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Antidepressant-Like Effects of Dopamine Agonists in an Animal Model of Depression Richard Muscat, Mariusz Papp, and Paul Willner
Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synapses. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, in. termittent administration of DA ugonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three tofour twice-weekly injections of quinpirole (100-200 ttglkg) or bromocriptine (2.3 mglkg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raciopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.
Introduction Chronic sequential exposure to mild unpredictable stress (chronic mild stress: CMS) has been found to depress the consumption of, and preference for, palatable sweet solutions (Wiilner et al 1987), and to decrease the rewarding properties of a variety of pharmacological and natural reinforcers in the place preference paradigm (Papp et al 1991, 1992a,b). CMS-induced behavioral deficits may be maintained for several months. However, normal behavior is restored, during continued application of CMS, by chronic treatment with tricyclic or atypical antidepressants (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Thi~ model has a number of features that make it a particularly attractive paradigm in which to study mechanisms of antidepressant action. 1. The behavior expressed in this model, subsensitivity to rewards, models the inability to experience pleasure (anhedonia), which is one of the central symptoms in depression (Fawcett et al 1983). In the majority of animal models the principal dependent
From Ihe Department of Psychology, City of London Polytechnic, London, England. Address reprint requests to Dr. Paul Willner, Dept. of Psychology, City of London Polytechnic, Old Castle St., London El 7NT, England. Received September 24, 1991; revised lY~'ember27, 1991. Present address (RM): Dept. of Biomedical Sciences, University of Malta, Msida, Malta. Present address (MP): Institute of Pharmacology, Polish Academy of Sciences Krakow, Poland. © 1992 Society of Biological Psychiatry
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variable is a change in locomotor behavior, which is a significant symptom of depression, but not a core symptom (see Willner 1991). The levels of stress needed to implement the model are ethically unproblematic, and represent a relatively realistic analogue of the stresses people encounter in their daily lives. The time course of antidepressant action closely resembles their clinical time course, and the effective daily dosage (5 mg/kg) is within the clinical range (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Antidepressants are without effect in control animals not subjected to CMS, again accurately reflecting the clinical picture (Wiliner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). There is clinical evidence supporting a relationship between anhedonia and levels of perceived stress (Willner ct al 1990).
Antidepressants are commonly thought to exert their therapeutic effects through actions at noradrenergic or serotonergic synapses (see Willner 1985). However, in addition to their effects on these "classical" systems, antidepressants also have a number of other actions. It is now well established that chronic antidepressant treatment causes an increase in behavioral responsiveness to dopamine (DA) agonists, administered either systemically or within the nucleus accumbens (see Willner 1989; Maj 1990). This appears to be the mechanism by which antidepressants exert their therapeutic actions in the CMS model, because these effects are reversed by acute administration of DA receptor antagonists, administered at low doses that are without effect in nonsttcssed animals or in untreated stressed animals (Muscat et al 1990, 1992; Sampson et al 1991). If antidepressants act, in this model, by increasing the responsiveness of DA synapses in the nucleus accumbens, it is possible that otbr'r treatments that increase responsiveness to DA agonists might also exert antidepressant-like effects. An obvious candid,,te is the intermittent administration of psychomotor stimulant drugs. Although continuous administration of DA agonists often results in tolerance, intermittent administration frequently leads to a progressive increase in their locomotor stimulant effect. Behavioral sensitization has been demonstrated both with indirectly acting DA agonists such as amphetamine, cocaine, and GBR 12909 (Robinson and Becker 1986; Kelley and Lang 1989; Post ¢t al 1991) and with directly acting agonists such as apomorphine, PHNO, and quinpirole (Martin-lverson et al 1988; Mattingley and Gotsick 1989; Willner et al 1991a). In this paper we present evidence that two D2/D3 agonists, quinpirole and bromocriptine (Sokoloff et ai 1990), administered intermittently, were effective in reversing the reduction of sucrose consumption in animals subjected to CMS. Quinpirole was used because other studies of sensitization to quinpirole were in progress in our laboratory at the time of these experiments (WiUner et al 1992), and bromocriptine was used because this compound is licensed for clinical use, and antidepressant efficacy has been reported (Theohar et al 1981; Waehrens and Gerlach 1981).
Method
Subjects Male Lister hooded rats, weighing approximately 250-300 g at the start of the experiment, were obtained from the National Institute for Medical Research (U.K.). Group sizes were n = 10 in experiment 1, n = 8 in experiment 2, and n = 11 in experiment 3. Except
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as described below, food and water were freely available and the animals were singly housed. All testing was carried out in the home cage, in order to obviate unnecessary stress and avoid any extraneous effects attributable to a novel environment. All procedures were approved by the U.K. Home Office under project license PPL 70/00985.
