Alcohol & Alcoholism. Vol. 31. No. 2. pp. 149-156. 1996

BUSPIRONE AS AN INHIBITOR OF VOLUNTARY ETHANOL INTAKE INMALE RATS

LARS HEDLUND and GORAN WAHLSTROM*

Department of Pharmacology. University of Umea. S-90187 Umca. Sweden

(Received 3 April 1995: in revised form 21 August 1995: accepted 1 September 1995)

Abstract — The effect of buspirone. a drug with mainly 5-HT|A-agonist activity, on voluntary ethanolintake was tested in a rat model of alcoholism. In this model the treatment consists of an injection ofethanol (2 Og/kg) or saline once a week, preceded by a 24 h choice between water and ethanol (10%.w/v). This weekly injection of ethanol reduces voluntary ethanol intake in male rats. Maximal inhibitionis seen after 5-6 weeks. At this maximal inhibition buspirone or saline was injected prior to the voluntary24 h intake of ethanol in both the ethanol- and saline-injected groups The tested doses were 5 mg/kg(week 5) and 20 mg/kg (week 6). There was no reduction in ethanol intake in the buspironc-injcctcdgroups when compared with their corresponding controls. A second experiment with buspirone wasperformed during the evaluation period following treatment with ethanol. This treatment consisted ofa choice between water and ethanol (10%. w/v) for 1 day each week, followed by an injection of ethanol(2.0g/kg) and lasted for 52 weeks. During the evaluation period the rats had a continuous choicebetween ethanol and water for 37 weeks and no injections were given In this situation, with a longerexposure toethanol. adose of 20 mg/kg of buspirone in week 90 reduced ethanol intake by approximately40%. when compared with controls. The effect of this buspirone dose lasted at least a week. Thisindicates that the long-term exposure to ethanol in the second experiment induces changes that affectthe serotonergic transmission, and that this changed neural system is involved in the regulation ofvoluntary ethanol intake.

INTRODUCTION

Ethanol is perhaps the drug of abuse with thegreatest cost to society, not to mention its effectson the abuser. Much money and effort have beenput into the development of drugs that can reduceethanol intake in alcoholics and that can counter-act the symptoms of ethanol withdrawal. Changesin the serotonergic system have been reportedafter ethanol exposure (Ballenger et al., 1979;Simonsson and Ailing, 1988; Alexi and Azmitia,1990). It has also been shown that rats with aninherent serotonin deficiency consume more etha-nol (Overstreet et al.. 1992). These facts indicatethat drugs affecting the serotonergic system mayalso affect ethanol intake. Buspirone is an anxio-lytic that has been in clinical use for some years. Ithas presynaptic agonistic and postsynaptic partialagonistic properties at the 5-HT1A-receptor (forfurther description, see Napoliello and Doman-tay. 1991). It has been shown to reduce ethanolintake in monkeys and rats (Collins and Myers,

"Author to whom correspondence should be addressed.

1987; Privette et al.. 1988). Similar effects havealso been shown for other 5-HT]A-agonists (Kos-towski and Dyr, 1992; Meert, 1993; Svensson etal.. 1993; Blomqvist et al., 1994). Clinical trialshave shown a beneficial effect of buspirone afterethanol withdrawal, especially in anxiousalcoholics (Bruno, 1989; Kranzler and Meyer,1989; Olivera et al., 1990; Tollefson et al., 1992).The major effect of buspirone in these studies inman has been a reduction of anxiety, and little orno direct effect has been shown on ethanol intake.However, buspirone treatment without effects hasalso been reported (Malcolm etal., 1992). Clinicaltrials have found buspirone effective in the acutestate of ethanol withdrawal (Dougherty andGates, 1990).

The present experiments were intended toexamine if buspirone could reduce ethanol intakein animals according to our rat model of alcohol-ism (Wahlstrom, 1983, 1987, 1994a, b). Buspironewas first given in the early phase of the inter-mittent treatment, used to induce psychologicaldependence. This exposure to ethanol resemblesthe drinking pattern of people in Nordic countries

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150 L. HEDLUND and G WAHLSTROM

(Simpura. 1987) and Wales (Bennett etal.. 1991).with heavy drinking at weekends. Buspirone wasthen given in the following evaluation period,where the animals had undergone a long andcontinuous exposure to ethanol. At this stage, therats, in a continuous choice situation, take thesame dose of ethanol independent of the offeredethanol concentration. Thus, in this model wehave an empirical sign of psychological depen-dence to ethanol, which has been induced by theintermittent treatment.

