand R. S~
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJ
MANTOV
of whether lithium affected the number or the affinity
of opiate antagonists to the brain opiate receptors.
IEZI
LiCl
Subjects were adult male C57BL/6J mice. The animals were housed in large plastic cages (IO/cage) in a
temperature- and light-regulated room (23”C, light on
from 8 am-8 p.m.). Experimental animals had free
access to Purina lab chow containing 0.2lzOi, LiCl
(Teklad test diets, Mod TD 74280. Madison, WI).
Control animals were fed regular Purina lab chow.
Water was available ad zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
libitum.
Saline or different doses of naloxone or naltrexone
RearingKmoming
Jumps
(Endo Laboratories, Garden City, NY) were injected
Fig. 1. Tfie effect of chronic lithium ~d~inistra&ion on rearto experimental and control mice intra~r~toneaily,
ing and grooming and jumps in a modified hot plate test
10min before testing. The e-ffects of the opiate antag(46”Cj in mice. Lithium was administered via the diet for
onists on the responsiveness to pain were assessed by
10 days. Control animals were fed normal laboratory
placing the mice on a constantly heated metal plate
chow. The bars and the vertical lines represent means Lt:
SEM of the behavioural measures. The asterisk indicates a
(46°C) within a circular glass enclosure (15 cm diam.
significant difference (t-test, P -K 0.05) from the lithium fed
20 cm high) for 5 min. The numbers of rearing and
group.
grooming episodes and escape attempts (iumps) displayed by the animals during the 5 min testing session
grooming was noted between the saline-treated lithwere used as the dependent variables.
ium fed and control mice.
Two types of experiments were conducted. In the
Figure 2 shows the effect of different doses of naloxfirst, mice were kept on the lithium-containing diet for
one on the response patterns of lithium-fed and con10 days and the effects of different doses of naloxene
and naltrexone were assessed. The second experiment
trol mice in the hot plate test. Because of the large
studied the effects of different lithium feeding regi- dilIerence between the jumping scores of the salinemens on the behaviour of naloxone (l~mg~g~treated
injected, lithium-fed and control mice, the means of
mice in the hot plate test. The amount of lithium in the rearing and grooming episodes and jumping responses of the naloxone-treated mice are expressed as
the brain was determined spectrophotometrically
a percentage of the mean activity of their respective
according to the method of Schou (1958).
All testing took place in the afternoon between 2 saline-treated baseline groups. As can be seen, naloxand 6pm. In all experiments the animals were used one produced a dose~ependent decrease in the frequency of rearing and grooming episodes of the lithonce only.
ium-treated mice with the largest dose (16Omgkg)
Opiate receptor binding experiments were conproducing over a 50% reduction in the magnitude of
ducted as described (Simantov, 1979). Control or mice
this response. In normally fed control mice naloxone
fed with lithium for 10 days were decapitated and the
also suppressed rearing and grooming with the largest
brain minus the cerebellum was rapidly removed and
placed in 30 ml of ice-cofd, 50mM Tris-HCl buffer, dose of the drug producing over 75% suppression.
Contrary to its effect on rearing and grooming, nalpH 7.4 at 25°C. The brains were weighed, homogenoxone markedly elevated the frequency of the jumpized with a Politron tissue homogenizer (15sec,
ing response in the lithium-fed mice with the strongest
setting 4) and centrifuged for 10min at 40,ooOg. The
effects (> 1300/,)seen with 40 mg/kg. In the normally
pellets were then suspended in the Tris-HCl buffer
fed control mice, naloxone produced only a moderate
(1 mg original wet weight per 1 ml buffer) and 2ml
increase in jumping frequency with the strongest effect
aliquotes were incubated with 0.65-14.4 nM E3Hfna(2VA) obtained with the largest dose of the drug
loxone (New England Nuclear, 25.4 Ci,/mmof) with or
(160 mgfig). This moderate effect of nafoxone may be
without 1 PM levaltorphan. Samples were incubated
attributed to the lower hot-plate temperature (46°C)
for 40min at 25” and further treated as described
used in this study as compared to previous studies
(Simantov. 1979).
(Jacob and Ramabadran, 1977).
