Lithium and the structure of exploratory behavior in the rat

Prog.Neum-Psychophamcol.Vol.4,pp.37-41,1980. Pergamon Press Ltd.Printed in Great Britain.

LITHIUM

AND

THE STRUCTURE OF EXPLORATORY JN THE RAT Richard

Mental University

of

J.

Health Research Insitute, Michigan Medical Center,

(Final

form,

BEHAVIOR

Katz Department Ann Arbor,

December

of Psychiatry Michigan 48109,

USA

1979)

Abstract 1. 2.

3. 4.

Adult male Sprague Dawley rats were given lithium as a dietary supplement, or a control diet. A single seven hour test of exploratory behavior was carried out after one week of chronic drug exposure . The structure of exploration was significantly altered by the diet, with experimental animals exploring less intensely and with increased spacing of activity episodes. These findings may represent a useful preclinical analog of some typically observed therapeutic effects of lithium.

Keywords:

biological

rhythms,

exploratory

activity,

lithium,

motor-behavior

Introduction The alkali metal lithium remains a drug of choice in the treatment of a disorders, particularly bipolar affective disorders, variety of psychiatric acute mania, and diverse other syndromes characterized by a recurrent and A number of laboratory models episodic nature (Gershon and Shopsin, 1973). have been used in investigating lithium’s pharmacological mode of action. One of class of model has concentrated upon psychomotor activation as an analog clinical hyperactivity (Carroll and Sharp, 1971; Cox et al., 1971; Johnson, 1973; Smith, 1976; Mukherjee et al., 1977; Smith and Smith, 1975). 1972, These and related reports (Gray et al., 1976; Syme and Syme, 1973) have (Gray et al., suggested that lithium selectively decreases rearing activity 1976; Johnson, 1972; Wolthius et al., 1975) or open field activity (Smith and not Smith, 1973; Syme and Syme, 1973) although these reports are consistent regarding the relative proportions to which the behaviors are reduced by noted only minor treatment. Other reports, moreover have occasionally changes in spontaneous activity with chronic treatment (D’Encarnacao and Anderson, 1970; Segal., et al 1975). The majority of reports, however, agrees that chronic lithium treatment does reduce some aspects of exploratory behavior. A second class of model has investigated lithium’s effects upon biological rhythms (Engelmann, 1973; Engelmann et al., 1974). It has been suggested that lithium alters the occurrence of biological rhythms and that its effects oscillating systems may be important in its clinical efficacy. The upon typical preparation used for the study of these effects unfortunately is a

37

38 plant (Kalanchoe blossfelhiana), rodents. There is considerable effects using mammalian behavior

R.

.I.

Katz

limited research has although utility in further investigating as a dependent variable.

