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Failure of neonatal clomipramine treatment to alter forced swim immobility
Physiology & Behavior 70 (2000) 407–411
Brief communication
Failure of neonatal clomipramine treatment to alter forced swim immobility: chronic treadmill or activity-wheel running and imipramine H.S. Yooa,c, B.N. Bunnellb, J.B. Crabbea, L.R. Kalisha, and R.K. Dishmana,* Departments of aExercise Science and bPsychology, The University of Georgia, Ramsey Student Center, 300 River Road, Athens, GA 30602-6554 USA Received 3 May 1999; received in revised form 15 February 2000; accepted 20 March 2000
Abstract We examined whether chronic running on a treadmill or activity wheel would attenuate the increased swim immobility that has been reported after neonatal clomipramine (CLI) treatment. Male Sprague–Dawley pups (N ⫽ 60) were injected with the monoamine reuptake inhibitor clomipramine hydrochloride (40 mg/kg per day i.p.) from 8 to 21 days of age. Another group (N ⫽ 12) received saline vehicle. At age 4 weeks, the CLI pups were randomly assigned to experimental conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary that received the antidepressant drug imipramine hydrochloride (10 mg/kg twice daily) during the last 10 days of the experiment; (4) activity wheel ⫹ imipramine; (5) treadmill running (30 m/min for 1 h at 0⬚incline, 6 days/week). At age 16 weeks, rats underwent the Porsolt swim test 48 h after the last imipramine injection and/or the last exercise session. The increase in swim immobility among CLI-treated rats was small (one quarter of SD) and not statistically significant (p ⬎ 0.10). The results are not consistent with our previous finding of antidepressant-like effects of activity-wheel running based on brain noradrenergic adaptations and enhanced male copulatory performance after neonatal CLI treatment. The lack of change in swim performance after clomipramine questions the generalizability of the CLI model of depression and the validity of the forced swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic activity-wheel running. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Exercise; Depression; Porsolt swim test; Rat model
1. Introduction We have reported elsewhere that activity-wheel running has antidepressant-like effects in rats. After 4–6 weeks of circadian wheel running, females had reduced latency to escape footshock concomitantly with reduced serotonin (5HT) in the central amygdala and increased norepinephrine (NE) in the locus coeruleus and dorsal raphe [1]. Males had enhanced copulatory performance, consistent with noradrenergic and serotonergic changes in frontal cortex that equaled or exceeded the effects of imipramine treatment after neonatal clomipramine (CLI) injection [2]. Those findings, coupled with evidence that activity-wheel running elevates basal levels of brain norepinephrine [3] and blunts release of norepinephrine in frontal cortex during footshock stress [4], have supported the hypothesis that chronic physical activity has antidepressant-like effects that may be ex-
* Corresponding author. Tel.: 706-542-9840; Fax: 706-542-3148 E-mail address: [email protected] c Current address: Yeungnam University, Gyongsan, Gyongbuk, South Korea.
plainable by a favorable cross-stressor adaptation of brain monoaminergic systems [5]. In an attempt to extend those results to another behavioral measure of depression, we now report results from a study of forced-swim behavior among male rats that ran on activity wheels or a motorized treadmill for 3 months after neonatal injection of CLI [6], which has induced depression-like signs in male rats at ages 3–7 months [7–10]. The duration of immobility during forced swimming [11] has been the most widely used screening test for new antidepressant drugs [12,13]. Increased swim immobility after neonatal CLI treatment has been reported as evidence for validity of the clomipramine model of endogenous depression [8], but we are unaware of studies that have examined whether chronic physical activity might moderate such an effect. Mechanisms explaining the depression-like outcomes of neonatal clomipramine injections have not, as yet, been elucidated. A seminal paper by Mirmaran et al. [14] implicated adult onset rapid eye movement (REM) sleep abnormalities resulting from acute REM-sleep deprivation during the CLI injection period [6]. Other studies [15,16] have suggested
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that the preferential selectivity of clomipramine for serotonin might partly explain the depression-like signs at adulthood because both REM sleep patterns and maturation of the brain serotonin system coincide during postnatal weeks 2–3 when CLI injections are administered [17]. Neonatal injections of both CLI and the selective serotonin reuptake inhibitor (SSRI) Lu 10-134-C increased mRNA for 5-HT transporter in dorsal raphe [18], and neonatal Lu 10-134-C increased forced-swim immobility at age 4 months [17]. Applications of the forced-swim test and the clomipramine model of depression have been made in sedentary rats, but several studies indicate that chronic physical activity alters brain biochemistry in ways that might interact with neonatal CLI treatment and modulate forced swim behavior, similar to the effects of pharmacotherapy. Novel swimming or running increases 5-HT and reduces NE levels in rat brain [19–21]. The increase in basal 5-HT after chronic wheel or treadmill running is about half that of the level of increase in norepinephrine [3,22,23]. Though CLI is preferentially selective for 5-HT, its main metabolite, demethyclomipramine, is a strong NE reuptake inhibitor, and neonatal treatment with desipramine, which is preferentially selective for NE reuptake, has led to an adultonset increase in forced-swim immobility that was equivalent to the effects of the serotonin reuptake inhibitor zimeldine [24]. Also, chronic treatment of adult rats with either desipramine or the SSRI fluoxetine has reduced forcedswim immobility [25]. Hence, we expected that chronic treadmill or activity-wheel running and imipramine, which has structure and action similar to CLI and blocks both NE and 5-HT reuptake, might reverse the increase in forcedswim immobility expected after neonatal CLI treatment via chronic adaptations in the brain serotonergic or noradrenergic systems.
2. Materials and methods 2.1. Subjects Pregnant female Sprague–Dawley-derived rats (N ⫽ 24) obtained from the Charles River Laboratory (Raleigh, NC) delivered their pups 1 week after arrival at our vivarium. Three days after birth, male pups were cross-fostered. Thirty-six female pups were saved as partners for sexual activity testing. Sixty males were treated intraperitoneally with clomipramine hydrochloride (40 mg/kg) once daily, at 1700 h on postnatal days 8 through 21 [26]. A control group of 12 pups received a saline vehicle treatment. At 4 weeks of age, all pups were weaned and individually housed in shoebox cages with activity wheels or in shoebox cages without activity wheels. The home cage was 20 ⫻ 18 ⫻ 24 cm in size. The rooms in which all rats were housed were maintained at 23 ⫾ 1⬚C. All animals were kept on a reversed 12:12-h light–dark cycle (light from 2400–1200 h). Rat chow and water were available ad lib.