Procedure All animals were firsttrained to consume a palatable weak (1%) sucrose solution. Training consisted of an initial48-hr exposure to sucrose, in place of water, followed by a series of three-five l-hr sucrose consumption testscarried out following 20 hr of food and water deprivation. Sucrose consumption was measured by weighing preweighed bottles. Subsequently, sucrose consumption was monitored at weekly intervals throughout the experiment, using the same procedure. Sucrose consumption tests took place on Tuesdays at 2 PM. Additional sucrose tests were sometimes scheduled on i:ridays, as described below. Half of the animals were then subjected to chronic unpredictable mild su~ss for a total of 12, 9, and 7 weeks, in experiments 1, 2, and 3, respectively. The stress regime, which was similar to that used previously (Willner et al 198"/; Muscat et al 1987, ! 990; Sampson et al 1991), deployed a variety of wild stressors, each for a period of between 30 rain and 20 hr. All of the individual stressors used were classified as being, at worst, mildly stressful, under the terms of the relevant (U.K.) legislation, the Animals (Scientific Procedures) Act of 1986. The stress regime consisted of: two 20-hr periods of food and water deprivation, one immediately prior to the sucrose-intake test, the other followed by 2 hr of restricted access to food (scattering of a few 45 mg precision pellets in the cage); one additional 16-hr period of water deprivation, followed by 1 hr exposure to an empty bottle; two periods of continuous overnight illumination; two periods (7 and 17 hr) of 45° cage tilt; one 17-hr period of grouped housing; one 17-hr period in a soiled cage (100 ml water in sawdust bedding); two periods (3 and 5 hr) of intermittent white noise (85 dB); three periods (7,9, and 17 hr) of low-intensity stroboscopic illumination (300 flashes/rain). The stress regime was administered according to a timetable similar to that described by Willner et al 1987). In experiment 1, drug treatment commenced after 4 weeks of stress. On the b~si~ of their week 4 sucrose consumption scores, stressed animals and controls (n = 33) were each divided into three matched groups (n - 11), to be treated with quinpirole (100 or 200 Izg/kg), or vehicle, respectively. A total of 5 quinpirole or vehicle injections were given, on the Wednesday and Saturday of week 5, the Wednesday of weeks 6 and 7, and the Wednesday of week 11. Throughout this period (i. e., from week 4 onward), sucrose tests were conducted twice weekly (Tuesdays and Fridays). In experiment 2, drag treatment commenced after 3 weeks of stress; sucrose consumption was monitored weekly. On the basis of their week 4 sucrose-consumption scores, stressed animals and controls (n =- 32) were c~ch divided into four matched groups (n = 8), to be treated with quinpirole (200 ~g/kg), bromocriptine (1.25 or 2.5 mg/kg), or vehicle, respectively. Four injections were given, on the Wednesday and Saturday of weeks 4 and 5. Subsequently, the bromocriptine groups received two further injections, on the Wednesday and Saturday of week 7. In experiment 2, stressed and control animals (n -- 20) were each divided into two matched groups (n -= 10), which received four injections of quinpirole (200 pLg/kg) or vehicle during weeks 2 and 3 of stress, with a further injection on {he Thursday of week
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5. During weeks 6 and 7, additional sucrose consumption tests were run on Fridays. The sucrose test on the Tuesday of week 7 was preceded, in all animals by a single injection of raclopride (100 p,g/kg).
Drugs Quinpirole hydrochloride (Lilly) and raclopride tartrate (Astra) were dissolved in distilled water, which was used for vehicle injections; bromoeriptine mesylate (Sigma) was dissolved in one drop of glacial acetic acid and made up to volume in distilled water. All injections were in a volume of I ml/kg body weight, and with the exception of raclopride, were administered at 5 I,M. Quinpirole was injected SC; bromocriptine was injected IP; vehicle injections were SC in experiments 1 and 3, and IP in experiment 2. Raclopride was injected IP 15-min prior to the sucrose test.
Analysis Results were analyzed by analysis of variance, supplemented by tests of simple main effects and F-tests for contrasts using the appropriate analysis of variance error term (Winer 1971). In all analyses, stress and drug treatment were between-subjects factors, and tests was a within-subjects factor. The effects of raclopride were analyzed by comparing sucrose consumption following racloprid¢ with the mean consumption in the two immediately preceding and the two immediately following tests.
Results
Experiment ! Prior to the onset of the chronic-stress procedure, sucrose intakes were comparable in control and to-be-stressed animals (Figure I). During the first weeks of stress exposure, sucrose intakes increased in control animals but decreased in stressed animals, such that by week 4, there was a significant difference between the two groups [F(I,60) = 94.6, p < 0.001]. With some fluctuations, this difference was maintained in vehicle-treated animals to the end of the experiment [p < 0.01 on all tests, except for the first test of week 9, for which 0.05 < p < 0. ! ]. Intermittent administration of quinpirole had no effect in control animals. However, in stressed animals there was a significant drug × tests interaction [F(32,960) = 1.72, p < 0.025], indicating that quinpirole increased sucrose intake at certain time points. Further analysis showed that the third injection of either dose of quinpirole led to a recovery of sucrose drinking in stressed animals on the following test [F(2,60) = 4.0, p < 0.025], followed by a relapse. A fourth injection at the start of week 7 led to a gradual, dose-dependent recovery that peaked 16 days later: stressed animals receiving the higher dose of quinpirole drank significantly more sucrose on each of the next 5 tests [p < 0.01; p < 0.025; p < 0.01; p < 0.05; p < 0.01]. This effect took a further 10 days to dissipate. A fifth injection at the start of week 11 was followed by a further dosedependent recover~, peaking i0 days later. At this point the experiment was terminated, owing to instability in the control baseline.
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n
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.~
OUIN-O.1
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15
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Figure 1. Sucrose intake (g) in l-hr twice-weekly tests in controls (open symbols) and stressed animals (closedsymbols). Animals received a total of 5 injections of quinpimle, each administered on the day following a sucrose test, at the times indicated by am0ws. Values are means; the values shown at week 0 are the results of the final baseline test prior to the onset of stress. Standard errors have been omitted, for clarity; the mean standard error, for all points after week 0, was 0.87 (range = 0.57-1.22). Stars represent significant differences, within the stressed group, between vehicle and 200 I~g/kgquinpirole (QUIN-0.2); hatch marks represent significantdifferences between vehicle and 100 p,g/kg qainpimle (QUIN-0.1): one symbol, p < 0.05; two symbols, p < 0.01.
