Involvement of GABAB receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats

BRAIN RESEARCH ELSEVIER

Brain Research 741 (1996) 240-245

Research report

Involvement of GABA B receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats Yutaka Nakagawa ~'*, Tsuyoshi Ishima b Yoshinori Ishibashi a Minoru Tsuji a, Toshiyuki Takashima a a Tsukuba Research Laboratories, Experimental Biomedical Research bw. ~Jisseiken), 8-5-1, Chuo, Ami-machi, Inashiki-gun, Ibaraki 300-03, Japan b Division of Research and Dec'elopment. Tokyo Branch Office. Nippon Shinyaku, Co. Ltd., 3-5-14, Nihonbashi-honcho, Chuo-ku, Tokyo 103, Japan

Accepted 30 July 1996

Abstract There are two "y-aminobutyric acid (GABA) hypotheses of the antidepressants action: an increase in GABA A neurotransmission or a decrease in GABA B neurotransmission may contribute to action of antidepressants. In this study, involvement of GABA A and GABA B receptor systems was examined in the learned helplessness paradigm in rats. Rats were injected with bicuculline or baclofen for 14 days. On day 14, the rats were subjected to 15 inescapable shocks. On day 15, they underwent the 40-trial escape test. Baclofen exacerbated the escape failures in the rats subjected to the inescapable shocks, although baclofen had no effects in the animals without shock pre-treatment. Bicuculline failed to influence the escape failures in the rats with the 15-shock pre-treatment. These results suggest that the long-term increase in GABA B neurotransmission but not the long-term attenuation of GABA A neurotransmission may be related to helplessness in rats. Keywords: GABAB receptor: GABAA receptor; Learned helplessness: Depression model; Rat

1. Introduction "y-Aminobutyric acid ( G A B A ) is the main inhibitory neurotransmitter in the brain. There are two different types of G A B A receptor in the brain, G A B A A and G A B A B [4,20]. G A B A A receptors are coupled with benzodiazepine receptors and C1--channels, and mediate neuronal inhibition through Cl--channels [28]. On the other hand, G A B A B receptors, which also have inhibitory property, are linked to G protein [14]. The activation of G A B A B receptors decreases the amplitude of Ca 2+ currents [10] and increases K + conductance [27]. Both G A B A receptors are located at presynaptic nerve terminals as well as postsynaptic neurons [3,4,20]. Although there is evidence to indicate an involvement of G A B A in depression [9,30,37], the role of G A B A A and G A B A B receptors remains controversial. For example, it was reported that there was a decrease in cortex G A B A B binding in the animal models of depression such as the helpless rats and the olfactory bulbectomized rats, and that chronic treatment with antidepressants increased G A B A B

* Corresponding author. Fax: + 81 (298) 87-9065.

binding and improved behavioral changes in the models [15,17,19]. Moreover, Lloyd [16] and Pilc and Lloyd [31] found that chronic treatment with antidepressants up-regulated G A B A B but not G A B A A binding in the rat frontal cortex. These results suggest that G A B A u receptors may be involved in depression, and that chronic antidepressants treatment may decrease G A B A B neurotransmission resulting in an increase in postsynaptic G A B A B binding. On the other hand, Dennis et al. [8] 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. Additionally, Suzdak and Gianutsos [39] reported that chronic treatment with antidepressants decreased G A B A A binding in the mouse cortex and hippocampus. These observations raise the possibility that G A B A A receptors may play an important role in depression, and that chronic treatment with antidepressants may increase G A B A a neurotransmission, thereby decreasing postsynaptic G A B A A binding. We previously examined the involvement of G A B A e r gic systems in antidepressants action in the forced swim test and the learned helplessness paradigm in rats [24,25]. We found that chronic [24] as well as acute treatment with baclofen ( G A B A B agonist) [25] attenuated the action of

