Psychopharmacology (1984) 84: 80 - 84
Psychopharmacology
Central depressant action of cesium in mice
Ranjan Bose and Carl Pinsky
Department of Pharmacology and Therapeutics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E 0W3, Canada
Abstract. Cesium chloride (CsC1) at several dose levels
(1.25- 20.0 mEq/kg IP) was administered acutely to albino
mice whose behavior was compared with that in correspond-
ing saline controls. Motor activity decreased and Straub
tail occurred in a dose-related manner. Signs of autonomic
disturbance, diarrhea, and salivation were seen with toxic
doses. Subchronic administration of CsC1 (5.0 mEq/kg/day
IP for 7 days) exerted a phenothiazine-like effect in mice,
reducing amphetamine-induced aggregation toxicity and en-
hancing pentobarbital-induced hypnosis. The antinocicep-
tive action of morphine was unaltered by identical multiple
administrations of CsC1. These results indicate a specific
neurosuppressant action of CsC1 on mouse CNS and suggest
exploration of this alkali earth metal for antipsychotic-like
activity.
Key words: Cesium - Neurotoxicology - Toxicology - CNS
drug modification - Antipsychotic effects - Motor activi-
ty - Pentobarbital hypnosis - Amphetamine aggregation
mortality
The close approximation of cesium (Cs) to the biologically
active alkali earth elements sodium, potassium, lithium, and
rubidium is intriguing for many reasons. The growing indus-
trial importance of Cs and the strong likelihood of it being
considered a future source of 'clean' energy (McKee et al.
1981; Pinsky et al. 1981) renders important the study of its
toxic effects on biological systems. Several such toxicological
studies have been conducted (Cochran et al. 1950; Johnson
et al. 1975; Bose and Pinsky 1980, 1983; Pinsky et al. 1981).
Cs has been shown to have specific effects on the CNS
of mammals, with most investigators (Johnson 1972; Jenner
et al. 1975; Messiha 1978 a, b; Rastogi et al. 1980) describing
excitant effects for this ion. In contrast, studies in this labora-
tory (Bose and Pinsky 1980, 1981, 1983; Pinsky et al. 1980)
have revealed a depressant component to CNS responses
with single and multiple administrations of CsC1 to mice
and rats. Also, a tendency for Cs to diminish aggression in
rats was noticed by Eichelman et al. (1973), although the
depressant effect was slightly short of statistical significance
in that study. Many of the studies compared the effects of
Cs with lithium or rubidium (Johnson 1972; Eichelman et
al. 1973; Jenner et al. 1975; Messiha 1978 b; Rastogi et al.
1980).
Offprint requests to: R. Bose
9 Springer-Verlag 1984
The present study reports findings on the effects of single
and short-term ('subchronic') multiple administration of Cs
on several parameters in mice. Single graded doses of CsC1
were administered to groups of mice whose general be-
havioral responses were quantitatively assessed. Other mice
received multiple administrations of CsC1 over several days,
after which selected CNS parameters were studied.
Materials and methods
Male Swiss-Webster mice (Canadian Breeding Laborato-
ries, St. Constant, PQ, Canada), weighing 2 5 - 3 0 g, were
housed in groups of six to ten (depending on experiment) in
temperature-controlled (22~C) and humidity-supplemented
quarters, maintaining a 12-h light-dark schedule.
All experiments and injections were conducted in the
light period (9:30 AM - 4 PM). Laboratory room
temperature was 22~ for all experiments. All drug and
salt solutions were injected in a volume of 10.0 ml/kg body
weight.
Acute single injections of CsCl
CsC1 was injected IP into 30 male mice at doses of 1.25, 2.5,
5.0, 10.0, and 20.0 mEq Cs*/kg. Six animals were injected
with each dose in separate groups of three. Similar three-
animal groups of 30 control mice were injected with normal
saline but otherwise handled identically. Cs-treated were
alternated with saline-treated groups without interruption
throughout the experimental day. This reduced the influence
of time-of-day variations in behavior and responsiveness on
the estimation of drug effects.
Motor activity. At 5 rain after injection each group of three
mice was transferred from their home cage to a circular
observation chamber (clear plastic cylinder, 30 cm
diameter x 30 cm high, top open). The animals were allowed
to explore the chamber for 5 rain. An observer then noted
their behavior for the next 15 min using a modified version
of Irving's observation list (Turner 1965). The observer
noted continually on audio tape each event of locomotion
(horizontal movements), rearing up (vertical activity),
grooming, sniffing, and teeth-chatter as it occurred. We
found this approach to be quicker and more error-free than
written observations, which was especially important in con-
trol groups that were active and therefore required rapid
recording of observations. Each total motor activity score
(presented as a single value in Fig. 1) is the mean of the sum
 81

amphetamine 9HC1 IP at two dose levels (20.0 and 40.0 mg/

8o. kg) 24 h after the last pretreatment injection. Each group
W was kept in a plastic cage (27 x 15 x 12 cm high) and the
0 aggregation-induced lethality (Chance 1946) noted at 6 h
0
after injection of amphetamine.
