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Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains
Bruin Restarch Bufierin. Vol. 32, pp. 471475, Printed in
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1993
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0361-923Of93 $6.00 + .OfI 0 I993 Pergamon Press Ltd.
Effect of Chronic Antidepressant Treatment on Responses to Apomo~hine in Selectively Bred Rat Strains OLGIERD
PUCILOWSKI’
AND DAVID
H. ~VERSTREET
Skipper Bowles Center-for Alcohol Studies and Department of Psychiatry, University of North Carolina at Chapel Hill, School qf Medicine, Chapel H&, NC 2 7.599-7115 PUCILOWSKI, 0. AND D. H. OVERSTREET. Effect chronic antidepressant trraimeni on rmponses to upmorphine in sdectively bred rat strains. BRAIN RES BULL 32(5) 471-475, 1993.-The purpose of this study was to verify the dopamine-
of
sensitizing behavioral effect of chronic antidepressant treatment in two selectively bred rat strains: the hy~rcholiner~c Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL). Two antidepres~nts. desipramine HCI (DMI) and sertraline HCI, were injected IP in separate groups of FSL and FRL rats in a dose of 16.5rmol/kg twice daily for 16 days. Twenty-four hours after withdrawal, locomotor and hypothermic responses to 0.2 mg/kg of apomorphine, SC, were examined. Attenuation of the effect of apomorphine was observed in the open held: FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was found in FSL rats. Chronic DMI resulted in similar changes in the locomotor activity. Sertraline treatment decreased apomo~hine-induced hy~the~ia by almost half in FSLs, whereas slight hy~~hermia was induced in FRL rats instead. The present results suggest that in these selectively bred strains, a serotonergic antidepressant such as sertraline may have sensitized dopaminergic autoreceptors and/or desensitized postsynaptic receptors, Apomorphine-induced hypothermia could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment. Chronic antidepressants Behavioral supersensitivity Hypothermia Locomotor activity Serotonin
Apomorphine Desipramine
Flinders sensitive line Sertraline
Dopamine
induced stereotypy following chronic antidepressants, are much less conclusive ( 1I ,3 I ,38). The results of subsequent microinjection studies supported the notion that prolonged antidepressant administration enhances dopaminergic transmission in the mesolimbic system, but not nigrost~atal or m~ohippocampa1 pathways (10,25,27). The effect of chronic antidepressant treatment on dopaminergic, as well as other monoaminergic systems, has employed almost exclusively normal, outbred rodents. It is known, however, that the ~havioral r~~nsiven~ to dopamjne~c agonists (locomotion, aggression) varies greatly among individuals in an outbred rodent population [e.g., (28,29)], casting some doubt on the generality of the conclusions regarding antidepressantinduced dopaminergic sensitization. The present experiments were intended to examine the effectiveness of select antidepressants in Flinders Sensitive Line (FSL) of rats-a putative genetic model of depression (23)-and to evaluate their potency to induce behavioral su~~nsitivity to apomorphine in this genetically selected and, thus, more homogeneous sample. Although in breeding of FSL rats brother-sister mating has been consistently avoided, it is anticipated that they are still more than 70% inbred at the present time (20). The FSL rats were originally proposed as a genetic animal model of depression because they
changes in sensitivity of interacting central aminergic systems have been attributed for the clinical effect of chronically administered antidepressant drugs (39). The most soiid evidence implies a facilitatory effect on noradrenergic transmi~ion (alpha, adren~e~tor upregulation, alpha2 adrenoceptor downregulation) as a most likely biological mechanism by which chronically administered antidepressants exert their therapeutic action (9,12). Serotonergic and cholinergic mechanisms are also likely to be involved in central actions of antidepressants (5,7.26). Interest in the dopamine~ic system was prompted by experimental evidence suggesting that forebrain dopamine may mediate reward-reinforcement (6), whereas it is known that inability to experience pleasure (reward), referred to as anhedonia, is one of the major clinical symptoms of depression (39). Considerable evidence was collected suggesting that chronic, but not acute, treatment with antidepressant drugs can facilitate behavioral responses to dopaminergic drugs (38). Specifically, chronic, but not acute, antidepressants enhanced amphetamine-induced locomotion or apomo~~ine-induced locomotion and aggression (10,l 1,13,33), the phenomena thought to be mediated by the mesolimbic dopamine (8,29). However, the data on similar adaptive changes in the nigrostriatal system function, as evidenced by alterations in the apomorphineNEUROA~APTIVE
’ Requests for reprints should be addressed to Dr. Olgierd Pucilowski, UNC-Center for Alcohol Studies, Medical Research Building A, CB# 7 175, Chapel Hill, NC 27599-7175.
