The effect of chronic treatment with imipramine on the responsiveness of hippocampal CA1 neurons to phenylephrine and serotonin in a chronic mild stress model of depression

ELSEVIER European Neuropsychopharmacology 5 (1995) 43-48

EUROPEANNEURO. PSYCHOPHARMACOLOGY

The effect of chronic treatment with imipramine on the responsiveness of hippocampal CA1 neurons to phenylephrine and

serotonin in a chronic mild stress model of depression

M. Bijak, M. Papp*

Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Cracow, Poland

Received 9 May 1994; revision received 17 August 1994; accepted 6 September 1994

Abstract

The effect of chronic mild stress (CMS) and chronic treatment with the tricyclic antidepressant drug imipramine (10 mg/kg/day for 5 weeks) on neuronal responsiveness to the al-noradrenergic agonist phenylephrine and serotonin (5-HT) was examined ex vivo, in the CA1 cell layer of the rat hippocampal slice preparation. We corroborated some previous findings that CMS, which had been used as an animal model of depression, decreased the consumption of a 1% sucrose solution and that that effect was reversed by chronic administration of imipramine. Imipramine did not change the sucrose consumption in control animals. In both control and stressed animals, phenylephrine (5/zM) and 5-HT (10/zM) attenuated the amplitude of the population spikes evoked in the CA1 pyramidal cell layer by stimulation of Schaffer collateral/commissural fibers. Those inhibitory effects of phenylephrine and 5-HT were significantly potentiated by chronic treatment with imipramine. The imipramine-induced potentiation was similar in slices from control and stressed animals. These results suggest that the imipramine-induced functional changes in al-noradrenergic and serotonergic receptors in the hippocampus are not involved in the anti-anhedonic effect of chronic imipramine administration in the CMS model of depression.

Keywords: Chronic mild stress; Imipramine; al-Adrenergic receptor; 5-HT1A receptor; Hippocampal slice

1. Introduction

There exists a considerable body of literature re- porting that long-term administration of antidepressants results in functional changes in many neurotrans- mitter systems in the brain of experimental animals (cf. Caldecott-Hazard et al., 1991). It is well known that antidepressants are devoid of mood-elevating effects in non-depressed individuals (Pillard and Fisher, 1978); therefore it has been postulated that studies into the action of antidepressants should be carried out on animal models of depression. One of these models, developed by Willner and his colleagues (Willner et al., 1992), is chronic mild stress (CMS). In this model, rats subjected to a variety of mild stressors show a gradual and long-lasting decrease in their response to rewarding stimuli (Papp et al., 1991; Moreau et al., 1992). This phenomenon seems to

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reflect anhedonia, which is regarded as a core symp- tom of major depression (APA, 1987). The CMS- induced deficit in responsiveness to reward is usually monitored by a substantial decrease in the consumption of a palatable, weak (1%) sucrose solution, which has been proved to be a simple measure of the animal's sensitivity to reward (cf. Willner et al., 1992). This effect of prolonged stress is reversed by long-term treatment with antidepressant drugs. Recent biochemical and binding studies have shown that CMS affects the noradrenergic and serotonergic systems (Willner et al., 1991; Papp et al., 1994). Both these systems are involved in a reaction to acute and chronic stress, and are regarded as potential targets of the antidepressant action (Joseph and Kennett, 1983; Stone et al., 1986; Kennett et al., 1987; Caldecott- Hazard et al., 1991; Kawahara et al., 1993; Watanabe et al., 1993). Previous in vivo and ex vivo electrophysiological studies demonstrated in normal animals that prolonged treatment with different antidepressant drugs significantly changed the responsiveness of hip-

44 M. Bijak, M. Papp / European Neuropsychopharmacology 5 (1995) 43-48

pocampal neurons to phenylephrine, an al-noradrenergic receptor agonist, and to the inhibitory action of serotonin, which is mediated by 5-HT1A receptors (Olpe et al., 1984; Rowan and Anwyl, 1985; Blier et al., 1987; Bijak, 1989; Segal et al., 1989; Dijck et al., 1991; Bijak and Tokarski, 1994). This study was designed to find out whether the responsiveness of hippocampal neurons to phenylephrine and 5-HT is affected by prolonged treatment with the antidepressant drug imipramine in the CMS model of depression.

were further divided into two matched subgroups (n = 8), and they received daily intraperitoneal injections of imipramine (Polfa; 10 mg/kg) or saline (1 ml/kg) for 5 subsequent weeks. Stress was continued throughout the treatment period. Twenty-four hours after the last injection, five animals from each group (saline- and imipramine-treated controls and saline- and imipramine-treated stressed animals) were randomly chosen for electrophysiological experiments.