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antidepressants, suggesting that baclofen may increase GABA B neurotransmission with results of attenuation of antidepressants action. On the other hand, acute [25] but not chronic injection of muscimol (GABA a agonist) [24] induced the behavioral changes as shown in the antidepressants-treated animals. Because the effect after chronic treatment is an action specific to antidepressants [44], it is unlikely that muscimol-induced behavioral changes under the acute treatment condition may be due to antidepressant action. Additionally, bicuculline (GABA a antagonist) failed to antagonize the effects of antidepressants [25]. Therefore, our previous findings support the above-mentioned GABA B hypothesis of depression but disagree with the GABA A hypothesis of depression. In this study, the effect of chronic baclofen treatment in the learned helplessness paradigm in rats was assessed to further examine the GABA B hypothesis. Based on the GABA B hypothesis, it is expected that the long-term increase in GABA B neurotransmission would exacerbate the escape failures. We also tested the effect of chronic treatment with bicuculline in the learned helplessness paradigm to see whether the long-term decrease in GABA A neurotransmission influence the escape failures.

period. Each trial began with the onset of a 5-s tone signal. If there was no avoidance response within this period, the tone signal remained on and a 1-mA shock (10-s duration) was applied to the grid floor. In the case of no escape response within this period, both the tone signal and shock were automatically terminated. Number of escape failures was recorded. Escape failure is referred to a non-crossing response during the shock delivery. Ten rats were used in each group.

2. Materials and methods

2.4. Drugs

2.1. Animals

Baclofen (RBI) and bicuculline (Sigma) were used. Baclofen was dissolved in saline, and injected in a volume of 4 m l / k g . Bicuculline was dissolved in 0.01 M HC1, and injected in a volume of 1 m l / k g . The dosages of baclofen and bicuculline were determined according to our previous studies [22-26], in which we found antagonism of 2-hydroxysaclofen and bicuculline against the baclofen- and muscimol-induced behavioral changes, respectively.

Male Wistar rats (Charles River Japan) weighing 130170 g, at the beginning of the experiment, were used. They were housed in groups in an air- and light-controlled room (temperature; 24 ___2°C, light phase; 08.00 h-20.00 h). Food and water were given ad libitum. 2.2. Apparatus A shock pre-treatment chamber (28 X 21 X 25 cm) and a two-way shuttle box (56 x 21 x 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).

2.3.2. Involvement of GABA A and GABA B receptors in learned helplessness Baclofen was repeatedly injected in the present study because the preliminary results in our laboratory showed that acute treatment with baclofen had no effects on helplessness in rats. Rats were injected i.p. with drugs once daily for 14 days, according to our previous study [24]. On day 14, the rats underwent 15 inescapable shocks. Immediately after the shock pre-treatment session, the rats were injected i.p. with the drugs. On day 15 (24 h after the final drug treatment), they received the 40-trial escape test. Number of escape failures was recorded as described above. Ten rats were used in each group.

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

3. Results 3.1. Learned helplessness induced by the inescapable shocks

2.3. Procedure 2.3.1. Learned helplessness induced by inescapable shocks The learned helplessness paradigm was conducted according to our previous study [24]. Rats were individually placed in the shock pre-treatment chamber and given 0, 15, 30, 60 and 90 inescapable shocks (1 mA) of 10 s duration at intervals of 2 s. Twenty-four h later, the rats received the 40-trial escape test with a 10-s intertrial interval. The rats were individually placed in the shuttle box and given a 5-min adaptation

As shown in Fig. 1, the exposure to inescapable shocks induced the subsequent increase in escape failures in a shock-dependent manner (F4,45 = 6.02, P < 0.01). Post hoc analysis showed that 15 inescapable shocks had no effects on the escape failures. Thirty and 60 inescapable shocks slightly increased the escape failures, although these effects were not significant. Ninety inescapable shocks significantly increased the escape failures in the test. Therefore, the rats were exposed to the 15 inescapable shocks in the following experiments.

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Y. Nakagawa et al. / Brain Research 741 (1996) 240-245 3O

30

20

20 {3..

~

{3...

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10"

d Z

1o

d

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0

15

o

30 60 90 Inescapable shocks

Fig. I. Escape failures in the rats subjected to 0, 15, 30, 60 and 90 inescapable shocks. Rats received 40-trial escape test 24 h after the shock pre-treatment. Ten rats were used in each group. * * P < 0.01 versus control without shock pre-treatment. Data are expressed as mean with S.E.M.