2.2. Research design The clomipramine-treated pups (N ⫽ 60) were randomly assigned to five groups: (1) sedentary home cage control; (2) voluntary activity-wheel running; (3) imipramine treatment; (4) activity-wheel running ⫹ imipramine treatment; and (5) treadmill training. Nine fatalities, balanced across conditions, occurred because of bacterial infection within the first month of the experiment. Three rats assigned to the treadmill condition stopped running before the end of the study and were excluded from analysis. The dependent measures included the duration of immobility and ratings of swimming activity during a 15-min induction swim and a 5-min forced-swim test. 2.3. Experimental treatments 2.3.1. Activity-wheel running Rats assigned to the activity wheel and the activity wheel ⫹ imipramine conditions were individually housed in cages with 24-h access to running wheels (MiniMitter, Sunriver, OR) for 12 weeks. Daily running distance was determined by an electromagnetic counter. 2.3.2. Treadmill training Rats assigned to the treadmill-training group were familiarized with a Stanhope (Davis, CA) motor-driven treadmill during a 3-day period. The rats ran for 5 min at 5 meters per minute and 0⬚incline and then were gradually adapted to treadmill running for 2 weeks [45]. The exercise duration was increased from 15 to 30 min, and the speed was increased from 15 to 25 m/min during the first week. By the end of the second week, animals ran for 60 min at 30 m per minute. This regimen was maintained 6 days per week for an additional 10 weeks. Treadmill training was conducted in a dim red light environment during the dark phase of the 12:12-h light–dark cycle to minimize circadian rhythm and sleep disturbance effects and to permit direct comparisons with activity-wheel running that occurs predominantly during the dark phase. This protocol corresponds to a moderate ⭈ exercise intensity of 50% to 60% of V O2peak for Sprague– Dawley males. 2.3.3. Imipramine injection Twelve days prior to the swim test, rats assigned to the imipramine and the wheel running ⫹ imipramine groups were injected intraperitoneally with imipramine hydrochloride (10 mg/kg) twice daily (0800 and 1800 h) for 10 days [27]. An equivalent volume of saline was injected into rats in other groups. 2.3.4. Forced-swim test Forty-eight hours after the last running session or imipramine injection, rats were individually forced to swim in a glass cylinder (height, 50 cm; diameter, 18 cm) containing water at a depth of 38 cm and maintained at 25⬚C. Testing time was between 1300–1700 h in a thermoneutral (21–
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22⬚C) testing room illuminated by a dim red light. Two trained raters blinded to treatment conditions timed immobility duration (s) for 15 min on the first testing day and for 5 min 24 h later. According to the criteria of Porsolt et al. [11], the rat was judged to be immobile when it floated passively, making only small movements to keep its nose above the surface. Moving limbs to break through the surface of the water or diving was judged as swimming. Similar to the method of Lucki [12] and Detke and Lucki [25], observers’ subjective ratings (1 to 5) of the small movements (swimming activity) also were recorded because complete immobility (giving up) was not observed in a pilot study: 1 ⫽ vigorous treading without floating; 2 ⫽ mostly treading, some slight movements, and no floating; 3 ⫽ slight movements and little floating; 4 ⫽ half slight movements, half floating; and 5 ⫽ mostly floating. After each swim test, rats were partially dried and placed in a Plexiglas cage illuminated with a heat lamp (32⬚C) for 20 min before being returned to their home or activity-wheel cages.
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3.2. Body mass and running distance The activity wheel and the wheel ⫹ imipramine groups’ running did not differ and peaked at about 50 km/week during weeks 6 to 8, about three times the weekly distance of the treadmill group. Wheel running then declined linearly, stabilizing at 30 km/week during weeks 11–12. Fitness, indicated by citrate synthase activity (moles/min per gram of wet weight) in hindlimb locomotory soleus muscle, was increased in treadmill (51 ⫾ 5 ) and both activity wheel (43 ⫾ 6) groups, compared with the case of the sedentary groups ( ⵑ36 ⫾ 3), p ⬍ 0.05. The saline vehicle group had higher body mass compared with all five experimental groups at the time of group assignment when rats were 4 weeks old. That difference persisted until the end of the experiment, indicating that neonatal clomipramine injection negatively affected weight gain. At the time of swim testing, mass differed (p ⬍ 0.05) as follows: wheel ⫹ imipramine (442 g) and wheel (472 g) ⬍ imipramine (508 g) ⬍ treadmill (522 g) and sedentary CLI (550 g) ⬍ sedentary saline control (596 g).
2.4. Statistical analysis Group means were compared by one-way ANOVA decomposed by using Duncan’s multiple range test (p ⬍ 0.05). Independent t-tests were used to compare the sedentary CLI and saline control groups on swim immobility and the sedentary and running groups on citrate synthase activity (p ⬍ 0.05). Group differences in weekly body mass and kilometers run were compared using mixed model repeated measures ANOVA; degrees of freedom were adjusted for sphericity by Hyunh-Feldt⑀. Final n was 9–12. 3. Results 3.1. Swim test There were no group effects for immobility duration, F(5, 56) ⫽ 1.38, p ⫽ 0.248, 2 ⫽ 0.11 (Table 1) or the subjective rating of swimming activity, F(5, 56) ⫽ 1.29, p ⫽ 0.282, 2 ⫽ 0.11 during the 15-min induction test. Neither swim immobility (p ⫽ 0.689) nor swim rating (p ⫽ 0.660) in the sedentary CLI group differed from the saline control group. The Pearson correlation coefficient between immobility and the rating of swimming activity was 0.53, p ⬍ 0.001. Similarly, there were no group effects for immobility duration, F(5, 56) ⫽ 1.04, p ⫽ 0.405, 2 ⫽ 0.09 (Table 1) and the subjective rating of swimming activity, F(5, 56) ⫽ 0.55, p ⫽ 0.739, 2 ⫽ 0.05 during the 5-min swim test. Neither swim immobility (p ⫽ 0.689) nor swim rating (p ⫽ 0.966) in the sedentary CLI group differed from the saline control group. The Pearson correlation coefficient between immobility and the rating of swimming activity during the 5-min test was 0.80, p ⬍ 0.001. The correlation between immobility during the 15-min and 5-min swim tests was 0.41, p ⫽ 0.001. Observer agreement was high for immobility duration (RI ⫽ 0.97) and ratings of swimming activity (RI ⫽ 0.92).
