Chronic antidepressant treatment modulates the release of somatostatin in the rat nucleus accumbens

Neuroscience Letters 395 (2006) 76–81

Chronic antidepressant treatment modulates the release of somatostatin in the rat nucleus accumbens Eleftherios G. Pallis, Christina Spyraki 1 , Kyriaki Thermos ∗ University of Crete, Faculty of Medicine, Department of Basic Sciences, Laboratory of Pharmacology, Heraklion, Crete, GR 71110, Greece Received 26 September 2005; received in revised form 21 October 2005; accepted 22 October 2005

Abstract This study investigated the in vivo neuronal release of somatostatin in the rat nucleus accumbens (NAc), and the effect of chronic administration of antidepressants. Microdialysis studies were performed on male Sprague–Dawley rats, in accordance with the EU guidelines (EEC Council 86/609). Somatostatin levels were quantified by radioimmunoassay (RIA) or enzyme linked immuno sorbent assay (ELISA). A high concentration of potassium ions (K+ , 100 mM) was used to ascertain the neuronal release of somatostatin. Antidepressant treatments involved the administration of citalopram (20 mg/2 ml/kg, i.p., once daily) or desipramine (DMI, 5 mg/2 ml/kg, i.p., twice daily) for 21 days. Control groups received saline (2 ml/kg for 21 days, i.p.) once or twice daily respective of the antidepressant treatment. Basal levels of somatostatin released were found to be 20.01 ± 0.52 fmol/sample. K+ (100 mM) increased somatostatin levels at 205% of basal. Chronic citalopram and desipramine treatments also increased the somatostatin levels by 83 ± 32% and 40 ± 6% of basal, respectively. These findings indicate that somatostatin is released neuronally in the NAc. Antidepressants influence its release in a positive manner, suggesting the necessity of further studies for the elucidation of the involvement of somatostatin in the putative therapeutic effects of these agents. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Somatostatin release; In vivo microdialysis; Citalopram; Desipramine; Monoamines

The neuropeptide somatostatin is a cyclic tetradecapeptide, which is widely distributed in the peripheral and central nervous system [4,10]. Somatostatin mediates a variety of physiological actions by interacting with specific receptors. Five somatostatin receptor subtypes (sst1 to sst5 ) have been cloned and found to be expressed differentially in different tissues, coupled to different G-proteins and to modulate the actions of diverse second messengers [13,24]. In the basal ganglia, somatostatin is synthesized in the caudate-putamen and the NAc [5,36] and it has been implicated in the pathophysiology of different psychiatric disorders [29], including depression [11,21,29]. Its levels are attenuated or increased in the cerebrospinal fluid (CSF) of depressed patients as compared to healthy subjects [11,21]. A limited number of studies have focused on the effect of antidepressants on the somatostatinergic system. Acute and chronic treatments with citalopram reduced somatostatin levels in the striatum [27]. Previous studies from our group have shown ∗

Corresponding author. Tel.: +30 2810 394533; fax: +30 2810 394530. E-mail address: [email protected] (K. Thermos). 1 Present address: University of Athens, School of Medicine, Laboratory of Pharmacology, Athens, Greece. 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.10.055

that chronic desipramine treatment increased somatostatin binding sites selectively in the NAc [12]. Therefore, the aim of the present study was to employ in vivo microdialysis methodology in order to examine in the NAc (a) the neuronal release of somatostatin, and (b) how this is affected by the chronic administration of citalopram and DMI. Male Sprague–Dawley rats (270–330 g; Charles Rivers, Italy) were used in all experiments. Rats were group-housed (2–3 per cage) in a temperature-controlled room (21 ± 1 ◦ C) with a 12 h light–dark cycle. Food and water were provided ad libitum. All procedures were performed in accordance with the guidelines for care and use of experimental animals (EEC Council 86/609). In the experiments involving antidepressant treatment, rats were assigned to four groups (n = 8 rats per group) according to treatment received. The chronic DMI group received DMI (5 mg/2 ml/kg, i.p.) twice daily for 21 days [22], the chronic citalopram group received citalopram (20 mg/2 ml/kg, i.p.) once daily for 21 days [23], and the two control groups received saline (2 ml/kg, i.p.) once or twice daily (respective of the antidepressant treatment) for 21 days. In the chronic DMI group, rats had a smaller weight gaining rhythm during the treatment period than