471
exhibited supersensitive responses to cholinergic agonists (2 I ). as do human depressives (5.7). Many other similarities between the FSL rats and depressed humans have also been recognized. These include lower body weight, reduced activity. increased REM sleep, learning difficulties. and increased immobility when exposed to stressors (21). Thus. FSL rats resemble depressed humans in a multitude of variables and, therefore. this model satishes the criterion of face validity. FSL rats also satisfy the criterion of predictive validity. because the immobility exhibited by the FSL rats when exposed to mild stressors (e.g.. foot shock. forced swim) can be counteracted by the classical tricyclic antidepressants imipramine and desipramine (20.32) and the atypical/new generation antidepressants rolipram (24) and sertraline (32). The FSL rats also exhibit altered responses to dopaminergic agonists: they are supersensitive to agonist-induced hypothermia (3) and aggression (30). but subsensitive to the stereotypy-inducing effect of apomorphine (3). There were two goals of this study. The hrst one was to confirm the effectiveness of chronic antidepressant treatment. and to compare it with the effect of typical subacute treatment. in counteracting increased immobility of FSL rats tested in the forced swim model. The second was to determine whether chronic antidepressant administration would result in enhanced responsiveness to apomorphine (dopaminergic supersensitivity) as verified by changes in hypothermic and locomotor responsiveness. METHOD
Male rats from the colonies of the FSL and FRL rats maintained in the Center for Alcohol Studies, University of North Carolina School of Medicine were used. They were approximately 70 days old and weighed a minimum of 300 g at the beginning of the study. All the rats had been previously challenged with oxotremorine to confirm their designation to either line (2 I). The rats were housed in groups of two to three per cage (25 X 45 X 20 cm), under reversed phase 12L: l2D cycles (lights off at 1000 h) in a temperature (21 +- I”C)-controlled room with free access to food and water.
The following compounds were used: apomorphine HCI, desipramine HCI (DMI) (both obtained from Sigma, St. Louis, MO) and sertraline HCl (a gift from Pfizer, Groton. CT). DMI and sertraline were dissolved in saline and administered in a volume of 2 ml/kg, apomorphine was dissolved in 0.2% ascorbic acid and administered in an injection volume of I ml/kg. Protocol
Subacute experiment. Equal numbers of FSL and FRL rats (24 each) were first preexposed for 15 min to the swim test. They were then randomly divided into three equal groups within each line to be treated with DMI, sertraline or a vehicle (saline). Each antidepressant was injected IP in a dose of 16.5 rmol/kg (5 mg/ kg DMI, 5.7 mg/kg sertraline) three times, at I5 min after pretest as well as 5 h and I h prior to a second swim test (5 min) performed 24 h after the pretest. The doses of antidepressants were selected based on our own experience and on the published literature ( I ). C’hronic experiment. Each antidepressant was injected IP in separate groups of FSL and FRL rats (six randomly assigned rats per group) in a dose of 16.5 pmol/kg twice daily, at 0830 and 1630 h. Control groups of FSL and FRL rats were similarly
treated with saline. Afttx I4 dabs of treatmum. 21 I1 aiict vvitl~drawal. the elfectivencss of armdepressants was \criticd lvith a forced swim test. The antidepressant treatment was then reinstated for a further 2 days after which, following another 24-h withdrawal period. hypothermic and locomotor (open held) rcsponses to 0.2 mg/kg of apomorphine, SC. were examined. 1’1.OW~111.f’\ Behavioral observations were carried out between 0900 and 1000 h in an experimental room next to the animal room under the same light and temperature conditions as in the animal room. The observer was unaware of the type of treatment applied to each rat. f*‘orccu srcijn fc~. Each rat was placed in a clear plastic cylinder ( 18 cm diameter. 40 cm high) filled up to a depth of 25 cm with warm (25°C) water. Because FSL rats consistently exhibit much higher immobility scores than FRL rats (2 I ). a single exposure to the swim tank was used in the chronic treatment experiment. The cumulative duration of immobility was scored over 5-min period. A rat was considered to stop swimming when both hind paws and at least one front paw were immobile. Following the test, each rat was dried under a heat lamp for IO min before being returned to its home cage. .,lpomorphine-indl4ceu’ locomotion and hypothermici. On the day of experiment, the basal temperature was first established as an average of two measurements spaced 15 min apart, T,,. Colonic temperature was recorded with a BAT-12 digital thermometer (Sensortek. Clifton. NJ). with a resolution of 0. I “C. Each rat was removed from its home cage, placed on a table. and a lubricated thermistor probe was inserted 6 cm into the rectum for approximately 30 s. The rats were returned to their home cages between temperature measurements. After taking the second baseline temperature reading, each rat was injected SC with apomorphine and carried over to the neighboring experimental room where the open field test was carried out 5 min later. The open field was a wooden square arena (80 X 80 cm). painted white inside, its floor divided into 36 equal squares. The rat was placed in one of the corners and the number of square crossings was recorded over 5 min by direct observation. The open field was wiped clean between observations and after the test each rat was immediately returned to its home cage. Subsequently. the third temperature measurement was performed 70 min after apomorphine injection, Tzo. The apomorphineinduced hypothermia was expressed as the difference between T,, and T:,,.
‘The data were analyzed using a two-way ANOVA with the rat line and treatment as factors. Between-group comparisons were then made with the Newman-Keuls test (36). All results are expressed as means f SEM and a confidence limit of I, i 0.05 was considered as statistically significant. RESULTS
Subacute treatment with DMI or sertraline failed to affect the immobility in either line of rats. This is based on lack of significant treatment effect. F(2,42) = 1.15, or interaction treatment X line, F(2, 42) = 0.13, in the ANOVA. Characteristically enhanced immobility of the FSL rats in the swim test. as compared to FRLs, was evident in all three treatment groups, F( I, 42) = 53.62. p < 0.001 (Fig. 1). Control, saline-treated FSL rats were significantly @ < 0.001) more immobile than control FRL rats, F( 1. 30) = 83.19, con-
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80 SUf3AClKE TREATMENT
CHRONIC TREATMENT I
SALINE
DMI
SERTRALINE SALINE
DMI
I. The effect of subacute and chronic antidepressant treatment on immobility of FRI.. and FSL rats in the forced swim test. Means k SEM from eight rats per group. subacute experiment. and six rats per group, chronic ex~riment. *I, <: 0.05 vs. FRL. l p < 0.05 vs. saline-treated controls (Newman-Keuls test).
sistent with previously published evidence (32). Chronic treatment with antidepressants significantly reduced overall immobility in both FSL and FRL rats, F(2, 30) = 10.01, p < 0.01.