4. Discussion The absence of effects of CLI or chronic exercise on forced-swim immobility questions the generalizability of the CLI model of depression when it is extended to forced swim immobility. Also, we found that imipramine treatment had no effect on the forced-swim test, consistent with other research that failed to show an anti-immobility effect of imipramine using a water depth that prevents standing by the rat [29]. We administered the swim test at 4 months of age to avoid an exercise detraining effect because wheel running in Sprague–Dawley males typically peaks 6 to 8 weeks after wheel access and decreases thereafter [3]. Administering the swim test at an older age (6 or 7 months) or using a different strain of rat might yield larger effects for immobility, but increased immobility has been reported at age 4 months after neonatal treatment with a SSRI [17]. The immobility durations we observed in the CLI sedentary control and saline control groups were shorter than reported for 6-monthold rats by Velazquez–Moctezuma and Ruiz [8], but in their study, increased swim immobility occurred only during the first 2 min of the 5-min swim. Though the forced-swim test has been reported to have predictive validity for antidepressant pharmaceuticals, numerous studies have reported false negative results for clomipramine, trazodone, and salbutamol [30] and false positive results for several stimulants [31], anticholinergics [32], and anxiolytics [e.g., 33]. Also, though early studies reported that the 5-HT uptake blocker fluoxetine decreased immobility time [30], a recent study found that 5-HT1A agonists reduced swim immobility in rat, but 5-HT reuptake inhibitors had no effect [34]. Others reported that the duration of immobility was increased by 5-HT activity and decreased by 5-HT antagonists [35]. The antidepressant Citalopram, a highly specific SSRI, does not alter swim
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Table 1 Mean (⫾SD) immobility duration and swim ratings during 15-min and 5-min forced-swim tests 15-min forced swim
5-min forced swim
Group
Immobility (s)
Swim rating*
Immobility (s)
Swim rating*
CLI-induced sedentary (n ⫽10) Activity wheel (n ⫽10) Imipramine treatment (n ⫽10) Wheel ⫹ imipramine (n ⫽11) Treadmill training (n ⫽9) Saline vehicle (n ⫽12)
572 ⫾ 113 670 ⫾ 75 615 ⫾ 85 595 ⫾ 178 621 ⫾ 54 552 ⫾ 125
3.10 ⫾ 0.74 3.50 ⫾ 0.97 2.50 ⫾ 0.85 2.73 ⫾ 1.35 2.78 ⫾ 0.67 2.92 ⫾ 1.0
142 ⫾ 49 176 ⫾ 70 151 ⫾ 80 173 ⫾ 65 158 ⫾ 47 123 ⫾ 72
2.60 ⫾ 0.52 3.00 ⫾ 1.05 2.70 ⫾ 0.95 3.00 ⫾ 0.77 2.56 ⫾ 0.88 2.58 ⫾ 1.08
*Scale: 1 ⫽ high swimming to 5 ⫽ mostly floating.
immobility in rat. Finally, evidence for the construct validity of forced swimming as a model of despair remains incomplete [36] and has been challenged [37]. Immobility might represent a learned coping response [38,39] or the absence of panic rather than behavioral despair. Psychopharmacological effects of forced swimming need to be described when the CLI model of depression is used in studies of chronic physical activity. For example, imipramine combined with acute swim stress elicits a greater down-regulation of brain adrenoceptors than does chronic imipramine treatment alone [40], and there are strain differences in forced-swim performance after imipramine treatment [41]. Forced swimming for durations approximating or exceeding 15 min leads to decreased NE and increased 5-HT levels in whole brain, which are normalized 2–6 h later [19]. Release of 5-HT in the striatum is increased during 15 min of forced swimming but habituates rapidly, so no increase is observed during a second bout of swimming 24 h later [42]. A comparison treatment of antidepressants with differing receptor selectivity, such as a 5-HT reuptake blocker (fluoxetine) versus a NE reuptake blocker (desipramine or reboxetine) needs to be studied (e.g., [43]) to determine whether immobility and swimming might be differentially affected [28] by chronic physical activity after neonatal CLI treatment. Also, forced-swim performance could differ between typical depression, which is characterized by psychomotor agitation, and atypical depression, which is characterized by psychomotor retardation [44]. In summary, the present results are not consistent with our other findings of antidepressant-like effects of wheel running [1,16]. In a companion paper on the present study [2], we reported that activity-wheel running enhanced male copulatory performance, concomitantly with increased levels of norepinephrine and decreased -adrenoreceptor binding in brain cortex, after the neonatal CLI treatment. Hence, the results presented here question the generalizability of the CLI model of depression when extended to forced swim immobility. The lack of change in swim immobility after neonatal CLI injections or imipramine treatment further questions the generalizability of the CLI model of depression, as well as the validity of the forced-swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic exercise.
Acknowledgment Thanks go to Gerald W. Vogel for his helpful advice about using the CLI model.
