Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats

BRAIN RESEARCH ELSEVIER

Brain Research 728 (1996) 225-230

Research report

Involvement of GABA B receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats Yutaka Nakagawa a,*, Tsuyoshi Ishima b Yoshinori Ishibashi a Minoru Tsuji '~ Toshiyuki Takashima a a Tsukuba Research Laboratories, Experimental Biomedical Research Inc. (Jisseiken), 8-5-1, Chuo, Ami-machi, lnashiki-gun, lbaraki 300-03, Japan b Division ~fResearch and Del,elopment, Tokyo Branch Office, Nippon Shinyaku Co. Ltd., 3-5-14, Nihonbashi-honcho, Chuo-ku, Tokyo 103. Japan Accepted 26 March 1996

Abstract

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABAF~ neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis thai activation of GABA a receptors may contribute to the action of antidepressants. Keywords: Desipramine: GABA B receptor; GABA A receptor; Learned helplessness; Rat

1. Introduction

"y-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. G A B A acts on two pharmacologically distinct receptor subtypes, G A B A A and GABA~ [3,22]. G A B A A receptors are coupled with benzodiazepine receptors and CI- channels [11,31]. On the other hand, G A B A B receptors are coupled with G protein [13]. The activation of G A B A s receptors decreases the amplitude of Ca 2+ currents [8] and increases K + conductance [30]. Muscimol and baclofen mimic the effects of G A B A on G A B A A and G A B A B receptors, respectively [3,22]. Although it is accepted that GABAergic systems are related to depression [17,33,38,39], there have been controversial data on the role of G A B A A and G A B A s receptors in depression. For example, Lloyd [16] and Pilc and Lloyd [34] found that chronic treatment with antidepressants upregulated G A B A B but not G A B A A binding in the rat

Corresponding author. Fax: + 81 (298) 87-9065. 0006-8993/96/$15.00 Published by Elsevier Science B.V. Pll S 0 0 0 6 - 8 9 9 3 ( 9 6 ) 0 0 4 1 3 - 1

frontal cortex. There have been many reports [ 10,19,36,37,42,43] supporting their findings. On the other hand, Cross et al. [4], Cross and Horton [5,6] and McManus and Greenshaw [23] failed to find chronic antidepressants treatment to increase G A B A B binding in the rodent frontal cortex. Additionally, Suzdak and Gianutsos [41] showed that chronic treatment with antidepressants decreased G A B A A binding in the mouse cortex and hippocampus. We previously examined the involvement of GABAergic systems in action of antidepressants in the forced swim test in rats [28]. In that study, rats received two swim sessions and two injections of drugs. We found that baclofen attenuated the immobility-decreasing effects of antidepressants such as desipramine, mianserin and buspirone although baclofen had no effects when it was injected alone. Muscimol dose-dependently decreased the duration of immobility. Bicuculline (GABA A antagonist) antagonized the decreased duration of immobility induced by muscimol, but failed to antagonize the immobility-decreasing effects of desipramine, mianserin and buspirone. Based on these findings, we concluded that the decrease in

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G A B A B but not increase in G A B A A neurotransmission might be involved in antidepressant action. However, further studies would be required to clarify whether the muscimol-induced decrease in immobility time was due to antidepressant action. In this study, we examined the effect of baclofen on the escape failures-improving effect of desipramine in the learned helplessness paradigm in rats. Drugs were injected i.p. once daily for 14 days to confirm the hypothesis that the 'long-term' decrease in G A B A B neurotransmission may cause action of antidepressants. Many antidepressants show their clinical effects after chronic treatment [32]. The learned helplessness paradigm was chosen because it is accepted that this paradigm responds to a wide range of clinically effective treatments and that there are no false negatives [47]. On the other hand, in the forced swim test employed in our previous study [28], many false positives have been reported for stimulants, convulsants, anticholinergics, antihistamines, pentobarbital, opiates and other brain peptides [15,47]. We also tested the effect of chronic treatment with muscimol in the learned helplessness paradigm to see whether chronic increase in G A B A A neurotransmission influences the increased escape failures.

adaptation period. A tone signal was presented during the first 5 s of each trial. If no avoidance response within this period, the tone signal remained on and a 1-mA shock (10 s duration) was delivered through the grid floor. In the case of no escape response within this period, both the tone signal and shock were automatically terminated. The intertrial interval was 10 s. Number of escape failures was recorded. Escape failure is referred to a non-crossing response during the shock delivery.

2.4. Drugs Desipramine hydrochloride (Sigma), baclofen (RBI), muscimol (Sigma) were used. All drugs were dissolved in saline. Baclofen was injected in a volume of 4 m l / k g . Other drugs were injected in a volume of 1 m l / k g . The dosages of muscimol and baclofen were determined according to our previous studies [26-29], in which we found antagonism of bicuculline and 2-hydroxysaclofen against the muscimol-and baclofen-induced behavioral changes, respectively. The dosages of desipramine were expressed as the salt.