Experiment 2 As in experiment 1, sucrose intakes in experiment 2 were comparable in control and tobe-stressed animals prior to the onset of the chronic stress procedure (Figure 2), but following 3 weeks of stress, there was a significant difference between the two groups [F(1,36) = 76.4, p < 0.001], which, with some fluctuations, wa: maintained, in vehicletreated animals, to the end of the experiment (p < 0.001, except for: week 5, 0.05 < p < 0.1; week 9, p < 0.025). Neither quinpirole nor bromocriptine significantly altered sucrose intake in control animals. (The apparent elevation of intake in week 6 in the quinpirole-treated control group was nonsignificant [simple main effect: F(1,56) = 2.0, NS)]. In stressed animals, the lower dose of bromocriptine (1.23 rr.~kg) was ineffective in increasing sucrose intake. However, quinpirole (200 Izg/kg) ~,nd the higher dose of bromocriptine (2.5 mg/kg), although having no effect after two inj~ctior~ (~,veek4), led to a complete recovery after two further injections (week 5) [F(1,56) ffi 5.8, p < 0.025; F(1,56) -- 7.6, p < 0.01, respectively]. Subsequently, sucrose consumption in the quinpirole-treated stressed animals was somewhat lower than in controls, but remained elevated, relative to vehicle-
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O
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Figure 2. Sucrose int~c (g) in I-hr weekly tests in controls (open symbols) and stressed animals (closedsymbols). During weeks 4 and 5, animals received 4 injections (arrows)of quinpirole (200 p.g/kg: QUIN-0.2) or bromocriptine (I.25 mglkg: BROM-I.25 or 2 5 mglkg: BROM-2.5); the bromocriptine groups received a further two injections during week 7 (brokenarrows). Values are means; the values shown at week 0 are the results of the final baseline test prior to the onset of stress. Standard errors have been omitted, for clarity; the mean standard error, for all points after week 0, was 0.53 (range, 0.15-1.02). Stars represent significant differences, within the stressed group, between vehicle and quinpirole; hatch marks represent significant differences between vehicle and the higher dose of bromoctiptine: one symbol, p < 0.05; two symbols, p < 0.01.
treated stressed animals, for a further 3 weeks [p < 0.025;p < 0.01 ;p < 0.05]. Following their recovery, the bromocriptine (2.5 mg/kg) group immediately relapsed (week 6), but two further injections in week 7 again increased sucrose intake, for 2 weeks, relative to vehicle-treated stressed animals [p < 0.01; p < 0.05].
Experiment 3 In experiment 3, a course of intermittent administrations of quinpirole (200 p.g/kg) again caused a recovery of sucrose drinking in stressed animals (Figure 3), without altering intake in nonstressed animals [stress × quinpirole interaction on vehicle-pretrcatment days: F(l,36) = 10.4, p < 0.01]. There was also a significant three-way interaction [sffess >~ quinpirole × raciopride: F(1,36) = 20.2,p < 0.001]: raclopride had no effect on sucrose intake in eiLher group of nonstressed animals or in the vehicle-treated stressed group, but signi~icaaitly deceased sucrose intake in the quinpirole-trcated stressed animals
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15-
TN
10-;
S-
i
VEH
QUIN CONTROL
i
VEIl
QUIN STRESS
Figure 3. Effects of raclopride on sucrose intake: values are means + standar~ error. Raclopride (hatched bars) was administered to all animals following 7 weeks of stress; conlrol data (white bars) arc ~hcmean of intake in the two precedingand two followingsucrose test~. Different groups of stresses or control animals had previously received a total of 5 injections of 'vehicle(VEH) or 200 ttg/kg quinpirole (QUIIq). Raclopride selectively decreased intake in the (luinpirole-treated stressed group: ***p < 0.001.
[F(1,36) = 83.7, p < ~.001]. These animals showed a complete recovery of sucrose drinking on subsequent d~ug-free tests (Figure 3).
Discussion These experiments have demonstrated that intermittent administration of directly acting DA agonists has antidepressant-like effects in the CMS model. Both quinpirole and bromocriptine dose-dependently reversed the decrease in sucrose intake in animals subjected to CMS. The effects were long lasting and appeared to grow with time for up to 3 weeks following the final injection Although a minimum of three injections was necessary before recovery commenced, a single booster injection of quinpirole appeared sufficient to reinstate sucrose drinking in treated animals, when peffc,,~ance eventually deteriorated. The spacing of injections may be critical: we previously did not observe recovery from CMS when animals received quinpirole injections at weekly intervals (M Papp et al unpublished data 1992). The effect of injections more frequent than twice weekly has not yet been examined. The effects of quinpirole and bromocriptine were specific to stressed ar,~¢~als: no increases in sucrose intake were observed in nonstressed controls. This difference is unlikely simply to represent a greater sensitivity in the stressed animals (for pharmacokinetic or other reasons), as stressed animals are actually subsensitive to quinpirole (Papp et al 1992b). The effects of intermittent administration of quinpirole and bromocriptine are strikingly similar to those of daily administration of tricyclic antidepressants. In both cases, recovery from CMS is slow (2-4 weeks), and sucrose intake does not increase in nonstressed