References [1] Dishman RK, Renner KJ, Youngstedt SD, Reigle T, Bunnell BN, Burke KA, Yoo HS, Mougey EH, Meyerhoff JL. Activity-wheel running reduces escape latency and alters brain monoamines after footshock. Brain Res Bull 1997;42:399–406. [2] Yoo HS, Tackett RL, Crabbe JB, Bunnell BN, Dishman RK. Antidepressant-like effects of physical activity vs. imipramine: neonatal clomipramine model. Psychobiology (in press). [3] Dunn AL, Reigle TG, Youngstedt SD, Armstrong RB, Dishman RK. Brain norepinephrine and metabolites after treadmill training and wheel running in rats. Med Sci Sports Exerc 1996;28:204–9. [4] Soares J, Holmes PV, Renner KJ, Edwards G, Bunnell BN, Dishman RK. Brain noradrenergic responses to footshock after chronic activity wheel running. Behav Neurosci 1999;113:558–66. [5] Sothmann MS, Buckworth J, Claytor RP, Cox RH, White–Welkley JE, Dishman RK. Exercise training and the cross-stressor adaptation hypothesis. Exerc Sport Sci Rev 1996;24:267–87. [6] Vogel GW, Neill D, Hagler M, Kors D. A new animal model of endogenous depression: a summary of present findings. Neurosci Biobehav Rev 1990;14:85–91. [7] Bonilla–Jaime H, Retana–Marquez S, Velazquez–Moctezuma J. Pharmacological features of masculine sexual behavior in an animal model of depression. Pharmacol Biochem Behav 1998;60:39–45. [8] Velazquez–Moctezuma J, Ruiz AO. Neonatal treatment with clomipramine increased immobility in the forced swim test: An attribute of animal models of depression. Pharmacol Biochem Behav 1992;42:737–9. [9] Vijayakumar M, Meti BL. Alterations in the levels of monoamines in discrete brain regions of clomipramine-induced animal model of endogenous depression. Neurochem Res 1999;24:345–9. [10] Vogel GW, Neill D, Hagler M, Kors D, Hartley D. Decreased intracranial self-stimulation in a new animal model of endogenous depression. Neurosci Biobehav Rev 1990;14:65–8. [11] Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730–2. [12] Lucki I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 1997;8:523–32. [13] Porsolt RD, Lenegre A, McArthur RA. Pharmacological models of depression. In: Oliver B, Mos J, Slangen JL, editors. Animal Models in Psychopharmacology. Basel, Switzerland: Birkhauser, 1991. pp. 137–159. [14] Mirmaran M, Van de Poll NE, Corner HG, Van Oyen H, Boer G. Suppression of active sleep by chronic treatment with clomipramine during early postnatal development: effect on adult sleep and behavior in the rat. Brain Res 1981;204:129–46. [15] Kinney GG, Vogel GW, Feng P. Decreased dorsal raphe nucleus neu-
H.S. Yoo et al. / Physiology & Behavior 70 (2000) 407–411
[16] [17]
[18]
[19] [20]
[21] [22]
[23] [24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
ronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression. Brain Res 1997;756:68–75. Yavari P, Vogel GW, Neill DB. Decreased raphe unit activity in a rat model of endogenous depression. Brain Res 1993;611:31–6. Hansen HH, Sanchez C, Meier E. Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression? J Pharmacol Exp Ther 1997;283:1333–41. Hansen HH, Mikkelsen JD. Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor. Eur J Pharmacol 1998;352:307–15. Barchas JD, Friedman DX. Brain amines: responses to physiological stress. Biochem Pharmacol 1963;12:1232–5. Chaouloff F, Kennett GA, Serrurrier B, Merino D, Curzon G. Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J Neurochem 1986;46:1647–50. Romanowski W, Grabiec S. The role of serotonin in the mechanism of central fatigue. Acta Physiologica Polonica 1974;25:127–34. Brown BS, Payne T, Kim C, Moore G, Krebs P, Martin W. Chronic response of rat brain norepinephrine and serotonin levels to endurance training. J Appl Physiol 1979;46:19–23. Dunn AL, Dishman RK. Exercise and the neurobiology of depression. Exerc Sport Sci Rev 1991;19:41–98. Hilakivi LA, Hilakivi I. Increased adult behavioral “despair” in rats neonatally exposed to desipramine or zimeldine: an animal model of depression. Pharmacol Biochem Behav 1987;28:367–9. Detke MJ, Johnson J, Lucki I. Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 1997;5:107–12. Vogel GW, Hagler M, Hennessey A, Richard C. Dose-dependent decrements in adult male rat sexual behavior after neonatal clorimipramine treatment. Pharmacol Biochem Behav 1992;54:605–9. Duncan GE, Paul IA, Breese GR. Neuroanatomical differences in the rate of beta-adrenergic receptor adaptation after repeated treatment with imipramine. Psychopharmacol Bull 1993;29:401–7. Detke MJ, Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res 1996;73:43–6. Abel EL, Hannigan JH. The immobility response in the forced swim test: paradoxical effect of imipramine. Eur J Pharmacol 1994;258: 261–4. Porsolt RD. Behavioral despair. In: Enna SJ, Malick JB, Richelson E, editors. Antidepressants: Neurochemical, Behavioral and Clinical Perspectives. New York: Raven Press, 1981. pp. 121–39. Howard JL, Ferris RM, Cooper BR, Soroko FE, Wang CM, Pollard
[32] [33]
[34] [35]
[36]
[37] [38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
411
GT. Models of depression used in the pharmaceutical industry. In: Koob GF, Ehlers CL, Kupfer DJ, editors. Animal Model of Depression. Boston: Birkhauser, 1989. pp. 187–203. Browne RG. Effects of antidepressants and anticholinergics in a mouse behavioral despair test. Eur J Pharmacol 1979;58:331–4. Prince CR, Collins C, Anisman H. Stress-provoked response patterns in a swim task: modification by diazepam. Pharmacol Biochem Behav 1988;24:323–8. Borsini F. Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 1995;19:377–95. Gibson CJ, Deikel SM, Young SN, Binik YM. Behavioral and biochemical effects of tryptophan tyrosine and phenylalanine in mice. Psychopharmacology 1982;76:118–21. Willner P. Animal models of depression: validity and applications. In: Gessa G, Fratta W, Pani L, Serra G, editors. Depression and Mania: From Neurobiology to Treatment. New York: Raven Press, 1995. pp. 19–41. Borsini F, Volterra G, Meli A. Does the behavioral “despair” test measure “despair”. Physiol Behav 1986;38:385–6. De Pablo JM, Ortiz–Caro J, Sanchez–Santed F, Guillamon A. Effects of diazepam, pentobarbital, scopolamine and the timing of saline injection on learned immobility in rats. Physiol Behav 1991;50:895–9. De Pablo JM, Parra A, Segovia S, Guillamon A. Learned immobility explains the behavior of rats in the forced swimming test. Physiol Behav 1989;46:229–37. Duncan GE, Paul IA, Harden K, Mueller RA, Stumpf WE, Breese GR. Rapid down regulation of beta adrenergic receptors by combining antidepressant drugs with forced swim: a model of antidepressant-induced neural adaptation. J Pharmacol Exp Ther 1985;234: 402–8. Paul IA, Duncan GE, Kuhn C, Mueller RA, Hong J–S, Breese GR. Neural adaptation in imipramine-treated rats processed in forced swim test: assessment of time course, handling, rat strain and amine uptake. J Pharmacol Exp Ther 1990;252:997–1005. Kirby LG, Lucki I. The effect of repeated exposure to forced swimming on extracellular levels of 5-hydroxytryptamine in the rat. Stress 1999;2:251–63. Reneric JP, Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacol 1998;136:190–7. Koob GF. Anhedonia as an animal model of depression. In: Koob GF, Ehlers CL, Kupfer DJ, editors. Animal Model of Depression. Boston: Birkhauser, 1989. pp. 162–83. White–Welkley JE, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK. Treadmill training and estradiol moderate hypothalamicpituitary-adrenal cortical responses to acute running and immobilization. Physiol Behav 1995;57:533–40.