The effect of both antidepressants was particularly evident in highly immobile FSL rats; DMI reduced immobility by 41%, sertraline by 28% in these animals (Fig. I). However, the clear difference in the swim time between the two lines was not changed by either antidepressant, F(2, 30) = 0.77. There was a significant (p < 0.01) overall difference in locomotor response to apomo~hine between FSL and FRL rats (line effect). F( I, 30) = 17.59. Also treatment effect was found to be significant, F(2. 30) = 5.66, p < 0.01. Lack of significant interaction line X treatment, F(2, 30) - 0.88, indicates that direction of changes in responsiveness to apomo~hine brought about by either antidepressant was similar in both rat lines. It is noteworthy that although the FSL rats withdrawn from either DMI or sertraline tended to be less responsive to apomo~hine than control FSL group, they appeared more active than corresponding FRL groups. In fact, sertraline-withdrawn FRL rats were significantly less active than both saline-treated FRL controls and sertraline-withdrawn FSLs (Fig. 2). There was, as expected, a highly significant overall difference in the thermic response to apomorphine between FSL and FRL rats, 9 1,30) = 181.69,p < 0.00 1. The treatment effect was also significant, F(2,30) = 48.63, p < 0.001, whereas no significance was found for the line X treatment interaction. F(2, 30) = 0.80. The influence chronic DMI treatment had on responsiveness to apomorphine was nondistinguishable from that of saline: in both cases apomorphine induced significantly greater 0, < 0.01) hypothermia in FSL than in FRL rats (Fig. 3). In contrast, following chronic sertraline treatment. the hypothermic response to apomorphine in FSL rats was significantly blunted, whereas slight hyperthermia was actually observed in FRLs.
I
SALINE
SERTRALINE
IX?.
El
FRI.
629 FSL
SERTRALINE
DMI
FIG. 2. The effect ofchronic antidepressant treatment on apomorphineinduced locomotor activity in FRL and FSL rats. Means rt SEM from six rats per group. *I, c 0.05 vs. FRL, l p i 0.05 vs. saline-treated controls (Newman-Keuls test).
both control and DMI-withdrawn groups. Senraline treatment decreased this effect of dopamine agonist by almost half in FSLs and actually induced a slight hyperthermia in FRL rats instead. Similarly decreased effect of apomo~hine was observed in the open field. FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was observed in FSL rats. The present results, thus, appear to contradict the existing evidence that suggests that sensitization of behavioral responses to dopaminergic agonists develops as a consequence of chronic treatment with tricyclic and atypical antidepressants [see (10,38)]. Neither antidepressant used in our study produced sensitization to effects of apomorphine, and, actually, sertraline even decreased responsiveness to the dopamine agonist. As there might be different reasons for changes in responsiveness to apomo~hine in both tests, they will be discussed separateiy. The hypothermic response to apomorphine is thought to be mediated by Dz dopaminergic receptors (15-18) within the preoptic anterior hypothalamus (POAH) (2.37). The arguments presented earlier (see the Introduction section) that behavioral sensitization to dopamine agonists following withdrawal from chronic antidepressants is observed in the mesolimbie system
0
FRL
fXi
FSL
l.OI
DISCUSSION
One of the characteristics of FSL rats that has been presently confirmed is that these rats show si~ni~cantly higher immobiljty than FRL rats in the forced swim test (20-22). Both antidepressants significantly decreased immobility although the between-line difference persisted on either treatment. As expected (3), FSLs responded to apomo~hine with significan~y greater hypothermia than FRL rats, the difference being about 1“C in
-2.0
I)
J SA!_lNE
DMI
SER~INE
FIG. 3. The effect of chronic antidepressant treatment on apomorphineinduced hypothermia in FRL and FSL rats expressed as the difference in core temperature from the baseline. Means i. SEM from six rats per group. *p < 0.05 vs. FRL, p < 0.05 vs. saline-treated controls (NewmanKeuls test).