Psychological dependence must be separatedfrom physical dependence. The physical depen-dence to a drug is the mainly adaptive changesof, for instance, receptor systems, that developduring exposure to a drug. The physical depen-dence is responsible for the main part of thesymptoms seen during the first part of withdrawal.These symptoms have a limited duration. Thepsychological type of dependence is more of a'memory' of the effect of the drug, and is respon-sible for the craving. This part of dependence doesnot end after a period of withdrawal, but persistsfor a much longer time. In the present experi-ments, single doses of buspirone were tested onvoluntary ethanol intake, both early in the treat-ment, with no dependence, and in 'psychologi-cally' dependent rats.

MATERIALS AND METHODS

Animals

Male Sprague-Dawley rats (Mol:SPRD, Molle-gaards Breeding Centre Ltd, Li Skensved, Den-mark) were kept in individual cages in a roomwith a reversed light/dark schedule (light on19:00-07:00) and at a room temperature around23°C. Each cage was equipped with two drinkingbottles. One of the bottles always contained tapwater, and the other contained either water or anethanol solution. The concentration of the ethanolsolution was 10% (w/v) during the treatmentperiod in both experiments. During the evaluationperiod of the second experiment, it was variedbetween 0% and 20% to test for psychologicaldependence.

Food (commercial rat pellets R34. Lactamin,Stockholm, Sweden) was available ad libitum.Before the start of the experiment, the rats wereaccustomed to our animal facilities for 10 days.The age of the animals was determined from the

age/weight curve (supplied by the breeder) andwas ~ 10 weeks at the start of the short experimentand 5 weeks at the start of the long experiment.

ChemicalsEthanol (AB Svensk Sprit) as a drinking fluid

was mixed with tap water to a 10% (w/v) solution.Ethanol for injection was dissolved in 0.9% (w/v)saline and administered intraperitoneally (i.p.) ina dose of 2.0g/kg at a concentration of 10%(w/v). Control animals were given isotonic saline.Buspirone (Bristol-Myers Squibb) was dissolvedin 0.9% NaCl and injected i.p. at the con-centrations of 5 mg/ml (5 mg/kg) and 20 mg/ml(20mg/kg).

Experimental designThe experimental design used in the two experi-

ments presented here has been described in detailin earlier publications (Wahlstrom, 1983, 1987,1994a, b). Three prerequisites founded on experi-ences in humans are involved: (1) intoxicationonce a week; (2) chronic treatment; (3) oral intake(Wahlstrom 1994a). The basic experiment incor-porating these prerequisites consisted of a treat-ment period and an evaluation period.

During the treatment period, the weekly etha-nol intake consisted of a voluntary oral choicefor 24 h which is ended by an ethanol injection(2.0g/kg i.p.). Thus the first prerequisite wasfulfilled. With such a treatment schedule, an inhi-bition of voluntary ethanol intake develops duringthe first 6 weeks of the treatment. The buspironetreatment in the present experiment with inter-mittently treated rats was performed at this mini-mum in the ethanol-injected groups. If thetreatment is continued the inhibition of ethanolintake gradually disappears. In a basic exper-iment, the treatment is pursued for 1 year. Thusthe second prerequisite is fulfilled.

During the following evaluation period, allethanol exposures are voluntary and given as acontinuous oral choice between ethanol andwater. Thus the third prerequisite is fulfilled. Theconcentration of the ethanol solution offered ischanged (tested range 5-20%) every third week,and our empirical definition of psychologicaldependence is that the voluntary daily dose ofethanol (in g/kg) is not changed by this manipu-lation. The buspirone treatment in the presentcontinuous exposure experiment was given to rats

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BUSPIRONE AND ALCOHOL INTAKE

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Fig I Design of the first experiment.Letters indicate injections of either saline (S). ethanol (E). or buspirone (B). Stippled bars denote a choice between

ethanol and water Solid bars denote a 24 h choice between ethanol and water preceded by an injection of buspirone orsaline

during the evaluation period. These rats had ful-filled the criterion of 'psychological" dependencewhen tested with changing concentrations of etha-nol prior to the administration of buspirone.