Brief communication
Failure of neonatal clomipramine treatment to alter forced swim immobility: chronic treadmill or activity-wheel running and imipramine H.S. Yooa,c, B.N. Bunnellb, J.B. Crabbea, L.R. Kalisha, and R.K. Dishmana,* Departments of aExercise Science and bPsychology, The University of Georgia, Ramsey Student Center, 300 River Road, Athens, GA 30602-6554 USA Received 3 May 1999; received in revised form 15 February 2000; accepted 20 March 2000
Abstract We examined whether chronic running on a treadmill or activity wheel would attenuate the increased swim immobility that has been reported after neonatal clomipramine (CLI) treatment. Male Sprague–Dawley pups (N ⫽ 60) were injected with the monoamine reuptake inhibitor clomipramine hydrochloride (40 mg/kg per day i.p.) from 8 to 21 days of age. Another group (N ⫽ 12) received saline vehicle. At age 4 weeks, the CLI pups were randomly assigned to experimental conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary that received the antidepressant drug imipramine hydrochloride (10 mg/kg twice daily) during the last 10 days of the experiment; (4) activity wheel ⫹ imipramine; (5) treadmill running (30 m/min for 1 h at 0⬚incline, 6 days/week). At age 16 weeks, rats underwent the Porsolt swim test 48 h after the last imipramine injection and/or the last exercise session. The increase in swim immobility among CLI-treated rats was small (one quarter of SD) and not statistically significant (p ⬎ 0.10). The results are not consistent with our previous finding of antidepressant-like effects of activity-wheel running based on brain noradrenergic adaptations and enhanced male copulatory performance after neonatal CLI treatment. The lack of change in swim performance after clomipramine questions the generalizability of the CLI model of depression and the validity of the forced swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic activity-wheel running. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Exercise; Depression; Porsolt swim test; Rat model
1. Introduction We have reported elsewhere that activity-wheel running has antidepressant-like effects in rats. After 4–6 weeks of circadian wheel running, females had reduced latency to escape footshock concomitantly with reduced serotonin (5HT) in the central amygdala and increased norepinephrine (NE) in the locus coeruleus and dorsal raphe [1]. Males had enhanced copulatory performance, consistent with noradrenergic and serotonergic changes in frontal cortex that equaled or exceeded the effects of imipramine treatment after neonatal clomipramine (CLI) injection [2]. Those findings, coupled with evidence that activity-wheel running elevates basal levels of brain norepinephrine [3] and blunts release of norepinephrine in frontal cortex during footshock stress [4], have supported the hypothesis that chronic physical activity has antidepressant-like effects that may be ex-
* Corresponding author. Tel.: 706-542-9840; Fax: 706-542-3148 E-mail address: [email protected] c Current address: Yeungnam University, Gyongsan, Gyongbuk, South Korea.
plainable by a favorable cross-stressor adaptation of brain monoaminergic systems [5]. In an attempt to extend those results to another behavioral measure of depression, we now report results from a study of forced-swim behavior among male rats that ran on activity wheels or a motorized treadmill for 3 months after neonatal injection of CLI [6], which has induced depression-like signs in male rats at ages 3–7 months [7–10]. The duration of immobility during forced swimming [11] has been the most widely used screening test for new antidepressant drugs [12,13]. Increased swim immobility after neonatal CLI treatment has been reported as evidence for validity of the clomipramine model of endogenous depression [8], but we are unaware of studies that have examined whether chronic physical activity might moderate such an effect. Mechanisms explaining the depression-like outcomes of neonatal clomipramine injections have not, as yet, been elucidated. A seminal paper by Mirmaran et al. [14] implicated adult onset rapid eye movement (REM) sleep abnormalities resulting from acute REM-sleep deprivation during the CLI injection period [6]. Other studies [15,16] have suggested
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that the preferential selectivity of clomipramine for serotonin might partly explain the depression-like signs at adulthood because both REM sleep patterns and maturation of the brain serotonin system coincide during postnatal weeks 2–3 when CLI injections are administered [17]. Neonatal injections of both CLI and the selective serotonin reuptake inhibitor (SSRI) Lu 10-134-C increased mRNA for 5-HT transporter in dorsal raphe [18], and neonatal Lu 10-134-C increased forced-swim immobility at age 4 months [17]. Applications of the forced-swim test and the clomipramine model of depression have been made in sedentary rats, but several studies indicate that chronic physical activity alters brain biochemistry in ways that might interact with neonatal CLI treatment and modulate forced swim behavior, similar to the effects of pharmacotherapy. Novel swimming or running increases 5-HT and reduces NE levels in rat brain [19–21]. The increase in basal 5-HT after chronic wheel or treadmill running is about half that of the level of increase in norepinephrine [3,22,23]. Though CLI is preferentially selective for 5-HT, its main metabolite, demethyclomipramine, is a strong NE reuptake inhibitor, and neonatal treatment with desipramine, which is preferentially selective for NE reuptake, has led to an adultonset increase in forced-swim immobility that was equivalent to the effects of the serotonin reuptake inhibitor zimeldine [24]. Also, chronic treatment of adult rats with either desipramine or the SSRI fluoxetine has reduced forcedswim immobility [25]. Hence, we expected that chronic treadmill or activity-wheel running and imipramine, which has structure and action similar to CLI and blocks both NE and 5-HT reuptake, might reverse the increase in forcedswim immobility expected after neonatal CLI treatment via chronic adaptations in the brain serotonergic or noradrenergic systems.
2. Materials and methods 2.1. Subjects Pregnant female Sprague–Dawley-derived rats (N ⫽ 24) obtained from the Charles River Laboratory (Raleigh, NC) delivered their pups 1 week after arrival at our vivarium. Three days after birth, male pups were cross-fostered. Thirty-six female pups were saved as partners for sexual activity testing. Sixty males were treated intraperitoneally with clomipramine hydrochloride (40 mg/kg) once daily, at 1700 h on postnatal days 8 through 21 [26]. A control group of 12 pups received a saline vehicle treatment. At 4 weeks of age, all pups were weaned and individually housed in shoebox cages with activity wheels or in shoebox cages without activity wheels. The home cage was 20 ⫻ 18 ⫻ 24 cm in size. The rooms in which all rats were housed were maintained at 23 ⫾ 1⬚C. All animals were kept on a reversed 12:12-h light–dark cycle (light from 2400–1200 h). Rat chow and water were available ad lib.