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animals (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Furthermore, in both cases, the recovery of performance in successfully treated animals was reversed by raclopride, a selective antagonist at D2 and D3 receptors (De Paulis et al 1986; Sokoloff et al 1990). The effect of tdcyclic and atypical antidepressants was also reversed by other DA receptor antagonists (Muscat et al 1990, 1992; Sampson et al 1991), and we have recently replicated the effect of raclopride in quinpirole-treated animals (Papp et al 1992b). These results suggest that both tricyclic and atypical antidepressants, administered chronicallyon a daily basis, and D2/D3 agonists, administered twice weekly, may increase sucrose intake in the CMS model by increasing the sensitivity of D2 or D3 receptors. The site of action is likely to be within the nucleus accumbens, as the DA innervation of this area is known to be crucially involved in responsiveness to rewards (Liehman and Cooper 1989; Willner and Scheel-Kruger 1991), and abnormalities of DA transmission specific to this region have been identified in chronically stressed animals (Willner et al 1991a; Stamford et al 1991). In addition to decreasing sucrose intake, CMS has also been shown to decrease the rewarding properties of a variety of pharmacological and natural reinforcers in the placepreference paradigm (Papp et al 1991, 1992a,b). On this basis, the CMS procedure has been proposed as an animal model of anhedonia (Willner et al 1991b), the decreased ability to respond to pleasuce (Fawcett et al 1983). Although anhedonia is a prominent feature of both depression and schizophrenia (Willner 1992), its reversal by antidepressant drugs suggests that the CMS model has greater relevance to depression. However, it is not proposed that this model captures the depressive syndrome in its entirety. Indeed, in certain other behavioral models, the therapeutic actions of imipramine are reverse0 by metergoline, a serotoain receptor antagonist, which is without effect on the antianhedonie action of imipramine in the CMS model (Muscat et al 1990; Willner et al 1989). Although anhedonia appears to have a dopaminergic substrate, other symptoms of depression ate likely to reflect different neurobiologicai substrates (Willner 1991). The present results suggest that intermittent administration of DA agonists may merit clinical investigation as a novel strategy for the treatment of depression, particularly in anhedonic patients. The literature already contains several reports of antidepressant effects using bromocriptine or another directly acting DA agonist, piribedil (reviewed by Wiilner 1983; Jimerson 1987). These were largely open studies, but two controlled trials found no difference in antidepressant efficacy between bromocriptine and imiprami~:e(Waehrens and Gerlach 1981; Theohar et al 198 !). Striking and rapid therapeutic effects of piribedfl have been described in previously nonresponsive patients whose sleep electroencephalograms (EEG) showed signs characteristic for Parkinson's disease; in patients not showing these signs, piribedil was ineffective (Mouret et ai 1987, 1988). It is also notable that DA uptake inhibition is a prominent feature of a number of newer antidepressants, including nomifensine, buproprion, and amineptine. Trials of DA agonists in depression are not currently fashionable, largely because DA agonists are perceived to carry a significant potential for abuse (of. Bozarth 1987; Adler and Cowan 1990). The present results suggest that with appropriate schedu!ing, very few administrations of a DA agonist may be needed to achieve antidepressant effects equivalent to those obtained with several weeks of daily tricyclic treatment. This study was supported in part by the Medical Research Council of Great Britain. We are grateful to Marc Lind for technical support and to Lilly and Astra for generous gifts of drugs.
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References Adler MW, Cowan A (eds) (1990): Testing and Evaluation of Drugs of Abuse. New York: Wiley. Bozarth MA (ed) (1987): Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer. De Paulis T, Kumar Y, Johansson L, et al (1986): Potential neuroleptic agents. 4. Chemistry, behavioural pharmacology and blocking of 3H-spipemne binding of 3,5-disubstituted N-[(Iethyl-2-pyrrolidinyl)methyi]-6-methoxy-salicyclarnide.J Med Chem 29:61-69. Fawcett J, Clark DC, Schefiner WA, Gibbons RD (1983): Assessing anbedonia in psychiatric patients: The pleasure scale. Arch Gen Psychiatry 40:79-84. Jimerson DC (1987): Role of dopamine mechanisms in affective disorders. In Meltzer HY (ed), Psychopharmacology : The Third Generation of Progress. New York: Raven, pp 515-51 I. Kelley AE, Lang CG (1989): Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat. Eur J Pharmacol 167:385-395. Liebman JM, Cooper SJ (eds), (I 989): The NeuropharmacologicaiBasis of Reward. Oxford: Oxford University Press. Maj J (1990): Behavioral effects of antidepressant drags given repeatedly on the dopaminergic system. In Gessa GL, Serra G (eds), Dopamine and Mental Depression. Oxford: Pergamon, pp 139-146. Martin-lverson MT, Stahl SM, Ivers~t~SD (1988): Chronic administrationof a selective dopamine D-2 agonist: factors determining behavioural tolerance and sensitisation. Psychopharmacology 95:534--539. Ma~dngleyBA, Gotsick JE (1989): Conditioningand experiential factors affecting the development of sensitization to apomorphine. Behav Neurosci 103:1311-1317. Mouret J, LeMoine P, Minuit M (1987): Marqueurs polygraphiques, cliniques et therapeutiques des depressions dopamino.dependantes (DDD). Comptes Rendus Acad Sci Paris 305: (S,~,ie IID 301-306. Mouret J, LeMoine P, Minuit M, Robelin N (1988): La L-tymsineguerit, immediatement eta ]ottg terme, les depressions dopamino-dependantes(DDD). Etude clinique et polygraphique. Comptes Rendus Acad Sci Paris 306: (Serie IH) 93-98. Muscat R, Towell A, Willner P (1987): Changes in dopamine autoreceptor sensitivity in an animal model of depression. Psychopharmacology 94:545-550. Muscat R~ Sampson D, Willner P (1990): Dopaminergic mechanism of imipramine action in an animal model of depressioI~. Biol Psychiatry 28:223-229. Muscat R, Papp M, Willner P (1992): Reversal of stress-induced anhedonia by the atypical antidepressa|:ts fluoxetine and maprotiline. Psychopharmacology (in press). Papp M, Willner P, Muscat R (1991): An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psycho. pharmacology 104:255-259. Papp M, Lappas S, Muscat R, Willner P (1992a): Attenuation of place preference conditioning but not place aversion conditioning by chronic mild stress. J Psychopharmacol (in press). Papp M, Muscat R, Willner P (1992b): Behavioral sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia. Psychopharmacology (in press). Post RM, Weiss SRB, Pert A (~991): Animal models of mania. In Willner P, Scheel-Kmger J (eds), The Mesolimbic Dopamine System: From Motivation to Action. Chichester: Wiley, pp 273-299. Robinson TE, Becket JB (1986): Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis. Brain Res Rev ! 1:157-198. Sampson D, Muscat R, Willner P (I 991): Reversal of antidepressant action by dopamine antagonists in an animal model of depression. Psychoplmrmacology 104:491-495.