Intermittent treatment. Using the first letters ofthe words Ethanol. Buspirone and Saline, werandomly divided the rats into the four groups SS.SB. ES and EB. as shown in Fig. 1. All handlingof the rats was conducted between 07:00 and09:00. In weeks 1-7. the rats had during the first6 days two bottles of water available. At thestart of day 7. a bottle of ethanol (10% w/v) wasinserted instead of the bottle from which the rathad consumed most water during days 1-6. Thenext morning, when the bottles were changed totwo bottles containing fresh water, the rats wereinjected with either 2.0g/kg ethanol i.p. [10%w/v, volume injected (7-12 ml) determined byweighing the rats], a dose that causes moderateintoxication, or a corresponding volume of saline.In week 5. the rats were given saline or buspironein a dose of 5 mg/kg at the start of day 7. In week6. the rats were given saline or buspirone in a doseof 20 mg/kg at the start of day 7. At the end ofweek 7, a final injection of ethanol or saline wasgiven. In week 8. the rats had a continuous choicebetween water and ethanol and no injections weregiven.

At the time of the maximal difference betweenthe groups it is possible to detect both stimulatoryand inhibitory effects of a drug on voluntary etha-

nol intake. Buspirone was tested at the above twolevels of ethanol intake.

Continuous exposure. In the treatment part ofthe second experiment the rats were allowed tochoose between water and ethanol for 1 day eachweek, and were at the end of the 24 h periodinjected with ethanol (2.0g/kg). This treatmentwas given during weeks 1-52. After this treatmentthe rats had. during an evaluation period, a con-tinuous choice between water and ethanol. Thisperiod lasted for 37 weeks (weeks 53-89), and noinjections were given until the treatment withbuspirone in week 90. During the evaluationperiod, the ethanol concentration was varied(according to experimental conditions notinvolved in the present experiment) between 0%and 20% (w/v). These conditions were used toevaluate the psychological dependence. Therewere two patterns of changes in ethanol con-centration in the two groups participating in thisexperiment. For this reason buspirone was givento half the rats in each group, yielding four dif-ferent groups. The rats in each group were ran-domly given either buspirone or saline, but sincethere were no differences between the rats withdifferent exposure patterns, neither in pre-injec-tion ethanol intake nor in the response to bus-pirone or saline, both the groups given buspirone(total n = 8) and both the groups given saline(total n = 10) were combined. In the first day ofweek 90. the rats were injected with buspirone

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152 L HEDLUND and G. WAHLSTROM

(20 mg/kg) or saline. The rats had a continuouschoice between water and a 10% (w/v) ethanolsolution during 3 weeks prior to the buspironetreatment and the period following the injection.A test of dependence, as described in earlierexperiments with this model (Wahlstrom. 1987.1994a, b), with 20% ethanol during weeks 61-63showed that the groups had developed a 'psycho-logical' dependence. The rats may also at this timehave been physically dependent, but no tests wereperformed.

Statistical methods

Conventional statistical methods were used.Differences between two groups were tested withStudenfs /-test. P < 0.05 was used as the basiclevel of significance; NS denotes value outside thisrange, n denotes numbers of observations. Valuesare given as means ± SEM.

RESULTSFluid intake

The total intake of fluid (data not shown) wasnot affected by buspirone in any significant wayin any of the experiments.

Intermittent treatment

Week I. There was no significant difference inethanol intake between the four groups (Fig. 2).

Weeks 2-4. The difference between the groupsinjected with ethanol (ES and EB) and the groupsinjected with saline (SS and SB) reached a stat-istically significant level (P < 0.05) in week 3, andthis difference remained throughout the exper-iment (Fig. 2).

Weeks 5-6. In weeks 5 and 6 the EB and SBgroups were injected with buspirone i.p. prior tothe 24 h choice between water and ethanol. Thegroups ES and SS were injected with a cor-responding volume of saline i.p. There was nodifference between the groups given buspironeand their corresponding controls in their intake ofethanol (Fig. 2).