2.3. Electrophysiological experiments

2. Experimental procedures

2.1. Animals

Male Wistar rats were brought into the laboratory 2 months before the start of the experiment; at that time they weighed approx. 300 g. If not stated otherwise (see below), the animals were singly housed, had food and water freely available, and were maintained on a 12-h light/dark cycle (light on at 08:00) at a temperature of 22 ___ 2°C.

2.2. Behavioral experiments

The animals were first trained to consume a 1% sucrose solution; the training consisted of seven 1-h baseline tests in which sucrose was given in the home cage, following 14 h of food and water deprivation. The intake was assessed by weighing pre-weighed bottles containing the sucrose solution at the end of the test. Subsequently, the sucrose consumption was monitored under similar conditions at weekly intervals throughout the experiment. On the basis of their sucrose intake in the final baseline test, the animals were divided into two matched groups. One group was subjected to a chronic mild stress procedure for a period of 8 consecutive weeks. Each week of the stress regime consisted of: two periods of food or water deprivation (12 and 14 h), two periods of 45 ° cage tilt (12 and 14 h), two periods of intermittent overnight illumination (light on and off every 2 h), two 14-h periods of soiled cage (200 ml water in sawdust bedding), two 14-h periods of paired housing and two 14-h periods of low intensity stroboscopic illumination (150 flashes/min). Stressors were applied continuously throughout the day and night, and were randomly scheduled. Control animals were housed in a separate room and had no contact with the stressed animals. They were deprived of food and water for 14 h before each sucrose test; otherwise, food and water were freely available in the home cage.

On the basis of their sucrose intake scores after 3 weeks of stress, both stressed and control animals

The animals were anesthetized with chloroform and killed by decapitation. The brain was removed and the hippocampi were dissected in a chilled solution. Trans- verse hippocampal slices (300 /zm thick) were prepared and maintained in a holding chamber in a medium composed of (in mM) 124 NaCI, 5 KC1, 1.25 NaH2PO4, 2.4 CaC12, 1.3 MgSO4, 26 NaHCO3, 10 glucose; the medium was gassed with 95% 0 2 and 5% CO 2 at room temperature. A single slice was trans- ferred to the recording chamber (volume 1 ml), where it was held submerged and continuously superfused (2 ml/min) with the medium at 32°C. Glass microelec- trodes (2-5 Mfl), filled with 2 M NaC1, were placed in the CA1 cell layer to record the extracellular field potentials induced by stimulation of Schaffer collateral/commissural fibers. Electrical stimulation (square- wave pulses, 0.1 ms pulse width, 5-10 V, at 0.1 Hz) was delivered via a bipolar electrode (twisted tungsten wires). Extracellular signals were amplified, bandpass- filtered (1 Hz-10 kHz) and stored on a PC hard disk after AD conversion at 10 kHz (a CED interface, Cambridge Electronic). A population spike which was 50% of the maximum amplitude was chosen to study the effects of phenylephrine and 5-HT. Stock solutions of phenylephrine (L-phenylephrine hydrochloride, Sigma) and serotonin (5-hydroxytryptamine creatinine sulfate, Sigma) were prepared with an antioxidant (0.01% sodium metabisulfite, Sigma), and the final drug solutions were prepared directly before administration. When a stable population spike was recorded for 15 min the drugs were administered in the bath (for 5 min) and the recovery was observed for 15 min. In control experiments the population spike was stable over a 2-h recording period. Effects of phenylephrine and serotonin were tested in different slices (each of the drugs in two slices from one animal). When used, spiperone (Sigma) was applied 15 min before application of 5-HT. Changes in the population spike amplitude were expressed as percent change in the mean baseline population spike (an average of three consecutive population spikes). The amplitude of the averaged population spike was calcu- lated by measuring the size of the population spike

M. Bijak, M. Papp / European Neuropsychopharmacology 5 (1995) 43 -48 45

from its negativity to the average of the positive components that preceded and followed the negativity.

3. Results

3.1. Behavioral experiments

2.4. Statistics

Behavioral data were analyzed by analysis of variance, followed by the Newman-Keuls test for post-hoc comparisons. For electrophysiological studies, statistical analysis was performed by analysis of variance and the Student t-test.