3.2. lnvoluement o f GABA 8 receptors in helplessness Baclofen had no effects on the escape failures in the rats without shock pre-treatment (Fig. 2A). A N O V A indicated no significant group differences (F2.27 = 0.86, P > 0.05). However, baclofen exacerbated the escape failures in the rats subjected to 15 inescapable shocks (Fig. 2B). A N O V A indicated significant group differences (F2.27 =

0.5 1 BIC (mg/kg, i.p.) 15 inescapable shocks SA

Fig. 3. Effects of bicuculline on the escape failures in the rats subjected to 15 inescapable shocks. Bicuculline (BIC) was injected i.p. once daily for 14 days. Ten rats were used in each group. See Fig. 2 for further information. 9.74, P < 0.01). Post hoc analysis of these data showed that in the baclofen (2 m g / k g ) - t r e a t e d groups there was a significant increase in the escape failures. 3.3. Involvement o f GABA A receptors in helplessness As shown in Fig. 3, bicuculline failed to influence the escape failures in the rats subjected to 15 inescapable shocks. A N O V A indicated no significant group differences (F2,27 = 0.81, P > 0.05).

A 4. Discussion

~- 20

~

t

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No inescapable shocks

B 30~

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o SA

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2

BAC(mg~g,i.p.)

15 inescapable shocks

Fig. 2. Effects of baclofen on the escape failures in the rats without shock-pre-treatment (A) and subjected to 15 inescapable shocks (B). Baclofen (BAC) was injected i.p. once daily for 14 days. On day 14, rats received no or 15 inescapable shocks, On day 15, they underwent the 40-trial escape test. Ten rats were used in each group. SA, saline; * * P < 0.01 versus saline control. Data are expressed as mean with S.E.M.

The major finding in this study is that baclofen exacerbated helplessness in the rats subjected to 15 inescapable shocks although baclofen had no effects in the animals without shock pre-treatment. Moreover, bicuculline failed to influence helplessness in the rats with 15 inescapable shocks. In the present study, the inescapable shocks increased the escape failures and the degree of escape failures was related to the n u m b e r of inescapable shocks (Fig. 1). Fifteen inescapable shocks had no effects on the escape failures. There was a slight increase in the escape failures in the rats exposed to 30 and 60 shocks. Ninety shocks significantly increased the escape failures. Our present results are in agreement with S h e r m a n and Petty [37]. The authors e x a m i n e d the changes in escape failures in the rats received 0, 5, 15, 30 and 45 rain of shock pre-treatment session, and observed that escape failures increased in a duration-dependent m a n n e r [37]. Therefore, it is likely that the m a g n i t u d e of helplessness is related to the a m o u n t s of stressor. W e found here that chronic baclofen treatment exacerbated the escape failures in the rats subjected to 15 inescapable shocks (Fig. 2B). Because baclofen has an analgesic action [36], baclofen-induced modulation of pain threshold may increase the escape failures. However, as shown in Fig. 2A, baclofen had no effects on the escape failures in the rats without shock pre-treatment, indicating

Y. Nakagawa et al. / Brain Research 741 (1996) 240-245

that the baclofen-induced exacerbation of escape failures may not be due to analgesic action. Joly et al. [15], Lloyd and Pichat [17] and Martin et al. [19] demonstrated that there was the decreased cortex GABA B binding in the animal models of depression such as the helpless rats and the olfactory bulbectomized ones. These results suggest that GABA B receptors may be involved in the experimental depression. Furthermore, antidepressants alter the activity of GABA B receptor systems. Lloyd et al. [18] found that there was an increase in GABA B binding in rat frontal cortex following chronic treatment with electroshock and different types of antidepressants such as tricyclics, monoamine oxidase inhibitors, atypicals and 5-hydroxytryptamine (5-HT) reuptake inhibitors, concluding that the increased GABA B binding may be a common action of antidepressants. There have been many reports supporting their findings [16,18,31,34,35,40,41]. It was reported that there was a decrease in cortex GABA B binding in the animal models of depression such as the helpless rats and the olfactory bulbectomized rats, and that chronic treatment with antidepressants increased GABA a binding and improved behavioral changes in the models [15,17,19]. Gray et al. [11] demonstrated that baclofen-induced hypothermia in mice was enhanced after repeated administration of antidepressants. In our previous study [24], chronic baclofen treatment attenuated the helplessness-improving effect of desipramine in the learned helplessness paradigm in the rats subjected to 90 inescapable shocks. Pratt and Bowery [35] found that not only desipramine but also CGP36742, a GABA B antagonist, increased GABA B binding in rat frontal cortex following chronic treatment, suggesting that GABA B antagonists may have an antidepressant action. Recently, Bittiger et al. [2] reported that GABA B antagonists such as CGP36742 and CGP51176A decreased the duration of immobility in the forced swim test. These results suggest that chronic treatment with GABA B antagonists and antidepressants may induce the long-term decrease in GABA a neurotransmission with results of the increased postsynaptic GABA B binding. Therefore, our present data that repeated injection of baclofen exacerbated the escape failures in the learned helplessness in rats are interpreted as follows: chronic treatment with baclofen may induce the long-term activation of GABA B receptor systems, thereby causing the experimental depression. This explanation is supported by the findings that baclofen showed the action opposite to antidepressants in the receptor binding study: the decreased GABA s binding was observed in mouse frontal cortex following chronic baclofen treatment [40]. In addition to these animal studies, it was clinically reported that baclofen exacerbated depression [33]. Although the mechanism(s) through which GABA B receptor systems influence depression state still remain to be elucidated, it seems suggestive that the increase in GABA B binding was observed in frontal cortex but not in hippocampus [18].