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Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990): Molecular cloning and characterization of a novel dopaniine receptor (D3) as a target for neurolepfics. Nature 347:146151. Stamford JA, Muscat R, O'Connor J J, et al (1991): Voltammetric evidence that subsensitivity to reward following chronic mild stress is associated with increased release of mesolimbic dopemine. Psychopharmacology 105:275-282. Theohar C, Fischer-Comellson K, Akesson HO, et al (1981): Bromocriptine as antidepressant: double-blind comparative study with imipramine in psychogenic and endogenous depression. Curt Ther Res 30:830-842. Waehrens J, Gerlach J (1981): Bromocriptine and imipramine in endogenous depression: A doubleblind controlled trial in out-patients. J Affective Disord 3:193-202. Willner P (1983): Dopamine and depression: A review of recent evidence. Brain Res Rev 6:211246. Wiliner P (1985): Depression: A Psychobiological Synthesis. New York: Wiley. Willner P (1989): Sensitization to the actions of antidepressant drags. In Emmett-Oglesby MV, Goudie AJ (eds), Psychoactive Drugs: Tolerance and Sensitization. Clifton, NJ: Humana Press, pp 407-,159. Willner P (1991): Animal models as simulations of depression. Trends Pharmacol $ci 12:131136. Willner P (1992): Anhedonia. In Costello CC (ed), Symptoms of Depression. New York: Wiley, in press. Willner P, Scheel-Kruger J (eds) (1991): The Mesolimbic Dopamine System: From Motivation to Action. Chichester: Wiley. Wiliner P, Toweli A, Sampson D, Muscat R, Sophokleous S (I 987): Reduction of sucrose preference by chronic mild stress and its restoration by a tricyclic antidep~ssant. Psychopharmacology 93:358-364. Willner P, Sampson D, Phillips G, Fichera R, Foxlow P, Muscat R (1989): Effects of isolated housing and chronic antidepressant treatment on cooperative social behaviour in rats. B,?hav Ph~trmacol 1:85-90. Willncr P, Wilkes M, Orwin A (1990): Attributionai style and perceived stress in endogenous and reactive depression. J Affective Disord 18:281-287, Wilincr P, Klimek V, Golembiowska K, Muscat R (1991a): Changes in mesolimbic dopamine may explain stress-induced anhedonia. Psychobiology 19:79--84. WiUner P, Sampson D, Papp M, Phillips G, Muscat R (1991b): Animal models of anhedonia. :In Soubrie P (eds), Animal Models of Psychiatric Disorders, Vol. 3. Basel: Karger, pp 71-99. Willner P, Papp M, Cheeta S, Muscat R ([992): Environmental influences on behavioural sensitization to the dopamine agonist quinpirole. Behav Pharmacol 3:43-50. Winer BJ (1971): Statistical Principles in Experimental Design. London: McGraw Hill.
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Antidepressant-Like Effects of Dopamine Agonists in an Animal Model of Depression Richard Muscat, Mariusz Papp, and Paul Willner
Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synapses. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, in. termittent administration of DA ugonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three tofour twice-weekly injections of quinpirole (100-200 ttglkg) or bromocriptine (2.3 mglkg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raciopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.
Introduction Chronic sequential exposure to mild unpredictable stress (chronic mild stress: CMS) has been found to depress the consumption of, and preference for, palatable sweet solutions (Wiilner et al 1987), and to decrease the rewarding properties of a variety of pharmacological and natural reinforcers in the place preference paradigm (Papp et al 1991, 1992a,b). CMS-induced behavioral deficits may be maintained for several months. However, normal behavior is restored, during continued application of CMS, by chronic treatment with tricyclic or atypical antidepressants (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Thi~ model has a number of features that make it a particularly attractive paradigm in which to study mechanisms of antidepressant action. 1. The behavior expressed in this model, subsensitivity to rewards, models the inability to experience pleasure (anhedonia), which is one of the central symptoms in depression (Fawcett et al 1983). In the majority of animal models the principal dependent
From Ihe Department of Psychology, City of London Polytechnic, London, England. Address reprint requests to Dr. Paul Willner, Dept. of Psychology, City of London Polytechnic, Old Castle St., London El 7NT, England. Received September 24, 1991; revised lY~'ember27, 1991. Present address (RM): Dept. of Biomedical Sciences, University of Malta, Msida, Malta. Present address (MP): Institute of Pharmacology, Polish Academy of Sciences Krakow, Poland. © 1992 Society of Biological Psychiatry
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2.
3.
4.
5.
variable is a change in locomotor behavior, which is a significant symptom of depression, but not a core symptom (see Willner 1991). The levels of stress needed to implement the model are ethically unproblematic, and represent a relatively realistic analogue of the stresses people encounter in their daily lives. The time course of antidepressant action closely resembles their clinical time course, and the effective daily dosage (5 mg/kg) is within the clinical range (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Antidepressants are without effect in control animals not subjected to CMS, again accurately reflecting the clinical picture (Wiliner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). There is clinical evidence supporting a relationship between anhedonia and levels of perceived stress (Willner ct al 1990).