Weeks 7-8. At the end of week 7, there was afinal 24 h choice between water and ethanol, butno significant difference between the rats thathad received buspirone or saline was detected. Inweek 8. the rats had a continuous choice betweenwater and ethanol (Fig. 2). When the rats had acontinuous access to ethanol a significant (SS,

/><0.01; SB. F<0.001; ES. P<0 .05 ; EB,P < 0.001) reduction in daily ethanol intake wasseen compared to the intakes in week 7. whenthe rats had access to ethanol for a single day.However, in week 8, there was also a significantdifference (P < 0.05) in ethanol intake betweengroup ES (0.46 ± 0.07 g/kg) and group EB(0.37 ± 0.05 g/kg). Whether this small differencehas any biological relevance is an open question.

Continuous exposure

In the first day of week 90 in the second exper-iment, an injection of buspirone (20 mg/kg i.p.)or saline was given. When comparing the weeklyethanol intake during weeks 88-93, the only weekwith a significant (P<0.05) difference betweenthe saline- and the buspirone-injected animalswas week 90. which is the week following thetreatment (Fig. 3).

A more detailed analysis of the treatment with20 mg/kg buspirone showed that ethanol intakewas significantly (P<0 .01 , n = 8. paired Mestweek 89 vs week 90) reduced during the dayof injection (Fig. 4A). There was no significantcorrelation between the intake of ethanol on thesetwo occasions, but all rats decreased their intakeafter the buspirone treatment (Fig. 5A). No cor-responding decrease was seen in the saline-injected animals (Fig. 4A).

A significantly (P<0.0l) decreased ethanolintake was also seen during the remaining part(days 2-7) of week 90 in the previously buspirone-injected rats (Fig. 4B), but since the intake is amean daily intake during days 2-7 of week 90, itis not possible to tell how this inhibition of ethanolintake changes with time. There was a significant(P < 0.05) correlation during days 2-7 of week 90with the corresponding intake during days 2-7 ofweek 89. Since the regression coefficient did notdeviate from 1.0 (0.91 ± 0.27), the reduction inintake was probably not influenced by a high anda low intake in the week prior to injection (Fig.5B). Also during this part of the experiment, nocorresponding changes were seen in the controls(Fig. 4B).

DISCUSSION

Effects of buspirone on ethanol intake in thepresent experiment were only found in rats witha heavy exposure to ethanol. This indicates that

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BUSPIRONE AND ALCOHOL INTAKE 153

WeekFig. 2. Weekly ethanol intake during the first experiment.

Group SS is indicated by open squares, group SB by solid squares, group ES by open circles and group EB by solidcircles. The marks along the abscissa are identical to those given in Fig. 1. Error bars are plotted only in one directionand indicate 1 SEM. No error bar indicates an SEM smaller than the corresponding symbol *P < 0.05 when comparinggroups SS and SB. or groups ES and EB Significance between the ethanol-injected and the corresponding saline-injectedgroups is given in the text.

ethanol exposure induces changes in a neural sys-tem regulating ethanol intake which, due to themain action of buspirone, includes a part whereserotonergic transmission is involved. The nega-tive results of our first experiment indicate thatthese changes have not yet developed in the earlystages of the treatment part of the present model.Since the treatment used here can induce 'psycho-logical' dependence (Wahlstrom 1994a) it is poss-ible that the effects of buspirone reported in theexperiment with continuous exposure could haveinfluenced this state. This means that psycho-logical dependence could be connected to neuralchanges in the serotonergic system. Anotherexplanation for the changed response to buspironeafter long-term ethanol exposure could be thatthe rats in our second experiment have grown old,or that there exists a combined effect of ethanolexposure and ageing. However, the younger ageof the rats in the other experiments with 5-HT1A-agonists, where a decreased ethanol intake wasseen (Kostowki and Dyr, 1992; Svensson et al.,1993; Meert, 1993) excludes age as an importantfactor.

In two earlier experiments (Kostowski and Dyr.1992; Meert, 1993) effects of buspirone on ethanol

90 91

WeekFig. 3 Daily intake of ethanol in the weeks involved in

experiment 2The saline-injected group is indicated by open circles and

the buspirone injected group by solid circles. Error barsare plotted only in one direction and indicate 1 SEM.