2.5. Statistics Between-group comparisons were assessed by Dunnett test following one-way ANOVA.

2. Materials and methods

2.1. Animals Male Wistar rats (Charles River Japan) weighing 160 g at the beginning of the experiment, were used. were housed in groups in an air-and light-controlled (temperature; 24 + 2°C, light phase; 8:00-20:00). and water were given ad libitum.

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2.2. Apparatus A shock pre-treatment chamber (28 × 21 × 25 cm) and a two-way shuttle box (56 × 21 × 25 cm; Toyo Sangyo, Toyama) were used. The shuttle box was divided into equal-size chambers by a stainless steel divider. The floors of the shock pre-treatment chamber and the shuttle box consisted of stainless steel rods. Scrambled shocks were delivered by a shock generator (MSG-001, Toyo Sangyo):

3. Results

3.1. Antidepressant effect of desipramine in the learned helplessness paradigm As shown in Fig. 1, the exposure to inescapable shocks induced the subsequent increase in escape failures and

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Rats were injected i.p. with drugs once daily for 14 days. On day 14, the rats were individually placed in the shock pre-treatment chamber and given 90 inescapable shocks (1 mA) of 10 s duration at intervals of 2 s. No shocks were delivered to control rats. Immediately after the shock pre-treatment session, the rats were injected i.p. with drugs. On day 15 (24 h after the final drug treatment), the rats received the 40-trial escape test. The rats were individually placed in the shuttle box and given a 5-min

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Fig. 1. Effects of desipramine on the escape failures in the learned helplessness paradigm in rats. Desipramine (DMI) was injected i.p. once daily for 14 days. On day 14, rats received 90 inescapable shocks. On day 15, they underwent the 40-trial escape test. Ten rats were used in each group. SA, saline: * * P < 0.01 vs. shocked control. Data are expressed as means S.E.M.

Y. Nakagawa et al. / Brain Research 728 (1996) 225-230

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Inescapable shocks Fig. 2. Effects of baclofen on the escape failures in the learned helplessness paradigm in rats. Baclofen (BAC) was injected i.p. once daily for 14 days. * * P < 0.01 vs. shocked control. See Fig. 1 for further information.

desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks (Fs.54 = 9.59, P<(I.01). Post hoc analysis showed that desipramine at doses of 1-10 m g / k g significantly improved the increased escape failures induced by the inescapable shocks. 3.2. Involcement ()f GABA B receptors" in antidepressant action

Baclofen had no effects on the increased escape failures (Fig. 2). Although ANOVA indicated significant group differences (EL36 = 5.59, P < 0.01), post hoc analysis showed there was no significant effect of baclofen on the increased escape failures. However, baclofen (4 m g / k g ) attenuated the improvement effect of desipramine (I0 m g / k g ) on the increased escape failures (Fig. 3). ANOVA indicated significant group differences ( F2.27 = 6.73, P < 0.01). Post hoc analysis of these data showed that in the baclofen-treated groups there was significant attenuation of the escape failures-improving effect of desipramine.

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SA DMI Inescapable shocks Fig. 3. Effects of baclofen on the escape failures-improving effect of desipramine in the learned helplessness paradigm in rats. Desipramine (DMI, 10 m g / k g ) and baclofen (BAC, 4 m g / k g ) were co-injected i.p. once daily for 14 days. ~ P < 0.05, * * P < 0.01 vs. D M I + S A . See Fig. I for further information,

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Fig. 4. Effectsof"muscimolon the escape failures in the learned helplessness paradigm in rats. Muscimol (MUS) was injected i.p. once daily for 14 days. * P < 0.05 vs. shocked control. See Fig. 1 for further information.

3.3. Involvement of GABA a receptors in antidepressant action

As shown in Fig. 4, muscimol failed to influence the increased escape failures induced by the inescapable shocks. ANOVA indicated significant group differences (F3.36=4.54 , P < 0 . 0 1 ) . However, post hoc analysis showed no significant effect of muscimol on the increased escape failures.

4. Discussion The most important finding in our present study is that baclofen attenuated the escape failures-improving effect of desipramine following chronic co-administration in the learned helplessness paradigm in rats. Moreover, chronic treatment with muscimol failed to influence the increased escape failures in the learned helplessness paradigm although we previously observed that acute muscimol treatment was effective in the forced swim test in rats [28]. In the present study, the rats exposed to the inescapable shocks showed the subsequent increase in escape failures in the escape test. Chronic treatment with desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks (Fig. 1). Therefore, our present results are in agreement with previous reports [17,21,24,25,35,38-40,45] and confirm that antidepressants are effective in the learned helplessness paradigm. We found here that baclofen had no effects on the increased escape failures induced by the inescapable shocks (Fig. 2). However, baclofen attenuated the improvement effect of desipramine on the increased escape failures following a 14-day co-injection (Fig. 3). Our present findings agree with our previous ones that baclofen attenuated the immobility-decreasing effect of desipramine in the forced swim test in rats [28] and suggest that GABA B receptors may be involved in action of antidepressants. Our present findings in combinatitm with our previous