also

involved related

its episodic One easily overlooked aspect of exploratory behavior is rats placed in particularly during extended tests. For example, organization, They environments generally are active for thirty to sixty minutes. novel following which they again are then are quiescent for an extended period, Activity and quiescence continue to oscillate over the testing active. session period. It follows that exploratory behavior tested over an extended the requisite properties for simultaneously modelling both has many of We have heightened activity and recurrent events with an episodic character. characteristics of extended exploration in further utilized these The present design both investigating the behavioral pharmacology of lithium. behavior, replicated and extended previous models of this drug’s effects upon utilizing a novel model of recurrent exploratory activity. Methods Subjects were sixteen experimentally naive adult male Sprague Subjects: obtained localy (Charles River Farms; Dawley rats (250-300g: eight/group) food and water. Rats were Portage, MI) and maintained on ad libitum tap housed four/cage in 36x33~17 cm polypropylene containers, and lighting cycles of 12h/12h were automatically programmed (lights on - 8:00-2O:OO). lithium and to more closely Drug: To insure continual exposure to approximate patterns of clinical ingestion the drug was administered in the chloride 120 mEq/Kg of normal diet of the experimental animals (as lithium Teklad 4% fat rodent diet SO836). To compensate for normal ionic loss which occurs during lithium treatment supplements of sodium and potassium chloride (1100 and 100 mEq ;;;;;;tively) were also added to the food, as recommended by The effective daily dose range for the present Olesen et al. experiment was .3-.7 mEq: based upon records of food consumption. At 9:00 h of the from Procedure: test rats were removed day group placed in cages containing a novel bedding housing and individually test (pinewood sawdust). Cage shape, bedding, and individual exposure were therefore all novel for the subjects. Subjects remained undisturbed on the and were then returned to their home cages. Data platforms for seven hours, were collected as ten minute blocks. Lithium treated subjects were maintained of drug exposure and then sacrificed (between for one additional day ll:OO-12:00 h) by decapitation, bloods immediately were collected in heparinized tubes and centrifuged for determination of plasts lithium levels. Statistical Analysis: median scores (table All data are presented as one) or untransformed individual scores (figure one). Due to large the variability across subjects all data were analyzed nonparametrically by Kolmogorov-Smirnov statistic and the Mann Whitney U-test (Siegel, 1956). To standardize comparisons an episode of activity was defined as such only if it contained greater than 50 counts/l0 min. Subthreshold activity was considered behavioral quiescence. Apparatus: The testing apparatus consisted of a 51x41~22 cm white cage. Four polypropylene cages were used at any time, and were placed upon commercially available field sensitive activity monitors (Stoelting, Chicago, Ill.) operating on a selective mode for the detection of gross body activity. Monitors were ad justed to within 5% sensitivity of each other, and care was counterbalance treatment taken to groups across monitors. The testing environment illuminated by was overhead fluorescent (70~) bulbs, and the normal operation of air circulating equipment provided 25 dB masking noise. Add it ion al details of the platforms have been presented elsewhere (Katz, et Plasma lithium was al., 1978). determined photometrically using a Perkin-Elmer 305-B atomic absorption spectrophotometer.

Lithium

Effects Min

10

Lithium Control N

q

860 542

8 each,

group

of

lithium

20

Lithium control in activity

median

39

activity

in

to

rats

50

60

70

80

104 0

250

220

104

values

induced

diets

1

40

Contr.

1. or

Table

277 484

First

Figure Lithium placement

exploration

on exploratory

30

752 635

and

f

(KP

Lithium

Contr.

Second

Second

in

alteration

were administered cages for a single

=

1: 13;

p
days

episodes. prior to

Lithium to

Third

the spacing chronically exposure

100

go

of

exploratory

for of

seven

seven hours.

Results

Lithium exploratory

which control

include groups.

produced episodes. the

a

initial

louering Table

1 exploratory

of

exploration

presents

the episode

and

first for

a

ten both

spacing of recording intervals experimental and

greater

40

R. J.

Katz

Table one shows that lithium produced a lowering of both t h ? intensity duration of a typical initial exploratory episode. Other results suggest and it also altered the typical profile of activity over time (figure one). When number of minute blocks to subsequent episode (i.e. inter-episode ten duration) was compared across groups the median number for the lithium treated while the median contol difference was 8.5 group was 11 (range = 3-15) (range = l-15). This difference was statistically reliable (U q 10.5, p
length between second animals of 12 (range l-24) last difference however was

and and not

examination of number of episodes/session for the two Finally, groups indicated lithium treated subjects has fewer (Median = 3; range = 2-5) episodes than control subjects (median = 4; range q 3-5) (U = 16; pc.05 by Mean plasma lithium value for the experimental group was .8 mEq median test. (range = .3-1.2). Discussion Lithium reduced initial and subsequent chronically treated rats. These changes reflect activity and a re-organization of exploratory lengthening of episodes and a reduction in results confirm earlier studies suggesting that and also suggest several novel parameters affected. It might be noted that while lithium the testing interval there apparently was a they were present. The reason for this may rest procedures. All subjects were tested after However testing continued over an extended period that drug levels would therefore decline over so might have the experimental effect.

patterns of exploration in both an initial lowering of behavior over time, with a total episodes. The present lithium reduces exploration, of exploratory behavior were effects persisted throughout decline in the degree to which with experimental testing their normal feeding cycle. and it might be anticipated time. As drug levels declined