*P<0.05

preference or intake have been shown in rats.However, these effects were only obtained in ratsselected for high ethanol intake, recorded afterforced exposure to ethanol. Other 5-HT1A-agon-

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154 L HEDLUND and G WAHLSTROM

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Fig. 4. Effect of a single dose of buspirone (20 mg/kg. i.p.) given at the start of day 1 oi week 90 on ethanol intake.Controls were given saline. The intake of ethanol in week 90 is compared with the corresponding pretreatment intake

recorded in week 89. Points indicate week 89 and diagonal lines indicate week 90. Error bars indicate 1 SEM. (A) Ethanolintake during day 1. (B) Daily ethanol intake during days 2-7.

i 2 3 4

Intake of elhanol in week 89 Intake of ethanol in week 89

Fig. 5. Correlations between ethanol intake in week 89 and the corresponding intake in week 90. after a single dose ofbuspirone (20mg/kg i.p.) given at the start of day one of week 90.

The unbroken lines indicate identical intake of ethanol in both weeks. (A) Ethanol intake during day 1. (B) Dailyethanol intake during days 2-7. The dashed line is the estimated regression line (correlation coefficient = 0.81. regression

coefficient = 0.91. n = 8. P<0.05).

ists have similar effects (Kostowski and Dyr. 1992;Svensson et al., 1993). These effects were alsoseen in rats with a high ethanol intake. Kostowskiand Dyr (1992) obtained this high intake by selec-tion, and Svensson el al. (1993) by utilizing theincrease following ethanol deprivation (Sinclair etal.. 1992). In the present experiment, both at anearly stage (Fig. 2) and with heavily exposed rats(Fig. 5), no difference in effects of buspirone wasseen between rats with a high and a low pre-treatment intake of ethanol.

In the second experiment, the effect of a singlebuspirone injection lasted for at least a week. Thisis far longer than would be expected from theelimination rate in rats, where buspirone has aplasma half-life of ~0.5 h (Per Hogberg, personalcommunication). The explanation for this couldbe that a single dose of buspirone causes lastingchanges in the serotonergic system, but otherexplanations cannot be excluded by the results ofthe present experiment.

Since buspirone has been shown to counteract

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BUSPIRONE AND ALCOHOL INTAKE 155

the anxiogenic effects of ethanol withdrawal inrats (Lai et at., 1991). and since buspirone alsoshows the best results in "anxious alcoholics" (Tol-lefson, 1991). the effects of buspirone on ethanolintake could be secondary to the anxiety oftencoupled with ethanol withdrawal. In experimentswith anxious alcoholics, the major clinical effecthas also been a reduction of anxiety, rather than aprimary decrease in ethanol intake. An importantdifference between a clinical trial and an animalmodel is that the clinical trial can produce a moreaccurate measure of anxiety in the patients, whilethe objective ethanol intake can be more easilymeasured in the animal model. If anxiety affectsethanol intake, it is difficult to discriminatebetween drugs that only affect anxiety, and drugsthat affect both anxiety and ethanol intake. How-ever, since there is a gradual development of theclinical anxiolytic effect of buspirone, the longduration of the effect seen in the second exper-iment could indicate that similar mechanisms areinvolved.

Several investigators have reported changes inthe serotonergic system following ethanolexposure. These changes could eventually lead toan explanation of how ethanol affects the sero-tonergic transmission. Alexi and Azmitia (1990)have reported that ethanol stimulates the pro-duction of 5-HT. An increase in the plasma levelsof the total amount of 5-HT degradation products(5-HIAA and 5-HTOL) has been reported byHelander et at. (1993) following acute ethanolexposure. A down-regulation of postsynapticreceptor function has been described by Simons-son and Ailing (1988) in platelets of alcoholics.Ballenger et at. (1979) have reported a decreasein 5-HT production following ethanol withdrawalin humans. Fawn-Hooded rats, which have adecreased 5-HT function, have both a high pref-erence for ethanol and show signs of depression(Rezvani el at., 1991; Overstreet et at., 1992).Drugs affecting the serotonergic system show lesseffect on ethanol intake in these rats.

If our results are combined with these obser-vations, it is evident that there is an interactionbetween the serotonergic system and voluntaryethanol intake. However, the present results indi-cate that it is not a simple relationship, and fur-thermore this relationship must be put in contextwith other transmitter systems that affect volun-tary ethanol intake.

Acknowledgements — This work was supported by the Systcm-bolagcts Fund for Alcohol Research and the Medical faculty.Umea University. We thank Bristol-Myers Squibb (throughPer Hogbcrg at the Swedish subsidiary) for the kind gift ofbuspirone and other support. The skilled technical assistanceby L Guslavsson. K. Wahlstrom and A. Olsson is gratefullyacknowledged.

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