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ones [28] support the published data from biochemical and behavioral studies: chronic treatment with antidepressants has been reported to increase G A B A B binding [16,19,34,36,37,42,43] but not G A B A A binding [16,34] in rodent frontal cortex. It was found that there was the decreased cortex G A B A B binding in the animal models of depression such as the helpless rats and the olfactory bulbectomized ones, and that chronic treatment with antidepressants improved the behavioral changes as well as decreased G A B A B binding in the models [14,18,20]. Furthermore, baclofen-induced hypothermia was enhanced by repeated administration of antidepressants in mice [9]. These observations suggest that chronic treatment with antidepressants may cause the long-term decrease in G A B A B neurotransmission, which may increase postsynaptic G A B A B binding. Our present findings support this hypothesis and may be interpreted as follows: chronic treatment with baclofen may attenuate the long-term decrease in G A B A B neurotransmission induced by chronic desipramine treatment with results of the attenuation of escape failures-improving effect of desipramine. This hypothesis has the following implication: G A B A B antagonists may possess an antidepressant effect. In fact, Pratt and Bowery [37] found that not only desipramine but also CGP36742, a G A B A B antagonist, increased GABAB binding in rat frontal cortex following chronic treatment. Additionally, Bittiger et al. [1] reported that G A B A B antagonists such as CGP36742 and CGP51176A decreased the duration of immobility in the forced swim test. However, it is not clear how antidepressants and G A B A B antagonists reduce the activity of G A B A B receptor systems. There is evidence that G A B A B antagonists act at presynaptic G A B A B receptors: CGP35348, another G A B A B antagonist, modulated release of [3 H]GABA from cortical slices [2,46]. Also, it is possible that G A B A B antagonists directly act at postsynaptic G A B A B receptors. On the other hand, little is known about the mechanism that antidepressants decrease G A B A B neurotransmission. Further studies will be required to clarify the mechanism that G A B A B antagonists and antidepressants increase G A B A B binding. Although it is accepted that GABAergic systems play an important role in depression [17,33,38,39], it remains controversial whether G A B A B but not G A B A A receptors are related to depression and antidepressants action. For example, it was reported that chronic administration of antidepressants failed to increase G A B A B binding in the rat frontal cortex [4-6,23]. Suzdak and Gianutsos [41] found chronic treatment with antidepressants to decrease G A B A A binding in the mouse cortex and hippocampus. Additionally, Dennis et al. [7] showed that there were increase in G A B A A binding and no changes in G A B A B binding in the olfactory bulbectomized rats. From these findings, Dennis et al. [7] concluded that G A B A A but not G A B A B receptor systems might play an important role in action of antidepressants. These findings suggest that the

reduced activity of G A B A A receptor systems may be related to depression and that antidepressants may increase G A B A A neurotransmission. We found here chronic muscimol treatment failed to influence the increased escape failures in the learned helplessness paradigm (Fig. 4). Our observations are in agreement with Sherman et al. [40]. They reported that repeated treatment with benzodiazepine agonists such as diazepam and chlordiazepoxide had no effects in the learned helplessness paradigm in rats [40]. Benzodiazepine and G A B A A agonists have a common pharmacological mechanism: both agonists act on common chloride ion channels [12,44]. Our present findings, however, disagree with our previous ones that muscimol dose-dependently decreased the duration of immobility in the forced swim test [28]. Interestingly, we also observed that bicuculline failed to antagonize the immobility-decreasing effects of desipramine, mianserin and buspirone in the forced swim test, and that diazepam had no effects in the test [28]. There are many false positives in the forced swim test: stimulants, convulsants, anticholinergics, antihistamines, pentobarbital, opiates and other brain peptides [15,47]. Kitada et al. [15] reported that acute treatment with an antihistamine decreased the duration of immobility in the forced swim test but that this effect disappeared following chronic administration. The authors concluded that the effect after chronic treatment might be an action specific to antidepressants [15]. As mentioned earlier, in our previous [28] and present studies, acute but not chronic muscimol treatment was active whereas chronic as well as acute injections of desipramine were effective in the behavioral testing. Additionally, it is accepted that the learned helplessness paradigm responds to a wide range of clinically effective treatments and that there are no false negatives [47]. Therefore, it is unlikely that the muscimol-induced decrease in immobility time observed in our previous study [28] is due to the antidepressant action. Taken together, our present results strongly support the hypothesis that action of antidepressants may be due to the long-term decrease in G A B A B neurotransmission, but disagree with the hypothesis that the long-term increase in activity of G A B A A receptor systems may be related to the action of antidepressants.

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