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Fig. 1. The effect of chronic treatment with saline (open bars) and imipramine (hatched bars) on the consumption of a 1% sucrose solution in controls and animals exposed to chronic mild stress. The values are the means ( ± SEM) of the sucrose intake measured following 8 weeks of stress and after 5 weeks of imipramine administration. * * * , P < 0.001 relative to saline-treated controls; # # # , P < 0.001 relative to saline-treated stressed animals.

Chronic mild stress caused a significant decrease in the consumption of a 1% sucrose solution; in animals treated with saline, that effect was maintained throughout the experiment (F(5,84)=75.63; P < 0.001). As shown in Fig. 1, imipramine had no significant effect on the sucrose consumption in control animals (F(1,84) = 0.877, NS). However, the drug caused a gradual increase in the sucrose intake in stressed animals (treatment effect: F(1,84)=26.88; P < 0.001 and treatment × weeks interaction: F(5,84)=2.89; P<0 .02 ) , resulting in a complete reversal of the effect of stress by the end of the treatment period.

3.2. Electrophysiological experiments

The mean amplitudes of the maximum population spikes (approximately 3 mY), and the range of stimulation intensities required to evoke the maximum population spikes (approximately 10 V) did not differ between slices prepared from control, stressed and imipramine-treated animals. Perfusion of the hippocampal slices with phenylephrine (5/~M) decreased the amplitude of the population spikes, and a 10-min washout completely reversed that effect (Fig. 2A). As shown in Fig. 2B, the phenylephrine-induced inhibitory effect was similar in slices prepared from saline- treated control and stressed animals (F(1,19)= 0.46; NS). Prolonged treatment with imipramine caused a significant increase in the inhibitory effect of phenylephrine (F(3,39) = 18.9; P < 0.01) in both control and stressed animals. The imipramine-induced sensitiza-

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Fig. 2. Effects of chronic stress and prolonged treatment with imipramine on the inhibition induced by phenylephrine. (A) An example of the inhibitory effect of phenylephrine (5 /~M) on the population spike recorded in the CA1 cell layer of a hippocampal slice prepared from a control, saline-treated animal. Population spikes recorded before, during (5 min), and after (10 min) application of phenylephrine. (B) The effect of chronic treatment with saline (open bars) and imipramine (hatched bars) on the inhibition induced by phenylephrine in control animals and in animals exposed to chronic mild stress. In each group, 10 slices obtained from five animals were tested. The values are the means ( ± SEM); , , P ~ 0.01 relative to respective saline-treated group, t-test.


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Fig. 3. Effects of chronic stress and prolonged treatment with imipramine on the inhibition induced by 5-HT. (A) An example of the inhibitory effect of 5-HT (10 p.M) on the population spike recorded in the CA1 cell layer of a hippocampal slice prepared from a control, saline-treated animal. Population spikes recorded before, during (5 min), and after (10 min) application of 5-HT. (B) The effect of chronic treatment with saline (open bars) and imipramine (hatched bars) on the inhibition induced by 5-HT in control animals and in animals exposed to chronic mild stress. In each group, 10 slices obtained from five animals were tested. The values are the means ( --- SEM); , , P ~< 0.01 relative to respective saline-treated group, t-test.

tion to phenylephrine was comparable in control and stressed animals (Fig. 2B).

5-HT (10 tzM) also decreased the amplitude of the population spikes (Fig. 3A). That effect was reversed by a 10-min washout. In some slices, a transient increase in the amplitude of the population spikes was observed at the beginning of the 5-HT washout (2-5 min). The inhibition induced by 5-HT was completely blocked by spiperone (5/xM, n = 5; not shown). 5-HT decreased the amplitude of the population spikes to the same extent in slices from saline-treated controls and stressed rats (F(1,19) = 0.58; NS). Both in control and in stressed animals the inhibitory effect of 5-HT was significantly enhanced by prolonged treatment with imipramine (F(3,39) = 6.47; P < 0.01) (Fig. 3B).