(nucleus accumbens) but not in the striatum or hippocampus f 10,25,27). The present results suggest that dopaminergic synapses within the POAH responsible for a~mo~hine-jnduced hypothermia also appear to be resistant to the sensitizing effect of chronic antidepressants. Fiypercholinergic FSL rats typically respond with greater hypothermia to dopamine agonists (apomorphine, quinpirole) than do FRL rats (3). Consequently, lack of potentiation of the hypothermic effect of apomorphine in DMI withdrawn FSL rats might be attributed to already near maximal thermic effect of apomo~hine in these animals (ceiling effect). However, there was also no potentiation of the effect following withdrawal from DMI in FRL rats, which normally respond to apomorphine with moderate hypothermia. Unexpectedly, there was significant attenuation (and even reversal in FRL rats) of the hypothermic response to apomorphine in both lines of rats after withdrawal from treatment with the specific serotonin reuptake blocker sertraline. This may indicate that adaptive changes that developed in the serotonergic system activity modify the thermic effect of apomorphine. Such an explanation would be consistent with the proposal of a serotonergic link in the apomorphine-induced hypothermia (2). It is conceivable that normally augmented hypothermic response to apomo~hine in FSL rats is dependent to large extent on supersensitive serotonergic and choiinergic mechanisms within the hypothalamus. FSL rats, in addition to dopamine agonists, arc supersensitive to the hypothermic effects induced by serotonergic (mCPP, buspirone) and muscarinic agonists (oxotremorine) [see (20) for review]. It has been known for some time that apomorphine increases serotonin and acetylcholine concentrations in the brain (4). The effect on serotonergi~ neurons may be region-specific as apomorphine, or dopamine, perfusion enhances the release of [3H]serotonin from the prelabelled hypothalamic. but not hippocampal slices (2). Moreover, the serotonergic antagonists, methysergide or cyproheptadine, antagonize the hypothermic elect of intrahypothalamically injected dopamine or serotonin, but have no effect on oxotremorine-induced hypothermia (2). There is no indication of dopamincrgic receptor su~rsensitivity in the FSL rat (3) that could explain exaggerated hypothermic response to apomorphine. Rather, we propose that serotonergic-1A (5-HT,,J and/or muscarinic receptors are indirectly involved in that effect of dopamine agonists. Our recent unpublished observations that pretreatment with methysergide suppresses apomo~hine-induced hypothermia in FSL rats (20) further supports the above notion. Chronic sertraline treatment would lead to increased availability of serotonin in the central synapses and consequent sustained stimulation of serotonergic receptors resulting in their subsensitivity. It has been demonstrated that prolonged stimulation of 5-HT,Areceptors results in a decreased hypothermic response to 5-HT,,agonist 8-OHDPAT. Conversely, chronic administration of 5-HTz agonist does not affect res~nsiveness of these receptors in thermoregulatory responses (19). The residual hypothermic eff‘ectof apomorphine in FSL rats withdrawn from chronic sertraline might be due to apomorphine-induced release of acetylcholine acting at supersensitive muscarinic receptors. The slight, but significant, hyperthermia that was induced in FRL rats withdrawn from sertraline by apomorphine injection is difficult to explain. However, we obtained virtually the same results in naive FRL rats injected with apomorphine following pretreatment with methysergide (20). Theoretically, the hyperthermia could be a consequence of the prevalence of 5-HT2 over 5-HT1, receptors (19) and/or dopaminergic D, over D2 receptors f 17). If supersensitive 5-HTTIAreceptors in FSL rats are only suppressed to some extent, then the same receptors in normosensitive FRL rats might be rendered subsensitive by chronic
scrtraline. thus permitting S-H_P-mediated hyperthermia to appear. As the endogenous amine has higher allinity fhr F-HT, than 5-HTZ receptors. this mechanism seem likely. Chronic treatment with classical tricyclir. antidepressants as well as specific scrotonin reuptake blockers (citalopram, Limelidine. fluoxetine) has been shown to augment amphetamincor apomorphine-induced locomotion (I 3,34.35). Thus. the present results with apomorphine-induced locomotion are in contrast to what is known from the literature. However. at least one other study reports that although chronic DMf produces prolonged (S-day) potentiation of amphetanljne-included locomotion. serotonin uptake blockers (zimelidinc, iluoxetine) do not ( 14). Because DMl has the most pronounced anticholinergic action of these antidepressants, and because similar potentiation of amphetamine-induced locomotion followed withdrawal from chronic scopolamine, the authors suggested that the effect of chronic DMI may be secondar? to its anticholincrgi~ properties (14). In our rats. both FRL and FSL, DMl failed to change apomorphine-induced locomotor response. FSL rats are genetically selected to he supersensitive to cholinergic agonists (23). and It is likely the! are unable to react with further increase in cholinergic sensitivltv to prolonged administration ofcholinolytic agents. The reason why FRL rats withdrawn from DMI similarly failed to react with enhanced response to aporn~)r~~h~ncis unclear. These rats. normosensitive in terms of their responsiveness to cholinergic agonists. appear to be resistant to the sensitizing effect of chronic DMI on dopaminergic transmission. One of the reasons why we decided to study the effect of chronic antidepressants on behavioral responsiveness to dopaminergit agonist in FSI. and FRL rats was a failure to demonstrate in previous experiments (Pucilowski. uIlpublished observations) j~otentiation oi apomo~hine-induced aggression in rats withdrawn from chronic DMI or citalopram. Such a potentiation was earlier described in outbred, unselected Wistar rats ( I I). Our negative findings were obtained using male Wistar rats previously selected for lack ofaggressive response to apomorphine (nonaggressive rats). Interestingly enough. FRL rats are also resistant to aggressioninducing effect of apomorphine (30). It may be that the initial, inborn sensitivity to a dopaminergic agonist weighs upon suhsequent appearance of behavioral sensitization in the mesolimbic system following withdrawal from chronic antidepressant treatment. In conclusion, the present results do not support the notion that chronic antidepre~ants produce generalized sensitization to dopami~ergic agonists. Moreover. the serotonin uptake blocker. sertraline appears to decrease responsiveness to hypothermic and locomotor effects of apomorphinc in the two selectively bred rat strains. FSL and FRL. The results seem to suggest that in these selectively bred strains a serotonergic antidepressant such as sertraline brought about sensitization of dopaminergic autoreceptors responsible for hypolo~omotion. Although withdrawal from chronic DMI resulted in qualitatively similar changes in the open field behavior, surprisingly sertralinebut not DMl-treated groups exhibited decrease in the hypothermic response to apomorphine. The effect of apomorphine on temperature could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment. Our results thus stress the potential differences in dopaminergi~ responsiveness following withdrawal from different antidepressants as well as point to the usefulness of using selectively bred strains to uncover subtle changes in drug-induced responses. ACKNOWLEDGEMENTS We
thank Patricia Garges for technical assistance. A gift of sertraline from Pfizer Inc. is gratefully acknowledged.