Antidepressants are commonly thought to exert their therapeutic effects through actions at noradrenergic or serotonergic synapses (see Willner 1985). However, in addition to their effects on these "classical" systems, antidepressants also have a number of other actions. It is now well established that chronic antidepressant treatment causes an increase in behavioral responsiveness to dopamine (DA) agonists, administered either systemically or within the nucleus accumbens (see Willner 1989; Maj 1990). This appears to be the mechanism by which antidepressants exert their therapeutic actions in the CMS model, because these effects are reversed by acute administration of DA receptor antagonists, administered at low doses that are without effect in nonsttcssed animals or in untreated stressed animals (Muscat et al 1990, 1992; Sampson et al 1991). If antidepressants act, in this model, by increasing the responsiveness of DA synapses in the nucleus accumbens, it is possible that otbr'r treatments that increase responsiveness to DA agonists might also exert antidepressant-like effects. An obvious candid,,te is the intermittent administration of psychomotor stimulant drugs. Although continuous administration of DA agonists often results in tolerance, intermittent administration frequently leads to a progressive increase in their locomotor stimulant effect. Behavioral sensitization has been demonstrated both with indirectly acting DA agonists such as amphetamine, cocaine, and GBR 12909 (Robinson and Becker 1986; Kelley and Lang 1989; Post ¢t al 1991) and with directly acting agonists such as apomorphine, PHNO, and quinpirole (Martin-lverson et al 1988; Mattingley and Gotsick 1989; Willner et al 1991a). In this paper we present evidence that two D2/D3 agonists, quinpirole and bromocriptine (Sokoloff et ai 1990), administered intermittently, were effective in reversing the reduction of sucrose consumption in animals subjected to CMS. Quinpirole was used because other studies of sensitization to quinpirole were in progress in our laboratory at the time of these experiments (WiUner et al 1992), and bromocriptine was used because this compound is licensed for clinical use, and antidepressant efficacy has been reported (Theohar et al 1981; Waehrens and Gerlach 1981).
Method
Subjects Male Lister hooded rats, weighing approximately 250-300 g at the start of the experiment, were obtained from the National Institute for Medical Research (U.K.). Group sizes were n = 10 in experiment 1, n = 8 in experiment 2, and n = 11 in experiment 3. Except
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as described below, food and water were freely available and the animals were singly housed. All testing was carried out in the home cage, in order to obviate unnecessary stress and avoid any extraneous effects attributable to a novel environment. All procedures were approved by the U.K. Home Office under project license PPL 70/00985.
Procedure All animals were firsttrained to consume a palatable weak (1%) sucrose solution. Training consisted of an initial48-hr exposure to sucrose, in place of water, followed by a series of three-five l-hr sucrose consumption testscarried out following 20 hr of food and water deprivation. Sucrose consumption was measured by weighing preweighed bottles. Subsequently, sucrose consumption was monitored at weekly intervals throughout the experiment, using the same procedure. Sucrose consumption tests took place on Tuesdays at 2 PM. Additional sucrose tests were sometimes scheduled on i:ridays, as described below. Half of the animals were then subjected to chronic unpredictable mild su~ss for a total of 12, 9, and 7 weeks, in experiments 1, 2, and 3, respectively. The stress regime, which was similar to that used previously (Willner et al 198"/; Muscat et al 1987, ! 990; Sampson et al 1991), deployed a variety of wild stressors, each for a period of between 30 rain and 20 hr. All of the individual stressors used were classified as being, at worst, mildly stressful, under the terms of the relevant (U.K.) legislation, the Animals (Scientific Procedures) Act of 1986. The stress regime consisted of: two 20-hr periods of food and water deprivation, one immediately prior to the sucrose-intake test, the other followed by 2 hr of restricted access to food (scattering of a few 45 mg precision pellets in the cage); one additional 16-hr period of water deprivation, followed by 1 hr exposure to an empty bottle; two periods of continuous overnight illumination; two periods (7 and 17 hr) of 45° cage tilt; one 17-hr period of grouped housing; one 17-hr period in a soiled cage (100 ml water in sawdust bedding); two periods (3 and 5 hr) of intermittent white noise (85 dB); three periods (7,9, and 17 hr) of low-intensity stroboscopic illumination (300 flashes/rain). The stress regime was administered according to a timetable similar to that described by Willner et al 1987). In experiment 1, drug treatment commenced after 4 weeks of stress. On the b~si~ of their week 4 sucrose consumption scores, stressed animals and controls (n = 33) were each divided into three matched groups (n - 11), to be treated with quinpirole (100 or 200 Izg/kg), or vehicle, respectively. A total of 5 quinpirole or vehicle injections were given, on the Wednesday and Saturday of week 5, the Wednesday of weeks 6 and 7, and the Wednesday of week 11. Throughout this period (i. e., from week 4 onward), sucrose tests were conducted twice weekly (Tuesdays and Fridays). In experiment 2, drag treatment commenced after 3 weeks of stress; sucrose consumption was monitored weekly. On the basis of their week 4 sucrose-consumption scores, stressed animals and controls (n =- 32) were c~ch divided into four matched groups (n = 8), to be treated with quinpirole (200 ~g/kg), bromocriptine (1.25 or 2.5 mg/kg), or vehicle, respectively. Four injections were given, on the Wednesday and Saturday of weeks 4 and 5. Subsequently, the bromocriptine groups received two further injections, on the Wednesday and Saturday of week 7. In experiment 2, stressed and control animals (n -- 20) were each divided into two matched groups (n -= 10), which received four injections of quinpirole (200 pLg/kg) or vehicle during weeks 2 and 3 of stress, with a further injection on {he Thursday of week
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5. During weeks 6 and 7, additional sucrose consumption tests were run on Fridays. The sucrose test on the Tuesday of week 7 was preceded, in all animals by a single injection of raclopride (100 p,g/kg).
Drugs Quinpirole hydrochloride (Lilly) and raclopride tartrate (Astra) were dissolved in distilled water, which was used for vehicle injections; bromoeriptine mesylate (Sigma) was dissolved in one drop of glacial acetic acid and made up to volume in distilled water. All injections were in a volume of I ml/kg body weight, and with the exception of raclopride, were administered at 5 I,M. Quinpirole was injected SC; bromocriptine was injected IP; vehicle injections were SC in experiments 1 and 3, and IP in experiment 2. Raclopride was injected IP 15-min prior to the sucrose test.