4. Discussion

Our data confirm that animals subjected to chronic mild stress are subsensitive to the rewarding properties of a sucrose solution, and that this effect can be reversed by chronic administration of imipramine (for review see Willner et al., 1992). This study also demonstrates that CMS does not change the imipramine-induced potentiation of inhibitory effects of phenylephrine and 5-HT in the hippocampal CA1 neurons, these effects being mediated by a~-adrenergic and 5-HT1A receptors, respectively (Mynlieff and Dunwiddie, 1988; Segal et al., 1989). CMS does not affect either the responsiveness of the hippocampal CA1 neurons to phenylephrine and 5-HT.

A variety of animal models of depression are based on the stress-induced behavioral deficits which are reversed by antidepressants (Katz et al., 1981; Weiss et al., 1981; WiUner, 1984). It has been suggested that stress may contribute to the development of depres-

sion, in part via alterations in monoaminergic trans- mission. Acute stressful stimuli have been reported to activate central noradrenergic and serotonergic neurons, leading to an increase in the release and turn- over of both these amines in terminal fields, par- ticularly in the limbic areas (Joseph and Kennett, 1983; Kawahara et al., 1993; Pacak et al., 1993). Some data presented by other authors suggest that chronic stress decreases, whereas prolonged treatment with antidepressants increases the number and function of al-noradrenergic and 5 - H T I A receptors in the brain. In biochemical ex vivo studies, it was shown that repeated restraint stress significantly reduced the a- noradrenergic component of the cyclic AMP response to norepinephrine in cortical slices, that component having been attributed to activation of the a 1-noradrenergic receptor subtype (Stone et al., 1986, 1987). Furthermore, it was suggested that that effect of stress might be mediated by pituitary adrenal hormones, since administration of adrenocorticotropin (ACTH) also decreased the effect of a-noradrenergic receptor stimulation (Duman et al., 1985; Stone et al., 1986). In contrast to the effects of chronic stress, prolonged treatment with antidepressants enhanced the effects of al-noradrenergic receptor activation (Menkes et al., 1981; Bijak, 1989) and increased binding to al-noradrenergic receptor (Vetulani et al., 1984; Maj et al., 1985).

Repeated stress decreased the binding to 5-HT1A receptors in the hippocampus (Watanabe et al., 1993). A similar effect was observed after prolonged expo- sure to high-level corticosterone, which mimicked the corticosterone elevations during repeated stress (Men- delson and McEwen, 1992). Experimental data indicate that adrenal steroids may regulate hippocampal 5-HT1A receptors (Chalmers et al., 1993) and their function (Joels et al., 1991). The ability of 5-HT~A

M. BOak, M. Papp / European Neuropsychopharmacology 5 (1995) 43-48 47

agonists to attenuate the stress-induced behavioral deficits suggests that activation of 5-HT1A receptors might have antidepressive properties (Kennett et al., 1987; for review see De Vry et al., 1991). In line, prolonged treatment with antidepressants reportedly increases the binding to 5-HT~A receptors and the responsiveness to 5-HT1A receptor-mediated inhibitory effects of serotonin in normal animals (Blier et al., 1987; Welner et al., 1989; Chaput et al., 1991; Dijck et al., 1991; Bijak and Tokarski, 1994); however, contradictory data have also been obtained (Olpe et al., 1984; Rowan and Anwyl, 1985; Beck and Halloran, 1989).

The fact that we did not observe any alterations in the neuronal responsiveness to phenylephrine and 5- HT after chronic mild stress may indicate that this stress procedure does not affect stress-related hormones to the extent observed in other models of stress. Such an effect might be due to the fact that the mild stress procedure consists of extremely mild stressful stimuli. In fact, it has been shown that CMS does not increase the corticosterone plasma level in hooded Listar rats (Willner et al., 1987); the effect may be strain-specific, however. Another possible explanation is that the receptor changes are highly region-specific. The latter assumption is corroborated by the binding studies that show stress-induced, regional changes in 5-HT receptors in different subfields of the hippocampus (Mendelson and McEwen, 1992; Watanabe et al., 1993). In contrast to other models involving repeated stress, CMS increases the binding to 5-HT1A receptors in the hippocampus and a similar effect is induced by prolonged treatment with imipramine (Papp et al., 1994). On the basis of the above data it has been suggested that 5-HT1A receptors are not involved in the anti-anhedonic action of imipramine. A similar conclusion, concerning both ~l-noradrenergic and serotonergic 5-HTLA receptors in the hippocampus, may be drawn from our results.

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The effect of chronic treatment with imipramine on the responsiveness of hippocampal CA1 neurons to phenylephrine and serotonin in a chronic mild stress model of depression