60-
i--
0
Nociception. Groups of five to seven mice were pretreated
< for 7 days with either CsC1 (5.0 mEq/kg/day IP) or with
t: 40"
0 equivolume physiological saline. They received 0.0, 3.0, 6.0,
0 and 12.0 mg/kg morphine sulphate (MS) in saline IP 24 h
...J after the seventh injection of Cs or saline. The tail-flick
<
I--
20" latency (time elapsing between beginning of heat application
0I-- and withdrawal of tail) was tested at 30 rain after morphine
administration.
0 Tail-flick latency was measured by a digitally controlled
/ / I ' I ' I version (Pinsky, Bidnick and Brockhausen, unpublished
0 + 100 200 data) of the heated-wire method of Davies et al. (1946).
log [Dose Cs* mEq/kg] xlO2 Animals were placed in the tail-flick chamber with no appli-
cation of heat for several minutes once-daily during the
Fig. 1. Log dose-response relationship for acute administration of 7-day regimen of pretreatment with Cs or saline. This
cesium ion (CsC1 IP) and mean total motor activity scores in mice. acclimatized the mice to the chamber, minimizing stress at
For each dose of CsC1 (N = 6), values plotted indicate mean _+SE the time of experiment. The maximum time during which
scores per animal. Saline control mean + SE value was obtained by
pooling data from 30 mice, tested in groups of three alternately with the wire was kept hot was 30 s to prevent tissue damage due
equal Cs groups throughout the experimental day. Best-fit straight to longer exposures in the presence of a positive antinocicep-
line and regression coefficient (r) calculated by method of least- tive response. This cut-off time was about eight times longer
squares than the mean initial (pre-morphine) response of the ani-
mals.
In the studies concerned with drug interactions and with
of the number of events in the five categories of motor antinociception, the observer was unaware of which chronic
activity, occurring in two groups of three mice each with pretreatment (saline or Cs) any animal had received and of
identical treatments. what dose of drug (amphetamine, pentobarbital, morphine,
saline) had been given for the experiment.
Involuntary activity. Urination and salivation were graded
in comparison to normally observed amounts in saline con-
trols, as follows: absent (0); less than in saline controls (1); Results
equal to that in saline controls (2); greater than in saline
controls (3). Straub tail is not normally present and was Acute single injections of CsCI
therefore graded as 0 when absent and 1 - 3 when present, Mortality. There were no deaths among the mice injected
depending on the approximate angle that the tail made to with CsC1 at doses of 1.25, 2.5, or 5.0 mEq Cs+/kg. Two of
the long axis of the body (maximum 90~ The data were six mice given 10 mEq Cs+/kg died within approximately
normalized by (X + 0.5) 1/2 transformation (Steel and Torrie 36 h after injection and all of six mice receiving 20.0 mEq
1960). Cs +/kg were dead within 30 min of injection.
All behaviors and activity were rated by the same
observer who was unaware of the nature of the treatments
until after the experiments were completed. Statistical pro- General behavior, motor activity, and toxicity. The initial
cedures were as appropriate to the nature of the phenomena response to acute administration of Cs over 5.0-20.0 mEq
studied. Cs+/kg IP was transient excitation and hyperactivity. This
never lasted more than a few minutes and was therefore
observed only while the mice were in their home cages before
Subchronic multiple injections of CsCI placement in the circular observation chamber for quantita-
Barbiturate hypnosis. Four groups of ten male mice were tive assessment of behavior. The transient hyperactivity was
treated for 7 days with either NaC1 or CsC1, both at 5.0 mEq/ characterized by darting horizontal movements and escape
kg IP. They were then given pentobarbital sodium in a near- attempts, especially during handling. This response was also
threshold and in a hypnotic dose (30.0 and 50.0 mg/kg IP, seen after each injection during multiple administrations of
respectively) at 24 h after the seventh CsC1 injection. The 5.0 mEq Cs+/kg/day for many days.
time interval between the loss and complete recovery of The initial excitement phase was followed by a significant
righting reflex (animal remaining for less than 5 s on its suppression of motor behavior over the entire 15-min period
back, on three subsequent trials) was taken as the sleeping of observation after acute CsC1 administration (1.25-
time. 20.0 mEq Cs +/kg IP). Cs-induced suppression of total motor
activity scores showed a significant rectilinear negative
Amphetamine aggregation toxicity. Four groups of ten male correlation with the logarithm of the dose of Cs administered
mice were pretreated for 7 days with NaC1 or with CsC1, (Fig. 1). When the data were normalized and expressed as
each at 5.0 mEq/kg IP. They were then given injections of percent suppression of total activity, a log dose-response