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the USA.
All
1993
Copyright
rights reserved.
0361-923Of93 $6.00 + .OfI 0 I993 Pergamon Press Ltd.
Effect of Chronic Antidepressant Treatment on Responses to Apomo~hine in Selectively Bred Rat Strains OLGIERD
PUCILOWSKI’
AND DAVID
H. ~VERSTREET
Skipper Bowles Center-for Alcohol Studies and Department of Psychiatry, University of North Carolina at Chapel Hill, School qf Medicine, Chapel H&, NC 2 7.599-7115 PUCILOWSKI, 0. AND D. H. OVERSTREET. Effect chronic antidepressant trraimeni on rmponses to upmorphine in sdectively bred rat strains. BRAIN RES BULL 32(5) 471-475, 1993.-The purpose of this study was to verify the dopamine-
of
sensitizing behavioral effect of chronic antidepressant treatment in two selectively bred rat strains: the hy~rcholiner~c Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL). Two antidepres~nts. desipramine HCI (DMI) and sertraline HCI, were injected IP in separate groups of FSL and FRL rats in a dose of 16.5rmol/kg twice daily for 16 days. Twenty-four hours after withdrawal, locomotor and hypothermic responses to 0.2 mg/kg of apomorphine, SC, were examined. Attenuation of the effect of apomorphine was observed in the open held: FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was found in FSL rats. Chronic DMI resulted in similar changes in the locomotor activity. Sertraline treatment decreased apomo~hine-induced hy~the~ia by almost half in FSLs, whereas slight hy~~hermia was induced in FRL rats instead. The present results suggest that in these selectively bred strains, a serotonergic antidepressant such as sertraline may have sensitized dopaminergic autoreceptors and/or desensitized postsynaptic receptors, Apomorphine-induced hypothermia could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment. Chronic antidepressants Behavioral supersensitivity Hypothermia Locomotor activity Serotonin
Apomorphine Desipramine
Flinders sensitive line Sertraline
Dopamine
induced stereotypy following chronic antidepressants, are much less conclusive ( 1I ,3 I ,38). The results of subsequent microinjection studies supported the notion that prolonged antidepressant administration enhances dopaminergic transmission in the mesolimbic system, but not nigrost~atal or m~ohippocampa1 pathways (10,25,27). The effect of chronic antidepressant treatment on dopaminergic, as well as other monoaminergic systems, has employed almost exclusively normal, outbred rodents. It is known, however, that the ~havioral r~~nsiven~ to dopamjne~c agonists (locomotion, aggression) varies greatly among individuals in an outbred rodent population [e.g., (28,29)], casting some doubt on the generality of the conclusions regarding antidepressantinduced dopaminergic sensitization. The present experiments were intended to examine the effectiveness of select antidepressants in Flinders Sensitive Line (FSL) of rats-a putative genetic model of depression (23)-and to evaluate their potency to induce behavioral su~~nsitivity to apomorphine in this genetically selected and, thus, more homogeneous sample. Although in breeding of FSL rats brother-sister mating has been consistently avoided, it is anticipated that they are still more than 70% inbred at the present time (20). The FSL rats were originally proposed as a genetic animal model of depression because they
changes in sensitivity of interacting central aminergic systems have been attributed for the clinical effect of chronically administered antidepressant drugs (39). The most soiid evidence implies a facilitatory effect on noradrenergic transmi~ion (alpha, adren~e~tor upregulation, alpha2 adrenoceptor downregulation) as a most likely biological mechanism by which chronically administered antidepressants exert their therapeutic action (9,12). Serotonergic and cholinergic mechanisms are also likely to be involved in central actions of antidepressants (5,7.26). Interest in the dopamine~ic system was prompted by experimental evidence suggesting that forebrain dopamine may mediate reward-reinforcement (6), whereas it is known that inability to experience pleasure (reward), referred to as anhedonia, is one of the major clinical symptoms of depression (39). Considerable evidence was collected suggesting that chronic, but not acute, treatment with antidepressant drugs can facilitate behavioral responses to dopaminergic drugs (38). Specifically, chronic, but not acute, antidepressants enhanced amphetamine-induced locomotion or apomo~~ine-induced locomotion and aggression (10,l 1,13,33), the phenomena thought to be mediated by the mesolimbic dopamine (8,29). However, the data on similar adaptive changes in the nigrostriatal system function, as evidenced by alterations in the apomorphineNEUROA~APTIVE
’ Requests for reprints should be addressed to Dr. Olgierd Pucilowski, UNC-Center for Alcohol Studies, Medical Research Building A, CB# 7 175, Chapel Hill, NC 27599-7175.