Parts of the behavioural experiments were recently
Whether these effects of naloxone reflect its opiate
reported (Amir and Simantov, 1980). zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE
antagonistic activity had to be further tested. Figure 3
shows the effects of different doses of the opiate anRESULTS
tagonist naltrexone. As with naloxone, naltrexone
The chronic administration of lithium for 10 days produced a dose-dependent suppression of the rearing
resulted in a marked suppression of the jumping re- and grooming response in both the lithium-treated
sponse of saline-treated mice in the hot plate test ! and the control mice. Similarly, naltrexone selectively
(Fig. f ). No difference in the frequency of rearing and j facilitated the jumping response of the lithium-treated
589 zyxwvutsrqpo
Chronic lithium and opiate receptors
r
0
f
300-
::
I
I
I
I
I
I
I
t
I
I
I
-
Licl
---0
Control
1
I
I
1
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
I
0) 300
treated
Jumps
.G
Jumps
:
150
100
1
d-
‘6---o
tn.1---o--_o
&=-cco
I
’
(*I)
I
I
0.156
0.625
I
2.5
I
10.0
I
40.0
(*Ml
-I
100
\
QcO
50
t
4
LiCI-treated
---0
Control
\
\
\
\
\
(*)
n= E/group
’
0.156
0
Q
14
1
0625
Naloxone(mg/kg)
mice with the strongest effect (z 1.500/,)obtained with
2.5 mg/kg. In both the lithium-fed and control mice
the largest dose of naltrexone strongly suppressed the
jumping response relative to the response frequency
seen in the respective saline-treated
control groups.
The effect of different lithium feeding regimens on
the response to naloxone (lOmg/kg) in the hot plate
test is shown in Figure 4. The behavioural data are
expressed as a percentage of the mean activity of the
respective lithium-fed, saline-injected
mice. As can be
seen, naloxone suppressed the rearing and grooming
response in the hot plate test with the most pronounced effect occurring with mice receiving 10 days
of lithium containing diet. The jumping response of
the lithium-fed, naloxone-injected
mice was markedly
elevated compared to the activity seen in the respective lithium-fed, saline-treated
controls and the naloxone-treated group that was not fed with lithium (zero
time). The most pronounced effect of naloxone on the
jumping response (> 75%) was noted in mice kept on
the lithium diet for 15 days (Fig. 4). However, a 5 day
lithium feeding regimen was sufficient to produce a
50% increase in the jumping response of naloxonetreated mice. At longer feeding regimens the effect of
naloxone was less pronounced but with a 40 day lith-
,a-,0
;--
1
I J
160.0
Fig. 2. The effect of different doses of naloxone
on rearing and grooming and jumps of lithium-fed (10 days), and
control mice in the hot plate test. Data are presented as
percentages
of the means of the behavioural
measures of
lithium-fed
or control mice injected with saline prior to
testing. *Significant
difference from the respective salineinjected base line group, P < 0.05; **significant
difference
from the respective lithium-treated
groups, P < 0.05. Comparisons
were made on the means of the behavioural
measures using Student’s t-tests. The level of significance
was corrected for multiple testing.
I*.**)
(.)
,0/c
I
2.5
I
00
I
40.0
1
16c
Naltrexone(mg/kg)
Fig. 3. The effect of different doses of naltrexone
on rearing, grooming and jumping of lithium-fed and contol mice.
Details of the experimental
procedure
were the same as
described in the Legend of Figure 2.
ium administration,
jumping
in naloxone-treated
miced was still over 50% higher than that of the respective
lithium-fed,
saline-injected
control
mice.
Notably. as in the first experiment,
lithium feeding
125
100
I
I
0
5
I
zyxwvutsrqponmlkjihgfedcbaZYXWV
I
I I
IO
Days
I
I5
!’
20
40
Fig. 4. The effect of different lithium feeding regimens on
the rearing and grooming and jumping responses of naloxone (lOmg/kg)-treated
mice and on brain lithium concentrations. The behavioural
data is presented as percentages
of the means of the respective lithium-fed.
saline-injected
mice. Open circles indicate whole brain lithium concentrations in lithium-fed
mice. Asterisks indicate significant
difference (P< 0.05)
from the respective lithium-fed. salinetreated mice.
S. AMIR and R. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFED
SIMANTOV
590
20
40
60
80
[3~]notoxone
100 12.0
(nM)
Fig. 5. Binding of [3H]naloxone to brain membrane preparations of lithium-fed mice. Five mice fed for 10 days with
a lithium-containing diet (circles) were compared to 10
control mice (triangles). The binding to crude membranes
prepared as described in Methods was conducted with
0.65-14.4nM [3H]naloxone without or with (solid symbols) 1 PM levallorphan. Data are average of triplicate
samples for each C3H]naloxone concentration.
resulted in a marked decrease in the frequency of the
jumping response compared to the jumping response
seen in normally fed mice. After 5 days of lithium
feeding there was a 31% reduction in the mean jumping response with a maximum effect (70%) occurring
following 20 days of lithium administration.
Interestingly, the brain lithium peaked after 10 days
of lithium feeding and no significant changes in lithium concentrations
were noted following
longer
periods of lithium administration
(Fig. 4).
The increased sensitivity to the opiate antagonists
in lithium-treated
mice may reflect changes in the
density or the affinity of the opiate binding sites to the
opiate
antagonists.
Therefore,
the
binding
of
0.65-14.4 nMC3H]naloxone
to brain membrane preparation of control, or mice fed with lithium was tested
in vitro (Fig. 5). The results show no significant
changes in binding of [3H]naloxone
upon lithium
treatment
in either
low (< 1.0 nM)
or high
(l@-14 nM) concentrations
of [3H]naloxone
(Fig. 5).