2.2. Research design The clomipramine-treated pups (N ⫽ 60) were randomly assigned to five groups: (1) sedentary home cage control; (2) voluntary activity-wheel running; (3) imipramine treatment; (4) activity-wheel running ⫹ imipramine treatment; and (5) treadmill training. Nine fatalities, balanced across conditions, occurred because of bacterial infection within the first month of the experiment. Three rats assigned to the treadmill condition stopped running before the end of the study and were excluded from analysis. The dependent measures included the duration of immobility and ratings of swimming activity during a 15-min induction swim and a 5-min forced-swim test. 2.3. Experimental treatments 2.3.1. Activity-wheel running Rats assigned to the activity wheel and the activity wheel ⫹ imipramine conditions were individually housed in cages with 24-h access to running wheels (MiniMitter, Sunriver, OR) for 12 weeks. Daily running distance was determined by an electromagnetic counter. 2.3.2. Treadmill training Rats assigned to the treadmill-training group were familiarized with a Stanhope (Davis, CA) motor-driven treadmill during a 3-day period. The rats ran for 5 min at 5 meters per minute and 0⬚incline and then were gradually adapted to treadmill running for 2 weeks [45]. The exercise duration was increased from 15 to 30 min, and the speed was increased from 15 to 25 m/min during the first week. By the end of the second week, animals ran for 60 min at 30 m per minute. This regimen was maintained 6 days per week for an additional 10 weeks. Treadmill training was conducted in a dim red light environment during the dark phase of the 12:12-h light–dark cycle to minimize circadian rhythm and sleep disturbance effects and to permit direct comparisons with activity-wheel running that occurs predominantly during the dark phase. This protocol corresponds to a moderate ⭈ exercise intensity of 50% to 60% of V O2peak for Sprague– Dawley males. 2.3.3. Imipramine injection Twelve days prior to the swim test, rats assigned to the imipramine and the wheel running ⫹ imipramine groups were injected intraperitoneally with imipramine hydrochloride (10 mg/kg) twice daily (0800 and 1800 h) for 10 days [27]. An equivalent volume of saline was injected into rats in other groups. 2.3.4. Forced-swim test Forty-eight hours after the last running session or imipramine injection, rats were individually forced to swim in a glass cylinder (height, 50 cm; diameter, 18 cm) containing water at a depth of 38 cm and maintained at 25⬚C. Testing time was between 1300–1700 h in a thermoneutral (21–
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22⬚C) testing room illuminated by a dim red light. Two trained raters blinded to treatment conditions timed immobility duration (s) for 15 min on the first testing day and for 5 min 24 h later. According to the criteria of Porsolt et al. [11], the rat was judged to be immobile when it floated passively, making only small movements to keep its nose above the surface. Moving limbs to break through the surface of the water or diving was judged as swimming. Similar to the method of Lucki [12] and Detke and Lucki [25], observers’ subjective ratings (1 to 5) of the small movements (swimming activity) also were recorded because complete immobility (giving up) was not observed in a pilot study: 1 ⫽ vigorous treading without floating; 2 ⫽ mostly treading, some slight movements, and no floating; 3 ⫽ slight movements and little floating; 4 ⫽ half slight movements, half floating; and 5 ⫽ mostly floating. After each swim test, rats were partially dried and placed in a Plexiglas cage illuminated with a heat lamp (32⬚C) for 20 min before being returned to their home or activity-wheel cages.
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3.2. Body mass and running distance The activity wheel and the wheel ⫹ imipramine groups’ running did not differ and peaked at about 50 km/week during weeks 6 to 8, about three times the weekly distance of the treadmill group. Wheel running then declined linearly, stabilizing at 30 km/week during weeks 11–12. Fitness, indicated by citrate synthase activity (moles/min per gram of wet weight) in hindlimb locomotory soleus muscle, was increased in treadmill (51 ⫾ 5 ) and both activity wheel (43 ⫾ 6) groups, compared with the case of the sedentary groups ( ⵑ36 ⫾ 3), p ⬍ 0.05. The saline vehicle group had higher body mass compared with all five experimental groups at the time of group assignment when rats were 4 weeks old. That difference persisted until the end of the experiment, indicating that neonatal clomipramine injection negatively affected weight gain. At the time of swim testing, mass differed (p ⬍ 0.05) as follows: wheel ⫹ imipramine (442 g) and wheel (472 g) ⬍ imipramine (508 g) ⬍ treadmill (522 g) and sedentary CLI (550 g) ⬍ sedentary saline control (596 g).
2.4. Statistical analysis Group means were compared by one-way ANOVA decomposed by using Duncan’s multiple range test (p ⬍ 0.05). Independent t-tests were used to compare the sedentary CLI and saline control groups on swim immobility and the sedentary and running groups on citrate synthase activity (p ⬍ 0.05). Group differences in weekly body mass and kilometers run were compared using mixed model repeated measures ANOVA; degrees of freedom were adjusted for sphericity by Hyunh-Feldt⑀. Final n was 9–12. 3. Results 3.1. Swim test There were no group effects for immobility duration, F(5, 56) ⫽ 1.38, p ⫽ 0.248, 2 ⫽ 0.11 (Table 1) or the subjective rating of swimming activity, F(5, 56) ⫽ 1.29, p ⫽ 0.282, 2 ⫽ 0.11 during the 15-min induction test. Neither swim immobility (p ⫽ 0.689) nor swim rating (p ⫽ 0.660) in the sedentary CLI group differed from the saline control group. The Pearson correlation coefficient between immobility and the rating of swimming activity was 0.53, p ⬍ 0.001. Similarly, there were no group effects for immobility duration, F(5, 56) ⫽ 1.04, p ⫽ 0.405, 2 ⫽ 0.09 (Table 1) and the subjective rating of swimming activity, F(5, 56) ⫽ 0.55, p ⫽ 0.739, 2 ⫽ 0.05 during the 5-min swim test. Neither swim immobility (p ⫽ 0.689) nor swim rating (p ⫽ 0.966) in the sedentary CLI group differed from the saline control group. The Pearson correlation coefficient between immobility and the rating of swimming activity during the 5-min test was 0.80, p ⬍ 0.001. The correlation between immobility during the 15-min and 5-min swim tests was 0.41, p ⫽ 0.001. Observer agreement was high for immobility duration (RI ⫽ 0.97) and ratings of swimming activity (RI ⫽ 0.92).