Analysis Results were analyzed by analysis of variance, supplemented by tests of simple main effects and F-tests for contrasts using the appropriate analysis of variance error term (Winer 1971). In all analyses, stress and drug treatment were between-subjects factors, and tests was a within-subjects factor. The effects of raclopride were analyzed by comparing sucrose consumption following racloprid¢ with the mean consumption in the two immediately preceding and the two immediately following tests.
Results
Experiment ! Prior to the onset of the chronic-stress procedure, sucrose intakes were comparable in control and to-be-stressed animals (Figure I). During the first weeks of stress exposure, sucrose intakes increased in control animals but decreased in stressed animals, such that by week 4, there was a significant difference between the two groups [F(I,60) = 94.6, p < 0.001]. With some fluctuations, this difference was maintained in vehicle-treated animals to the end of the experiment [p < 0.01 on all tests, except for the first test of week 9, for which 0.05 < p < 0. ! ]. Intermittent administration of quinpirole had no effect in control animals. However, in stressed animals there was a significant drug × tests interaction [F(32,960) = 1.72, p < 0.025], indicating that quinpirole increased sucrose intake at certain time points. Further analysis showed that the third injection of either dose of quinpirole led to a recovery of sucrose drinking in stressed animals on the following test [F(2,60) = 4.0, p < 0.025], followed by a relapse. A fourth injection at the start of week 7 led to a gradual, dose-dependent recovery that peaked 16 days later: stressed animals receiving the higher dose of quinpirole drank significantly more sucrose on each of the next 5 tests [p < 0.01; p < 0.025; p < 0.01; p < 0.05; p < 0.01]. This effect took a further 10 days to dissipate. A fifth injection at the start of week 11 was followed by a further dosedependent recover~, peaking i0 days later. At this point the experiment was terminated, owing to instability in the control baseline.
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CONTROL
n
941
STRESS
.~
OUIN-O.1
,,
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~
m
15
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0
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fff 0
4
f 5
6
f 7
8
9
10
11
12
WEEKS
Figure 1. Sucrose intake (g) in l-hr twice-weekly tests in controls (open symbols) and stressed animals (closedsymbols). Animals received a total of 5 injections of quinpimle, each administered on the day following a sucrose test, at the times indicated by am0ws. Values are means; the values shown at week 0 are the results of the final baseline test prior to the onset of stress. Standard errors have been omitted, for clarity; the mean standard error, for all points after week 0, was 0.87 (range = 0.57-1.22). Stars represent significant differences, within the stressed group, between vehicle and 200 I~g/kgquinpirole (QUIN-0.2); hatch marks represent significantdifferences between vehicle and 100 p,g/kg qainpimle (QUIN-0.1): one symbol, p < 0.05; two symbols, p < 0.01.
Experiment 2 As in experiment 1, sucrose intakes in experiment 2 were comparable in control and tobe-stressed animals prior to the onset of the chronic stress procedure (Figure 2), but following 3 weeks of stress, there was a significant difference between the two groups [F(1,36) = 76.4, p < 0.001], which, with some fluctuations, wa: maintained, in vehicletreated animals, to the end of the experiment (p < 0.001, except for: week 5, 0.05 < p < 0.1; week 9, p < 0.025). Neither quinpirole nor bromocriptine significantly altered sucrose intake in control animals. (The apparent elevation of intake in week 6 in the quinpirole-treated control group was nonsignificant [simple main effect: F(1,56) = 2.0, NS)]. In stressed animals, the lower dose of bromocriptine (1.23 rr.~kg) was ineffective in increasing sucrose intake. However, quinpirole (200 Izg/kg) ~,nd the higher dose of bromocriptine (2.5 mg/kg), although having no effect after two inj~ctior~ (~,veek4), led to a complete recovery after two further injections (week 5) [F(1,56) ffi 5.8, p < 0.025; F(1,56) -- 7.6, p < 0.01, respectively]. Subsequently, sucrose consumption in the quinpirole-treated stressed animals was somewhat lower than in controls, but remained elevated, relative to vehicle-
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CONTROL O
O
A C
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STRESS VEHICLE QUIN-0.2
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Figure 2. Sucrose int~c (g) in I-hr weekly tests in controls (open symbols) and stressed animals (closedsymbols). During weeks 4 and 5, animals received 4 injections (arrows)of quinpirole (200 p.g/kg: QUIN-0.2) or bromocriptine (I.25 mglkg: BROM-I.25 or 2 5 mglkg: BROM-2.5); the bromocriptine groups received a further two injections during week 7 (brokenarrows). Values are means; the values shown at week 0 are the results of the final baseline test prior to the onset of stress. Standard errors have been omitted, for clarity; the mean standard error, for all points after week 0, was 0.53 (range, 0.15-1.02). Stars represent significant differences, within the stressed group, between vehicle and quinpirole; hatch marks represent significant differences between vehicle and the higher dose of bromoctiptine: one symbol, p < 0.05; two symbols, p < 0.01.
treated stressed animals, for a further 3 weeks [p < 0.025;p < 0.01 ;p < 0.05]. Following their recovery, the bromocriptine (2.5 mg/kg) group immediately relapsed (week 6), but two further injections in week 7 again increased sucrose intake, for 2 weeks, relative to vehicle-treated stressed animals [p < 0.01; p < 0.05].