DISCUSSION
The results of the present study show that chronic
lithium administration
for 5-10 days, potentiated
the
effect of the opiate antagonists naloxone and naltrexone on the jumping response of mice in the hot plate
test. Both antagonists
produced
a dose-dependent
biphasic effect on the jumping response, with maximal
activation of the jumping at 40 and 2Smg/kg,
for
naloxone
and naltrexone,
respectively.
Naltrexone
was also more effective as a suppressor of the jumping
response if high concentrations
of the antagonists (i.e.
16Omg/kg) were used. This is in line with previous
studies that indicated the longer duration of the naltrexone effect as compared to naloxone. In addition,
the possibility that naltrexone in large doses may possess agonistic properties should be considered. Since
the suppressive effect of high concentrations
of antagonists was observed both in lithium-fed and in the
control mice, further experiments are necessary to determine the specificity of this effect, including the use
of the inactive isomer of the antagonist.
The finding that chronic administration
of lithium
activates the response of mice to opiate antagonists
should only be considered within the context that the
lithium itself strongly suppressed
the jumping
response of saline-injected mice. It is, therefore, possible
to argue that naloxone or naltrexone
reversed the
suppressive effect of lithium. That lithium attenuates
the normal resporse of animals to external stimuli has
been recently discussed (Johnson, 1979). This effect of
lithium may be relat-r.’ at least in part, to its ability to
selectively increase the level of methionine enkephalin
in the striatum (Gillin et al. 1978). an area which is
notable for its role in the control of motor activation.
Since increased levels of the brain endogenous opioids
have been reported to correlate with changes in pain
responsiveness
(Madden, Akil, Patrick and Barchas.
1977), it may be suggested that in mice treated chronically with lithium, the opiate antagonists unmask the
effect of elevated striatal levels of methionine
enkephalin.
It is of interest that the increased jumping response
to naloxone was fully developed within 5 days of lithium application.
At this time the striatal levels of
methionine enkephalin reach plateau levels (Gillin et
al., 1978). However, whereas the enkephalin levels decrease to normal after prolonged
treatment,
the
potentiated
jumping response to naloxone was sustained for 40 days if lithium was continuously applied,
suggesting
differential
mechanisms.
Earlier studies
have demonstrated
that lithium attenuates the morphine-induced
behavioural activation in mice (Carrol
and Sharp, 1971). Byck (1976) and Gold and Byck
(1978) have speculated that the ability of lithium to
decrease the high affinity binding of opiate agonists to
brain opiate receptors may account for this finding.
Furthermore,
these investigators
argued that lithium
may attenuate the binding of endogenous
opioids to
their receptors and that this effect may account for
some of the antieuphoric
effects of lithium in manic
patients (i.e. Byck, 1976; Gold and Byck, 1978). Since
lithium, like sodium has been reported to increase the
binding affinity of opiate antagonists to opiate receptors under some in vitro conditions (Pert and Snyder,
1974). a similar mechanism
underlying
the effects
observed here may be proposed. Although chronic
lithium administration
is not likely to produce any
significant changes in sodium concentrations,
such
treatment might produce some alterations in the total
cationic level within specific brain sites. This effect, in
turn, may increase the binding affinity of exogenous
antagonists.
decrease
the binding
of endogenous
opioid agonists, and subsequently
potentiate the behavioral effects of the injected antagonists. The find-
Chronic lithium and opiate receptors
ina reoorted
here. that chronic lithium does not
change
the affinity
of radiolabeled
antagonist,
[3H]naloxone.
to opiate receptors in nitro, nor the
total number of opiate binding sites (as tested in
saturating concentrations
of C3H]naloxone). does not
exclude the possibility of changes in specific brain
regions in uiuo.
The observed interaction between opiate antagonists and LiCl may be of clinical interest. Several recent
studies have reported
that naloxone
produced
a
notable improvement
of symptoms in manic patients
(Janowsky. Judd. Huey, Roitman, Parker and Segal,
1978; Davis and Bunney. 1980). Others have reported
beneficial
effects of naloxone
in schizophrenics,
although negative results in both manic and schizophrenic patients have also been recorded (Janowsky,
Segal, Bloom, Abrams. Guillemin,
1977; Volavka,
Mallaya. Baig, Perez-Cruet, 1977). Lithium is the drug
of first choice in the treatment
of manic patients
(Schou and Thomsen,
1975) and it has also been
shown to have antipsychotic
effects in schizophrenic
patients
(Alexander,
Van Kammen
and Bunney.
1979). The co-administration
of small doses of lithium
simultaneously
with naloxone may alter the antipsychotic and antimanic effects of these agents. Yet, the
interaction between low, clinically relevant levels of
lithium and opiate antagonists should be studied.
Y
Y
591
rats treated with lithium. zyxwvutsrqponmlkjihgfedcba
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