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exhibited supersensitive responses to cholinergic agonists (2 I ). as do human depressives (5.7). Many other similarities between the FSL rats and depressed humans have also been recognized. These include lower body weight, reduced activity. increased REM sleep, learning difficulties. and increased immobility when exposed to stressors (21). Thus. FSL rats resemble depressed humans in a multitude of variables and, therefore. this model satishes the criterion of face validity. FSL rats also satisfy the criterion of predictive validity. because the immobility exhibited by the FSL rats when exposed to mild stressors (e.g.. foot shock. forced swim) can be counteracted by the classical tricyclic antidepressants imipramine and desipramine (20.32) and the atypical/new generation antidepressants rolipram (24) and sertraline (32). The FSL rats also exhibit altered responses to dopaminergic agonists: they are supersensitive to agonist-induced hypothermia (3) and aggression (30). but subsensitive to the stereotypy-inducing effect of apomorphine (3). There were two goals of this study. The hrst one was to confirm the effectiveness of chronic antidepressant treatment. and to compare it with the effect of typical subacute treatment. in counteracting increased immobility of FSL rats tested in the forced swim model. The second was to determine whether chronic antidepressant administration would result in enhanced responsiveness to apomorphine (dopaminergic supersensitivity) as verified by changes in hypothermic and locomotor responsiveness. METHOD
Male rats from the colonies of the FSL and FRL rats maintained in the Center for Alcohol Studies, University of North Carolina School of Medicine were used. They were approximately 70 days old and weighed a minimum of 300 g at the beginning of the study. All the rats had been previously challenged with oxotremorine to confirm their designation to either line (2 I). The rats were housed in groups of two to three per cage (25 X 45 X 20 cm), under reversed phase 12L: l2D cycles (lights off at 1000 h) in a temperature (21 +- I”C)-controlled room with free access to food and water.
The following compounds were used: apomorphine HCI, desipramine HCI (DMI) (both obtained from Sigma, St. Louis, MO) and sertraline HCl (a gift from Pfizer, Groton. CT). DMI and sertraline were dissolved in saline and administered in a volume of 2 ml/kg, apomorphine was dissolved in 0.2% ascorbic acid and administered in an injection volume of I ml/kg. Protocol
Subacute experiment. Equal numbers of FSL and FRL rats (24 each) were first preexposed for 15 min to the swim test. They were then randomly divided into three equal groups within each line to be treated with DMI, sertraline or a vehicle (saline). Each antidepressant was injected IP in a dose of 16.5 rmol/kg (5 mg/ kg DMI, 5.7 mg/kg sertraline) three times, at I5 min after pretest as well as 5 h and I h prior to a second swim test (5 min) performed 24 h after the pretest. The doses of antidepressants were selected based on our own experience and on the published literature ( I ). C’hronic experiment. Each antidepressant was injected IP in separate groups of FSL and FRL rats (six randomly assigned rats per group) in a dose of 16.5 pmol/kg twice daily, at 0830 and 1630 h. Control groups of FSL and FRL rats were similarly
treated with saline. Afttx I4 dabs of treatmum. 21 I1 aiict vvitl~drawal. the elfectivencss of armdepressants was \criticd lvith a forced swim test. The antidepressant treatment was then reinstated for a further 2 days after which, following another 24-h withdrawal period. hypothermic and locomotor (open held) rcsponses to 0.2 mg/kg of apomorphine, SC. were examined. 1’1.OW~111.f’\ Behavioral observations were carried out between 0900 and 1000 h in an experimental room next to the animal room under the same light and temperature conditions as in the animal room. The observer was unaware of the type of treatment applied to each rat. f*‘orccu srcijn fc~. Each rat was placed in a clear plastic cylinder ( 18 cm diameter. 40 cm high) filled up to a depth of 25 cm with warm (25°C) water. Because FSL rats consistently exhibit much higher immobility scores than FRL rats (2 I ). a single exposure to the swim tank was used in the chronic treatment experiment. The cumulative duration of immobility was scored over 5-min period. A rat was considered to stop swimming when both hind paws and at least one front paw were immobile. Following the test, each rat was dried under a heat lamp for IO min before being returned to its home cage. .,lpomorphine-indl4ceu’ locomotion and hypothermici. On the day of experiment, the basal temperature was first established as an average of two measurements spaced 15 min apart, T,,. Colonic temperature was recorded with a BAT-12 digital thermometer (Sensortek. Clifton. NJ). with a resolution of 0. I “C. Each rat was removed from its home cage, placed on a table. and a lubricated thermistor probe was inserted 6 cm into the rectum for approximately 30 s. The rats were returned to their home cages between temperature measurements. After taking the second baseline temperature reading, each rat was injected SC with apomorphine and carried over to the neighboring experimental room where the open field test was carried out 5 min later. The open field was a wooden square arena (80 X 80 cm). painted white inside, its floor divided into 36 equal squares. The rat was placed in one of the corners and the number of square crossings was recorded over 5 min by direct observation. The open field was wiped clean between observations and after the test each rat was immediately returned to its home cage. Subsequently. the third temperature measurement was performed 70 min after apomorphine injection, Tzo. The apomorphineinduced hypothermia was expressed as the difference between T,, and T:,,.
‘The data were analyzed using a two-way ANOVA with the rat line and treatment as factors. Between-group comparisons were then made with the Newman-Keuls test (36). All results are expressed as means f SEM and a confidence limit of I, i 0.05 was considered as statistically significant. RESULTS
Subacute treatment with DMI or sertraline failed to affect the immobility in either line of rats. This is based on lack of significant treatment effect. F(2,42) = 1.15, or interaction treatment X line, F(2, 42) = 0.13, in the ANOVA. Characteristically enhanced immobility of the FSL rats in the swim test. as compared to FRLs, was evident in all three treatment groups, F( I, 42) = 53.62. p < 0.001 (Fig. 1). Control, saline-treated FSL rats were significantly @ < 0.001) more immobile than control FRL rats, F( 1. 30) = 83.19, con-
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80 SUf3AClKE TREATMENT
CHRONIC TREATMENT I
SALINE
DMI
SERTRALINE SALINE
DMI
I. The effect of subacute and chronic antidepressant treatment on immobility of FRI.. and FSL rats in the forced swim test. Means k SEM from eight rats per group. subacute experiment. and six rats per group, chronic ex~riment. *I, <: 0.05 vs. FRL. l p < 0.05 vs. saline-treated controls (Newman-Keuls test).
sistent with previously published evidence (32). Chronic treatment with antidepressants significantly reduced overall immobility in both FSL and FRL rats, F(2, 30) = 10.01, p < 0.01.