4. Discussion The absence of effects of CLI or chronic exercise on forced-swim immobility questions the generalizability of the CLI model of depression when it is extended to forced swim immobility. Also, we found that imipramine treatment had no effect on the forced-swim test, consistent with other research that failed to show an anti-immobility effect of imipramine using a water depth that prevents standing by the rat [29]. We administered the swim test at 4 months of age to avoid an exercise detraining effect because wheel running in Sprague–Dawley males typically peaks 6 to 8 weeks after wheel access and decreases thereafter [3]. Administering the swim test at an older age (6 or 7 months) or using a different strain of rat might yield larger effects for immobility, but increased immobility has been reported at age 4 months after neonatal treatment with a SSRI [17]. The immobility durations we observed in the CLI sedentary control and saline control groups were shorter than reported for 6-monthold rats by Velazquez–Moctezuma and Ruiz [8], but in their study, increased swim immobility occurred only during the first 2 min of the 5-min swim. Though the forced-swim test has been reported to have predictive validity for antidepressant pharmaceuticals, numerous studies have reported false negative results for clomipramine, trazodone, and salbutamol [30] and false positive results for several stimulants [31], anticholinergics [32], and anxiolytics [e.g., 33]. Also, though early studies reported that the 5-HT uptake blocker fluoxetine decreased immobility time [30], a recent study found that 5-HT1A agonists reduced swim immobility in rat, but 5-HT reuptake inhibitors had no effect [34]. Others reported that the duration of immobility was increased by 5-HT activity and decreased by 5-HT antagonists [35]. The antidepressant Citalopram, a highly specific SSRI, does not alter swim
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Table 1 Mean (⫾SD) immobility duration and swim ratings during 15-min and 5-min forced-swim tests 15-min forced swim
5-min forced swim
Group
Immobility (s)
Swim rating*
Immobility (s)
Swim rating*
CLI-induced sedentary (n ⫽10) Activity wheel (n ⫽10) Imipramine treatment (n ⫽10) Wheel ⫹ imipramine (n ⫽11) Treadmill training (n ⫽9) Saline vehicle (n ⫽12)
572 ⫾ 113 670 ⫾ 75 615 ⫾ 85 595 ⫾ 178 621 ⫾ 54 552 ⫾ 125
3.10 ⫾ 0.74 3.50 ⫾ 0.97 2.50 ⫾ 0.85 2.73 ⫾ 1.35 2.78 ⫾ 0.67 2.92 ⫾ 1.0
142 ⫾ 49 176 ⫾ 70 151 ⫾ 80 173 ⫾ 65 158 ⫾ 47 123 ⫾ 72
2.60 ⫾ 0.52 3.00 ⫾ 1.05 2.70 ⫾ 0.95 3.00 ⫾ 0.77 2.56 ⫾ 0.88 2.58 ⫾ 1.08
*Scale: 1 ⫽ high swimming to 5 ⫽ mostly floating.
immobility in rat. Finally, evidence for the construct validity of forced swimming as a model of despair remains incomplete [36] and has been challenged [37]. Immobility might represent a learned coping response [38,39] or the absence of panic rather than behavioral despair. Psychopharmacological effects of forced swimming need to be described when the CLI model of depression is used in studies of chronic physical activity. For example, imipramine combined with acute swim stress elicits a greater down-regulation of brain adrenoceptors than does chronic imipramine treatment alone [40], and there are strain differences in forced-swim performance after imipramine treatment [41]. Forced swimming for durations approximating or exceeding 15 min leads to decreased NE and increased 5-HT levels in whole brain, which are normalized 2–6 h later [19]. Release of 5-HT in the striatum is increased during 15 min of forced swimming but habituates rapidly, so no increase is observed during a second bout of swimming 24 h later [42]. A comparison treatment of antidepressants with differing receptor selectivity, such as a 5-HT reuptake blocker (fluoxetine) versus a NE reuptake blocker (desipramine or reboxetine) needs to be studied (e.g., [43]) to determine whether immobility and swimming might be differentially affected [28] by chronic physical activity after neonatal CLI treatment. Also, forced-swim performance could differ between typical depression, which is characterized by psychomotor agitation, and atypical depression, which is characterized by psychomotor retardation [44]. In summary, the present results are not consistent with our other findings of antidepressant-like effects of wheel running [1,16]. In a companion paper on the present study [2], we reported that activity-wheel running enhanced male copulatory performance, concomitantly with increased levels of norepinephrine and decreased -adrenoreceptor binding in brain cortex, after the neonatal CLI treatment. Hence, the results presented here question the generalizability of the CLI model of depression when extended to forced swim immobility. The lack of change in swim immobility after neonatal CLI injections or imipramine treatment further questions the generalizability of the CLI model of depression, as well as the validity of the forced-swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic exercise.
Acknowledgment Thanks go to Gerald W. Vogel for his helpful advice about using the CLI model.