243

Further studies will be required to examine the GABAcontaining pathways associated with depression. It has been widely accepted that antidepressants influence the activity of monoaminergic systems in the brain: decrease in {3-adrenoceptors [1] and 5-HT 2 receptors [29] has been found after chronic injection of antidepressants. There is evidence that GABA s receptor systems may interact with monoaminergic systems in antidepressants action. Suzdak and Gianutsos [40] demonstrated that baclofen-induced stimulation of cyclic AMP formation by noradrenaline in rat cortical slices was greater after chronic treatment with imipramine, which also increased GABA B binding. A GABA B antagonist, CGP36742, which had an immobility-decreasing effect in rat forced swim test [2], decreased 13-adrenoceptor binding and increased GABA B binding in rat frontal cortex following chronic treatment [35]. Chronic treatment with antidepressants produced a significant enhancement of the baclofen-induced inhibition of 5-HT release from slices of mouse frontal cortex [12]. However, it is not clear how GABA B receptor systems interact with monoaminergic systems. In this regard, further studies will be required. Although it is accepted that GABAergic systems are related to depression [9,30,37], it remains controversial whether GABA B but not GABA A receptors are related to depression and antidepressants action. For example, Dennis et al. [8] showed that there were increase in GABA A binding and no changes in GABA B binding in the olfactory bulbectomized rats. It was reported that chronic administration of antidepressants failed to increase GABA B binding in the rat frontal cortex [5-7,21]. Additionally, Suzdak and Gianutsos [39] found chronic treatment with antidepressants to decrease GABA A binding in the mouse cortex and hippocampus. From these findings, Dennis et al. [8] concluded that GABA A but not GABA B receptor systems might play an important role in action of antidepressants. These findings suggest that the reduced activity of GABA A receptor systems may be related to depression and that antidepressants may increase GABA A neurotransmission. Based on the GABA A hypothesis of depression, it is expected that the attenuation of GABA A neurotransmission would exacerbate the experimental depression. Contrary to the GABA A hypothesis, however, it was shown here that chronic bicuculline injection failed to exacerbate the escape failures in the rats subjected to 15 inescapable shocks (Fig. 3). We previously reported that chronic treatment with muscimol failed to attenuate the increased escape failures in the rats with 90 inescapable shocks [24]. Sherman et al. [38] observed that benzodiazepine agonists such as diazepam and chlordiazepoxide had no effects on helplessness in rats. Benzodiazepine and GABA A agonists have a common pharmacological mechanism: both agonists act on common C1- channels [13]. Additionally, it was demonstrated that neither picrotoxin (C1--channel antagonist) nor bicuculline antagonized the action of antide-

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p r e s s a n t s in t h e f o r c e d s w i m test in rats [25,32], a n d that d i a z e p a m h a d n o e f f e c t s in that test [25,42,43]. T h e r e f o r e , it is u n l i k e l y that t h e G A B A A r e c e p t o r s are i n v o l v e d in t h e experimental depression and antidepressants action. Taken together, our present results strongly support the hypothesis that G A B A B b u t n o t G A B A A r e c e p t o r s y s t e m s m a y b e r e l a t e d to d e p r e s s i o n a n d a n t i d e p r e s s a n t s action.

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