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rats from the other groups, but no statistical significance was found between the groups. Experiments were performed with vertical design microdialysis probes with concentric flow arrangement as mentioned earlier [28,33]. The exposed tip of the semi permeable polyacrylonitrile dialysis membrane (Filtral© 16, AN69© HF membrane, Hospal, Meyzieu, France, c.o. 20000 Daltons) was 2.5 mm. The length of the membrane was cut to approximately 2.5 mm and the tip of the membrane plugged with epoxy glue and the active dialyzing surface was ∼2.0 mm. In order to determine the optimal conditions for somatostatin recovery, in vitro studies were performed using the microdialysis probe as described previously [28]. The dialysis probe was perfused with a solution medium (artificial cerebrospinal fluid) containing 125 mM NaCl, 2.5 mM KCl, 1.2 mM CaCl2 , 1.0 mM MgCl2 , 3.5 mM NaH2 PO4 , 0.2 mM Ascorbic Acid, and 0.025% Bovine Serum Albumin-BSA (pH 7.4), using a microdialysis pump (CMA 100, CMA Microdialysis AB, Sweden), at a flow rate of 1.0 ␮l/min. The probe was immersed into an eppendorf tube (1.5 ml) containing the perfusion solution medium and the in vitro stand placed in a water bath at 37 ◦ C for 1 h in order for the probes to adjust to the temperature, the flow rate, and the perfusion solution. Subsequently, the probe was immersed into another eppendorf tube containing a standard solution with a known concentration of synthetic somatostatin (100 fmol/60 ␮l). A total of six samples were collected every hour (60 ␮l) from each probe (n = 5). All samples and standard solutions were stored immediately at −80 ◦ C until they were analyzed for somatostatin using RIA. For the in vivo studies, rats were anaesthetized with ketamine HCl (100 mg/kg, i.m.) plus xylazine (10 mg/kg, i.m.) and placed in a stereotaxic apparatus (David Kopf Instruments, USA). The microdialysis probes were implanted bilaterally in the NAc using the coordinates [NAc: AP +1.6 mm; ML ±1.5 mm; DV −8.2 mm] obtained from Paxinos and Watson [26]. The probes were secured to the skull, the incision sutured and the animal was immediately placed in a microdialysis cage for freely moving animals (CMA 120, Carnegie Medicin AB, Sweden) and attached to a microdialysis pump (CMA 100, Carnegie Medicin AB, Sweden) using polyethylene tubing (PE 10, Portex Limited, UK), according to Pallis et al. [25]. The dialysis probe was perfused with the artificial CSF solution, mentioned in the previous paragraph, at a flow rate of 1.0 ␮l/min while the animal recovered overnight. For the release experiments, the day following surgery, the flow rate was maintained at 1.0 ␮l/min. Ten samples were collected every 30 min. The samples from the two bilateral probes were pooled, and thus 2 × 30 = 60 ␮l were collected per sample from each experimental animal. To ascertain the neuronal release of somatostatin in the NAc, a second perfusion solution medium was used containing an increased K+ concentration (27.5 mM NaCl, 100 mM KCl, 1.2 mM CaCl2 , 1.0 mM MgCl2 , 3.5 mM NaH2 PO4 , 0.2 mM Ascorbic Acid, 0,025% BSA, pH 7.4) [28]. During the fifth sampling, this second perfusion solution was administered via the probe. Somatostatin concentrations in the perfusate samples and all samples studied were measured by RIA using [125 I]-Tyr11 -

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Somatostatin (IM 161, Amersham, UK) and a somatostatin antibody (N 1611, Amersham, UK), as described previously [28]. A standard curve was prepared using [125 I]-Tyr11 -somatostatin (3000 cpm, 2000 Ci/mmol), the antibody (final dilution 1/200) and synthetic cyclic somatostatin in a 0.8 ml solution containing 50 mM sodium phosphate, 10 mM EDTA and 0.3% BSA (pH 7.2). All samples were found to be within the detection range of the assay (0.78–100 femtomoles per sample of 60 ␮l). In the experiments involving antidepressant treatment, the microdialysis probes were implanted 24 h after the last treatment administration. The day following surgery, that is 48 h after treatment cessation, the flow rate was maintained at 1.0 ␮l/min and 10 samples were collected as mentioned in the previous paragraph. Somatostatin concentrations in the perfusate samples were measured by ELISA using a kit (EIAS(r) 8001, Peninsula Laboratories Inc. USA). The ELISA method was used for quantification of somatostatin for pure technical reasons, due to the sudden unavailability of the somatostatin antibody used for the RIA analysis. All samples were found to be within the detection range of the assay (0.04–25 ng/ml or 1.22–763 femtomoles per sample of 50 ␮l). Confirmation of probe placement was established at the end of each experiment. Each brain was sliced at 50 ␮m slices, using a cryostat (Reichtert-Jung 1206, Cambridge Instruments GmbH, Germany) through the level of the NAc. Confirmation of probe implantation was observed after staining with cresyl violet using a light microscope (Nikon, USA). Only data from animals with probe verification in the NAc were included in the study. Simple statistics (mean ± S.D.) were calculated for the in vitro perfusate samples. Relative recovery (Rr) of the microdialysis probe was counted as the percentage of the mean sample concentration to the concentration of the standard somatostatin solution. For the somatostatin release experiments, data were expressed in fmol of somatostatin per sample (60 ␮l). The first four samples were designated as “basal levels” and all samples were expressed as the percent of basal levels. A one-tailed t-test analysis was used for the comparison of the baseline and the K+ induced release. For the antidepressant treatment experiments, data were expressed in fmol of somatostatin per sample (50 ␮l), since this volume was employed for the ELISA measurements. Percent values were analyzed by a one-way analysis of variance (ANOVA) with Newman–Keuls multiple comparison post test. Primary to the statistical analysis of the antidepressant effect, a comparison between the two control groups was carried out (paired two-tailed t-test). The two control groups received saline (2 ml/kg, i.p.) once (Control 1 Group) or twice daily (Control 2 Group) for 21 days, respectively, to the antidepressant treatment (DMI or Citalopram). The statistical software GraphPad Prism v. 2.01 (GraphPad Software Inc., USA) was employed for the statistical analysis. Under the present experimental conditions (flow rate 1.0 ␮l/min and temperature 37 ◦ C) the relative in vitro recovery rate of the microdialysis probe was found to be 9.53 ± 1.9% (n = 5). The basal levels of somatostatin were found to be 20.01 ± 0.52 fmol/sample (0.333 ± 0.008 fmol/␮l) (n = 20). A