The effect of both antidepressants was particularly evident in highly immobile FSL rats; DMI reduced immobility by 41%, sertraline by 28% in these animals (Fig. I). However, the clear difference in the swim time between the two lines was not changed by either antidepressant, F(2, 30) = 0.77. There was a significant (p < 0.01) overall difference in locomotor response to apomo~hine between FSL and FRL rats (line effect). F( I, 30) = 17.59. Also treatment effect was found to be significant, F(2. 30) = 5.66, p < 0.01. Lack of significant interaction line X treatment, F(2, 30) - 0.88, indicates that direction of changes in responsiveness to apomo~hine brought about by either antidepressant was similar in both rat lines. It is noteworthy that although the FSL rats withdrawn from either DMI or sertraline tended to be less responsive to apomo~hine than control FSL group, they appeared more active than corresponding FRL groups. In fact, sertraline-withdrawn FRL rats were significantly less active than both saline-treated FRL controls and sertraline-withdrawn FSLs (Fig. 2). There was, as expected, a highly significant overall difference in the thermic response to apomorphine between FSL and FRL rats, 9 1,30) = 181.69,p < 0.00 1. The treatment effect was also significant, F(2,30) = 48.63, p < 0.001, whereas no significance was found for the line X treatment interaction. F(2, 30) = 0.80. The influence chronic DMI treatment had on responsiveness to apomorphine was nondistinguishable from that of saline: in both cases apomorphine induced significantly greater 0, < 0.01) hypothermia in FSL than in FRL rats (Fig. 3). In contrast, following chronic sertraline treatment. the hypothermic response to apomorphine in FSL rats was significantly blunted, whereas slight hyperthermia was actually observed in FRLs.
I
SALINE
SERTRALINE
IX?.
El
FRI.
629 FSL
SERTRALINE
DMI
FIG. 2. The effect ofchronic antidepressant treatment on apomorphineinduced locomotor activity in FRL and FSL rats. Means rt SEM from six rats per group. *I, c 0.05 vs. FRL, l p i 0.05 vs. saline-treated controls (Newman-Keuls test).
both control and DMI-withdrawn groups. Senraline treatment decreased this effect of dopamine agonist by almost half in FSLs and actually induced a slight hyperthermia in FRL rats instead. Similarly decreased effect of apomo~hine was observed in the open field. FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was observed in FSL rats. The present results, thus, appear to contradict the existing evidence that suggests that sensitization of behavioral responses to dopaminergic agonists develops as a consequence of chronic treatment with tricyclic and atypical antidepressants [see (10,38)]. Neither antidepressant used in our study produced sensitization to effects of apomorphine, and, actually, sertraline even decreased responsiveness to the dopamine agonist. As there might be different reasons for changes in responsiveness to apomo~hine in both tests, they will be discussed separateiy. The hypothermic response to apomorphine is thought to be mediated by Dz dopaminergic receptors (15-18) within the preoptic anterior hypothalamus (POAH) (2.37). The arguments presented earlier (see the Introduction section) that behavioral sensitization to dopamine agonists following withdrawal from chronic antidepressants is observed in the mesolimbie system
0
FRL
fXi
FSL
l.OI
DISCUSSION
One of the characteristics of FSL rats that has been presently confirmed is that these rats show si~ni~cantly higher immobiljty than FRL rats in the forced swim test (20-22). Both antidepressants significantly decreased immobility although the between-line difference persisted on either treatment. As expected (3), FSLs responded to apomo~hine with significan~y greater hypothermia than FRL rats, the difference being about 1“C in
-2.0
I)
J SA!_lNE
DMI
SER~INE
FIG. 3. The effect of chronic antidepressant treatment on apomorphineinduced hypothermia in FRL and FSL rats expressed as the difference in core temperature from the baseline. Means i. SEM from six rats per group. *p < 0.05 vs. FRL, p < 0.05 vs. saline-treated controls (NewmanKeuls test).