It is of particular interest that lithium affects bipolar affective disorders both by lengthening the intervals between episodes and by reducing the number of episodes per unit of time. It also reduces the severity of a episode (Gershon and Shopsin, The present model therefore given 1973). phenomenology and captured several distinct aspects of lithium’s normal intensity of pharmacological mode of action. Not only was the activation reduced but its temporal structure was systematically altered in a data speak to the ability of the lithium ion to predictable fashion. These simultaneously reduce activity while altering normally occurring biological oscillations. While it was not established whether these two classes of the present model effects are mediated by the same physiological mechanism, does offer a means of further investigating this and related problems. Acknowledgements These data were collected while the author was supported grant MH07417 from the National Institute of Mental Health. assistance of J. Ritchie and B. Perry, and the guidance J. Carroll are acknowledged with gratitude.

by

postdoctoral The technical of Dr. Bernard

References and CARROLL, B.J. on amine mediated

SHARP, P.T. excitement.

(1971) Rubidium Science 172:

and lithium 1355-1357.

opposite

effects

Lithium and

41

exploration

HARRISON-READ, P.E., STEINBERG, H. and TOMKIEWICZ, M. (1971) Lithium induced drug hyperactivity in rats. Nature (Land.) 232: 336-338. D'mARNACAO, P.S. and ANDERSON, K. (1970) Effects of lithium pretreatment on amphetamine and DMI tetrabenazine produced psychomotor behavior. Dis. Nerv. 31: 494-496. Syst. ENGELMANNFW. (1973) A slowing down of circadian rhythms of lithium ions. 2. Naturforsch. 28: 733-736. ENCELMANN, W., MAURm, A., MULBACH, M. and JOHNSSON, A. (1974) Action of lithium ions and heavy water in slowing circadian rhythms of petal movement in Kalanchoe. 5: 199-205. J. Interdiscipl. Cycle Res. GERSHON, S. and SHOPSIN, B. (1973) Lithium: Its Role in Psychiatric Research and Treatment. Plenum, New York, 358 pp. GRAY, P., SOLOMON, J., DUNPHY, M., CARR, F. and HESSION M unst;esied(1966) Effects of lithium on open field behavior in stressed and rats. Psychopharmacology. 48: 277-281. JOHNSON, F.N. (lq2) Effects of alkali metal chlorides on activity in rats. Nature (Land.) 238: 333-334. JOHNSON, F.N. (19m Lithium effects upon components of activity in rats. Experientia. 32: 212-213. KATZ, R.J., CARREL, B.J. and BALDRICHI, G. (1978) Behavioral activation by enkephalins in mice. Pharmac. Biochem. Behav. 8: 493-496. MUKHERJEE, B.P., BAILEY, P.T. and PRADHAN, S.N. (7977) Correlation of lithium activity with its brain concentration in effects on motor rats. Neuropharmacol. 16: 241-244. (1975) Effect of potassium on OLESEN, O.V., JENSEK J. and THOMSEN, K. lithium induced growth retardation and polyuria in rats. Acta Pharmacol. et Toxicol. 36: 161-171. (1975) Alterations in behavior SECAL, D.S., CAEACHAN, M. and MANDELL, A.J. and catecholamine biosynthesis induced by lithium. Nature 254: 58-59. SIEGEL, S. (1956) Nonparametric Statics for the Behavioral Sciences. McGraw Hill, New York, 312 pp. effect of short term SMITH, D.F. (1975) Biogenic amines and the lithium in rats. administration open field activity Psychopharmacologia. (Berl.) 30: 295-y:O. effect of SMITH, D.F.and SMITH, The prolonged lithium acFIvith1g73) reactivity and endurance in the rat. administration Psychopharmacology: (Berl.) $0: 83-88. (1973)Tffects of lithium chloride on the activity of SYME L.A. and SYME G.J. rats tested alone or in pairs. Psychopharmacologia. ;;;;;;I 85-89. Automatically WOLTHIUS, O.L., DEVROOME, H. and VANWERSCH, R.A. determined of lithium, scopolamine, and methamphetamine on motor effects activity in rats. Pharmac. Biochem. Behav. 2: 515-518. cox,

c., attenuates

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to:

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USA