Experiment 3 In experiment 3, a course of intermittent administrations of quinpirole (200 p.g/kg) again caused a recovery of sucrose drinking in stressed animals (Figure 3), without altering intake in nonstressed animals [stress × quinpirole interaction on vehicle-pretrcatment days: F(l,36) = 10.4, p < 0.01]. There was also a significant three-way interaction [sffess >~ quinpirole × raciopride: F(1,36) = 20.2,p < 0.001]: raclopride had no effect on sucrose intake in eiLher group of nonstressed animals or in the vehicle-treated stressed group, but signi~icaaitly deceased sucrose intake in the quinpirole-trcated stressed animals
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15-
TN
10-;
S-
i
VEH
QUIN CONTROL
i
VEIl
QUIN STRESS
Figure 3. Effects of raclopride on sucrose intake: values are means + standar~ error. Raclopride (hatched bars) was administered to all animals following 7 weeks of stress; conlrol data (white bars) arc ~hcmean of intake in the two precedingand two followingsucrose test~. Different groups of stresses or control animals had previously received a total of 5 injections of 'vehicle(VEH) or 200 ttg/kg quinpirole (QUIIq). Raclopride selectively decreased intake in the (luinpirole-treated stressed group: ***p < 0.001.
[F(1,36) = 83.7, p < ~.001]. These animals showed a complete recovery of sucrose drinking on subsequent d~ug-free tests (Figure 3).
Discussion These experiments have demonstrated that intermittent administration of directly acting DA agonists has antidepressant-like effects in the CMS model. Both quinpirole and bromocriptine dose-dependently reversed the decrease in sucrose intake in animals subjected to CMS. The effects were long lasting and appeared to grow with time for up to 3 weeks following the final injection Although a minimum of three injections was necessary before recovery commenced, a single booster injection of quinpirole appeared sufficient to reinstate sucrose drinking in treated animals, when peffc,,~ance eventually deteriorated. The spacing of injections may be critical: we previously did not observe recovery from CMS when animals received quinpirole injections at weekly intervals (M Papp et al unpublished data 1992). The effect of injections more frequent than twice weekly has not yet been examined. The effects of quinpirole and bromocriptine were specific to stressed ar,~¢~als: no increases in sucrose intake were observed in nonstressed controls. This difference is unlikely simply to represent a greater sensitivity in the stressed animals (for pharmacokinetic or other reasons), as stressed animals are actually subsensitive to quinpirole (Papp et al 1992b). The effects of intermittent administration of quinpirole and bromocriptine are strikingly similar to those of daily administration of tricyclic antidepressants. In both cases, recovery from CMS is slow (2-4 weeks), and sucrose intake does not increase in nonstressed
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animals (Willner et al 1987; Muscat et al 1987, 1990, 1992; Sampson et al 1991). Furthermore, in both cases, the recovery of performance in successfully treated animals was reversed by raclopride, a selective antagonist at D2 and D3 receptors (De Paulis et al 1986; Sokoloff et al 1990). The effect of tdcyclic and atypical antidepressants was also reversed by other DA receptor antagonists (Muscat et al 1990, 1992; Sampson et al 1991), and we have recently replicated the effect of raclopride in quinpirole-treated animals (Papp et al 1992b). These results suggest that both tricyclic and atypical antidepressants, administered chronicallyon a daily basis, and D2/D3 agonists, administered twice weekly, may increase sucrose intake in the CMS model by increasing the sensitivity of D2 or D3 receptors. The site of action is likely to be within the nucleus accumbens, as the DA innervation of this area is known to be crucially involved in responsiveness to rewards (Liehman and Cooper 1989; Willner and Scheel-Kruger 1991), and abnormalities of DA transmission specific to this region have been identified in chronically stressed animals (Willner et al 1991a; Stamford et al 1991). In addition to decreasing sucrose intake, CMS has also been shown to decrease the rewarding properties of a variety of pharmacological and natural reinforcers in the placepreference paradigm (Papp et al 1991, 1992a,b). On this basis, the CMS procedure has been proposed as an animal model of anhedonia (Willner et al 1991b), the decreased ability to respond to pleasuce (Fawcett et al 1983). Although anhedonia is a prominent feature of both depression and schizophrenia (Willner 1992), its reversal by antidepressant drugs suggests that the CMS model has greater relevance to depression. However, it is not proposed that this model captures the depressive syndrome in its entirety. Indeed, in certain other behavioral models, the therapeutic actions of imipramine are reverse0 by metergoline, a serotoain receptor antagonist, which is without effect on the antianhedonie action of imipramine in the CMS model (Muscat et al 1990; Willner et al 1989). Although anhedonia appears to have a dopaminergic substrate, other symptoms of depression ate likely to reflect different neurobiologicai substrates (Willner 1991). The present results suggest that intermittent administration of DA agonists may merit clinical investigation as a novel strategy for the treatment of depression, particularly in anhedonic patients. The literature already contains several reports of antidepressant effects using bromocriptine or another directly acting DA agonist, piribedil (reviewed by Wiilner 1983; Jimerson 1987). These were largely open studies, but two controlled trials found no difference in antidepressant efficacy between bromocriptine and imiprami~:e(Waehrens and Gerlach 1981; Theohar et al 198 !). Striking and rapid therapeutic effects of piribedfl have been described in previously nonresponsive patients whose sleep electroencephalograms (EEG) showed signs characteristic for Parkinson's disease; in patients not showing these signs, piribedil was ineffective (Mouret et ai 1987, 1988). It is also notable that DA uptake inhibition is a prominent feature of a number of newer antidepressants, including nomifensine, buproprion, and amineptine. Trials of DA agonists in depression are not currently fashionable, largely because DA agonists are perceived to carry a significant potential for abuse (of. Bozarth 1987; Adler and Cowan 1990). The present results suggest that with appropriate schedu!ing, very few administrations of a DA agonist may be needed to achieve antidepressant effects equivalent to those obtained with several weeks of daily tricyclic treatment. This study was supported in part by the Medical Research Council of Great Britain. We are grateful to Marc Lind for technical support and to Lilly and Astra for generous gifts of drugs.
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