(nucleus accumbens) but not in the striatum or hippocampus f 10,25,27). The present results suggest that dopaminergic synapses within the POAH responsible for a~mo~hine-jnduced hypothermia also appear to be resistant to the sensitizing effect of chronic antidepressants. Fiypercholinergic FSL rats typically respond with greater hypothermia to dopamine agonists (apomorphine, quinpirole) than do FRL rats (3). Consequently, lack of potentiation of the hypothermic effect of apomorphine in DMI withdrawn FSL rats might be attributed to already near maximal thermic effect of apomo~hine in these animals (ceiling effect). However, there was also no potentiation of the effect following withdrawal from DMI in FRL rats, which normally respond to apomorphine with moderate hypothermia. Unexpectedly, there was significant attenuation (and even reversal in FRL rats) of the hypothermic response to apomorphine in both lines of rats after withdrawal from treatment with the specific serotonin reuptake blocker sertraline. This may indicate that adaptive changes that developed in the serotonergic system activity modify the thermic effect of apomorphine. Such an explanation would be consistent with the proposal of a serotonergic link in the apomorphine-induced hypothermia (2). It is conceivable that normally augmented hypothermic response to apomo~hine in FSL rats is dependent to large extent on supersensitive serotonergic and choiinergic mechanisms within the hypothalamus. FSL rats, in addition to dopamine agonists, arc supersensitive to the hypothermic effects induced by serotonergic (mCPP, buspirone) and muscarinic agonists (oxotremorine) [see (20) for review]. It has been known for some time that apomorphine increases serotonin and acetylcholine concentrations in the brain (4). The effect on serotonergi~ neurons may be region-specific as apomorphine, or dopamine, perfusion enhances the release of [3H]serotonin from the prelabelled hypothalamic. but not hippocampal slices (2). Moreover, the serotonergic antagonists, methysergide or cyproheptadine, antagonize the hypothermic elect of intrahypothalamically injected dopamine or serotonin, but have no effect on oxotremorine-induced hypothermia (2). There is no indication of dopamincrgic receptor su~rsensitivity in the FSL rat (3) that could explain exaggerated hypothermic response to apomorphine. Rather, we propose that serotonergic-1A (5-HT,,J and/or muscarinic receptors are indirectly involved in that effect of dopamine agonists. Our recent unpublished observations that pretreatment with methysergide suppresses apomo~hine-induced hypothermia in FSL rats (20) further supports the above notion. Chronic sertraline treatment would lead to increased availability of serotonin in the central synapses and consequent sustained stimulation of serotonergic receptors resulting in their subsensitivity. It has been demonstrated that prolonged stimulation of 5-HT,Areceptors results in a decreased hypothermic response to 5-HT,,agonist 8-OHDPAT. Conversely, chronic administration of 5-HTz agonist does not affect res~nsiveness of these receptors in thermoregulatory responses (19). The residual hypothermic eff‘ectof apomorphine in FSL rats withdrawn from chronic sertraline might be due to apomorphine-induced release of acetylcholine acting at supersensitive muscarinic receptors. The slight, but significant, hyperthermia that was induced in FRL rats withdrawn from sertraline by apomorphine injection is difficult to explain. However, we obtained virtually the same results in naive FRL rats injected with apomorphine following pretreatment with methysergide (20). Theoretically, the hyperthermia could be a consequence of the prevalence of 5-HT2 over 5-HT1, receptors (19) and/or dopaminergic D, over D2 receptors f 17). If supersensitive 5-HTTIAreceptors in FSL rats are only suppressed to some extent, then the same receptors in normosensitive FRL rats might be rendered subsensitive by chronic
scrtraline. thus permitting S-H_P-mediated hyperthermia to appear. As the endogenous amine has higher allinity fhr F-HT, than 5-HTZ receptors. this mechanism seem likely. Chronic treatment with classical tricyclir. antidepressants as well as specific scrotonin reuptake blockers (citalopram, Limelidine. fluoxetine) has been shown to augment amphetamincor apomorphine-induced locomotion (I 3,34.35). Thus. the present results with apomorphine-induced locomotion are in contrast to what is known from the literature. However. at least one other study reports that although chronic DMf produces prolonged (S-day) potentiation of amphetanljne-included locomotion. serotonin uptake blockers (zimelidinc, iluoxetine) do not ( 14). Because DMl has the most pronounced anticholinergic action of these antidepressants, and because similar potentiation of amphetamine-induced locomotion followed withdrawal from chronic scopolamine, the authors suggested that the effect of chronic DMI may be secondar? to its anticholincrgi~ properties (14). In our rats. both FRL and FSL, DMl failed to change apomorphine-induced locomotor response. FSL rats are genetically selected to he supersensitive to cholinergic agonists (23). and It is likely the! are unable to react with further increase in cholinergic sensitivltv to prolonged administration ofcholinolytic agents. The reason why FRL rats withdrawn from DMI similarly failed to react with enhanced response to aporn~)r~~h~ncis unclear. These rats. normosensitive in terms of their responsiveness to cholinergic agonists. appear to be resistant to the sensitizing effect of chronic DMI on dopaminergic transmission. One of the reasons why we decided to study the effect of chronic antidepressants on behavioral responsiveness to dopaminergit agonist in FSI. and FRL rats was a failure to demonstrate in previous experiments (Pucilowski. uIlpublished observations) j~otentiation oi apomo~hine-induced aggression in rats withdrawn from chronic DMI or citalopram. Such a potentiation was earlier described in outbred, unselected Wistar rats ( I I). Our negative findings were obtained using male Wistar rats previously selected for lack ofaggressive response to apomorphine (nonaggressive rats). Interestingly enough. FRL rats are also resistant to aggressioninducing effect of apomorphine (30). It may be that the initial, inborn sensitivity to a dopaminergic agonist weighs upon suhsequent appearance of behavioral sensitization in the mesolimbic system following withdrawal from chronic antidepressant treatment. In conclusion, the present results do not support the notion that chronic antidepre~ants produce generalized sensitization to dopami~ergic agonists. Moreover. the serotonin uptake blocker. sertraline appears to decrease responsiveness to hypothermic and locomotor effects of apomorphinc in the two selectively bred rat strains. FSL and FRL. The results seem to suggest that in these selectively bred strains a serotonergic antidepressant such as sertraline brought about sensitization of dopaminergic autoreceptors responsible for hypolo~omotion. Although withdrawal from chronic DMI resulted in qualitatively similar changes in the open field behavior, surprisingly sertralinebut not DMl-treated groups exhibited decrease in the hypothermic response to apomorphine. The effect of apomorphine on temperature could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment. Our results thus stress the potential differences in dopaminergi~ responsiveness following withdrawal from different antidepressants as well as point to the usefulness of using selectively bred strains to uncover subtle changes in drug-induced responses. ACKNOWLEDGEMENTS We
thank Patricia Garges for technical assistance. A gift of sertraline from Pfizer Inc. is gratefully acknowledged.
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