References [1] Dishman RK, Renner KJ, Youngstedt SD, Reigle T, Bunnell BN, Burke KA, Yoo HS, Mougey EH, Meyerhoff JL. Activity-wheel running reduces escape latency and alters brain monoamines after footshock. Brain Res Bull 1997;42:399–406. [2] Yoo HS, Tackett RL, Crabbe JB, Bunnell BN, Dishman RK. Antidepressant-like effects of physical activity vs. imipramine: neonatal clomipramine model. Psychobiology (in press). [3] Dunn AL, Reigle TG, Youngstedt SD, Armstrong RB, Dishman RK. Brain norepinephrine and metabolites after treadmill training and wheel running in rats. Med Sci Sports Exerc 1996;28:204–9. [4] Soares J, Holmes PV, Renner KJ, Edwards G, Bunnell BN, Dishman RK. Brain noradrenergic responses to footshock after chronic activity wheel running. Behav Neurosci 1999;113:558–66. [5] Sothmann MS, Buckworth J, Claytor RP, Cox RH, White–Welkley JE, Dishman RK. Exercise training and the cross-stressor adaptation hypothesis. Exerc Sport Sci Rev 1996;24:267–87. [6] Vogel GW, Neill D, Hagler M, Kors D. A new animal model of endogenous depression: a summary of present findings. Neurosci Biobehav Rev 1990;14:85–91. [7] Bonilla–Jaime H, Retana–Marquez S, Velazquez–Moctezuma J. Pharmacological features of masculine sexual behavior in an animal model of depression. Pharmacol Biochem Behav 1998;60:39–45. [8] Velazquez–Moctezuma J, Ruiz AO. Neonatal treatment with clomipramine increased immobility in the forced swim test: An attribute of animal models of depression. Pharmacol Biochem Behav 1992;42:737–9. [9] Vijayakumar M, Meti BL. Alterations in the levels of monoamines in discrete brain regions of clomipramine-induced animal model of endogenous depression. Neurochem Res 1999;24:345–9. [10] Vogel GW, Neill D, Hagler M, Kors D, Hartley D. Decreased intracranial self-stimulation in a new animal model of endogenous depression. Neurosci Biobehav Rev 1990;14:65–8. [11] Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730–2. [12] Lucki I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 1997;8:523–32. [13] Porsolt RD, Lenegre A, McArthur RA. Pharmacological models of depression. In: Oliver B, Mos J, Slangen JL, editors. Animal Models in Psychopharmacology. Basel, Switzerland: Birkhauser, 1991. pp. 137–159. [14] Mirmaran M, Van de Poll NE, Corner HG, Van Oyen H, Boer G. Suppression of active sleep by chronic treatment with clomipramine during early postnatal development: effect on adult sleep and behavior in the rat. Brain Res 1981;204:129–46. [15] Kinney GG, Vogel GW, Feng P. Decreased dorsal raphe nucleus neu-
H.S. Yoo et al. / Physiology & Behavior 70 (2000) 407–411
[16] [17]
[18]
[19] [20]
[21] [22]
[23] [24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
ronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression. Brain Res 1997;756:68–75. Yavari P, Vogel GW, Neill DB. Decreased raphe unit activity in a rat model of endogenous depression. Brain Res 1993;611:31–6. Hansen HH, Sanchez C, Meier E. Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression? J Pharmacol Exp Ther 1997;283:1333–41. Hansen HH, Mikkelsen JD. Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor. Eur J Pharmacol 1998;352:307–15. Barchas JD, Friedman DX. Brain amines: responses to physiological stress. Biochem Pharmacol 1963;12:1232–5. Chaouloff F, Kennett GA, Serrurrier B, Merino D, Curzon G. Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J Neurochem 1986;46:1647–50. Romanowski W, Grabiec S. The role of serotonin in the mechanism of central fatigue. Acta Physiologica Polonica 1974;25:127–34. Brown BS, Payne T, Kim C, Moore G, Krebs P, Martin W. Chronic response of rat brain norepinephrine and serotonin levels to endurance training. J Appl Physiol 1979;46:19–23. Dunn AL, Dishman RK. Exercise and the neurobiology of depression. Exerc Sport Sci Rev 1991;19:41–98. Hilakivi LA, Hilakivi I. Increased adult behavioral “despair” in rats neonatally exposed to desipramine or zimeldine: an animal model of depression. Pharmacol Biochem Behav 1987;28:367–9. Detke MJ, Johnson J, Lucki I. Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 1997;5:107–12. Vogel GW, Hagler M, Hennessey A, Richard C. Dose-dependent decrements in adult male rat sexual behavior after neonatal clorimipramine treatment. Pharmacol Biochem Behav 1992;54:605–9. Duncan GE, Paul IA, Breese GR. Neuroanatomical differences in the rate of beta-adrenergic receptor adaptation after repeated treatment with imipramine. Psychopharmacol Bull 1993;29:401–7. Detke MJ, Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res 1996;73:43–6. Abel EL, Hannigan JH. The immobility response in the forced swim test: paradoxical effect of imipramine. Eur J Pharmacol 1994;258: 261–4. Porsolt RD. Behavioral despair. In: Enna SJ, Malick JB, Richelson E, editors. Antidepressants: Neurochemical, Behavioral and Clinical Perspectives. New York: Raven Press, 1981. pp. 121–39. Howard JL, Ferris RM, Cooper BR, Soroko FE, Wang CM, Pollard
[32] [33]
[34] [35]
[36]
[37] [38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
411
GT. Models of depression used in the pharmaceutical industry. In: Koob GF, Ehlers CL, Kupfer DJ, editors. Animal Model of Depression. Boston: Birkhauser, 1989. pp. 187–203. Browne RG. Effects of antidepressants and anticholinergics in a mouse behavioral despair test. Eur J Pharmacol 1979;58:331–4. Prince CR, Collins C, Anisman H. Stress-provoked response patterns in a swim task: modification by diazepam. Pharmacol Biochem Behav 1988;24:323–8. Borsini F. Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 1995;19:377–95. Gibson CJ, Deikel SM, Young SN, Binik YM. Behavioral and biochemical effects of tryptophan tyrosine and phenylalanine in mice. Psychopharmacology 1982;76:118–21. Willner P. Animal models of depression: validity and applications. In: Gessa G, Fratta W, Pani L, Serra G, editors. Depression and Mania: From Neurobiology to Treatment. New York: Raven Press, 1995. pp. 19–41. Borsini F, Volterra G, Meli A. Does the behavioral “despair” test measure “despair”. Physiol Behav 1986;38:385–6. De Pablo JM, Ortiz–Caro J, Sanchez–Santed F, Guillamon A. Effects of diazepam, pentobarbital, scopolamine and the timing of saline injection on learned immobility in rats. Physiol Behav 1991;50:895–9. De Pablo JM, Parra A, Segovia S, Guillamon A. Learned immobility explains the behavior of rats in the forced swimming test. Physiol Behav 1989;46:229–37. Duncan GE, Paul IA, Harden K, Mueller RA, Stumpf WE, Breese GR. Rapid down regulation of beta adrenergic receptors by combining antidepressant drugs with forced swim: a model of antidepressant-induced neural adaptation. J Pharmacol Exp Ther 1985;234: 402–8. Paul IA, Duncan GE, Kuhn C, Mueller RA, Hong J–S, Breese GR. Neural adaptation in imipramine-treated rats processed in forced swim test: assessment of time course, handling, rat strain and amine uptake. J Pharmacol Exp Ther 1990;252:997–1005. Kirby LG, Lucki I. The effect of repeated exposure to forced swimming on extracellular levels of 5-hydroxytryptamine in the rat. Stress 1999;2:251–63. Reneric JP, Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacol 1998;136:190–7. Koob GF. Anhedonia as an animal model of depression. In: Koob GF, Ehlers CL, Kupfer DJ, editors. Animal Model of Depression. Boston: Birkhauser, 1989. pp. 162–83. White–Welkley JE, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK. Treadmill training and estradiol moderate hypothalamicpituitary-adrenal cortical responses to acute running and immobilization. Physiol Behav 1995;57:533–40.