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Fig. 1. Neuronal release of somatostatin in the NAc. Effect of increased K+ concentration (100 mM) on somatostatin basal release. A perfusion solution with the increased K+ concentration was administered during the fifth sampling and resulted in an increase on the basal somatostatin levels by 207% (n = 18). Data are expressed as percentages of basal levels (defined as the mean of the first four samples from each group) and they represent mean ± S.D. Basal somatostatin release was 20.01 ± 0.52 fmol/sample (n = 20). ** p < 0.01, *** p < 0.001 compared to basal levels.

high concentration of K+ (100 mM) present in the perfusion solution medium produced a statistical significant increase (t = 21.14 d.f. = 36, p < 0.001, R-squared = 0.9254, F-test (6.109) [17,19], p < 0.001) of somatostatin levels to 41.42 ± 0.99 fmol/sample (n = 18). Somatostatin levels were increased to 207 ± 5.0% of baseline at the time of high K+ pulse (Fig. 1). The statistical significant difference between the two groups lasted for two samples. Somatostatin release was also detected by ELISA. The baseline levels of somatostatin were found to be 17.4 ± 3.7 fmol/sample (0.347 ± 0.073 fmol/␮l) (n = 8). Comparison between the two analytical assays (two-tailed t-test, t = 0.8695 d.f. = 26, p = 0.3925, R-squared = 0.02826) did not reveal any statistical difference. The two control groups were compared and the statistical analysis did not reveal any significant difference (t = 0.6622, d.f. = 9, p = 0.5244, R-squared = 0.04646) (Fig. 2A). Therefore, the values from the two control groups were pooled and employed as a single group (Control Group) with which the antidepressant treated groups were compared. Chronic treatment with desipramine increased the basal release of somatostatin to 140.2 ± 6.5% (n = 8) of control levels, while chronic treatment with citalopram similarly produced an increase of somatostatin to 183.4 ± 31.9% (n = 8) (F2,29 = 13510, R-squared = 0.9990, p < 0.001). A Newman–Keuls multiple comparison post hoc test showed a statistical significant difference (p < 0.001) between the control group and the two groups receiving antidepressants. In addition, a statistical significant difference (p < 0.001) was observed between the Citalopram and the DMI groups (Fig. 2B). The actual data of the above studies are shown in Fig. 3. The present study investigated the in vivo neuronal release of somatostatin in the rat NAc and how chronic antidepressant treatment influences this release. Brain microdialysis and subsequent RIA or ELISA methodologies were used for the detection and quantification of extracellular somatostatin in the NAc of awake, freely moving rats. In our experimental conditions the in

Fig. 2. Effect of antidepressant treatment on somatostatin release in the NAc. (A) Comparison of the baseline somatostatin levels in the two Control Groups (Control 1 Group: saline 2 ml/kg, i.p., once daily, 21 days, Control 2 Group: saline 2 ml/kg, i.p., twice daily, 21 days). (B) DMI (5 mg/2 ml/kg, i.p., twice daily, 21 days) increased somatostatin release by 140% of basal levels (n = 8). Citalopram (20 mg/2 ml/kg, i.p., once daily, 21 days) increased somatostatin release by 183% of basal levels (n = 8). Control somatostatin release was 17.37 ± 3.66 fmol/sample (n = 16). *** p < 0.001 compared to control group, ### p < 0.001 compared to DMI group.

vitro relative recovery was found to be 9.5 ± 1.9%, within the range of that reported in previous studies [17,28]. Somatostatin was shown to be neuronally released. While this finding was expected, it was not substantiated till the present study. These data are in agreement with earlier findings from our laboratory showing the neuronal release of somatostatin in the striatum [28], but also in agreement with data from studies by

Fig. 3. Somatostatin release in the NAc in control and antidepressant treated rats. Somatostatin levels in fmol/sample in the three groups presented in the caption of Fig. 2, namely Control, DMI and Citalopram.

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others in the striatum [20], in the hippocampus [20,35], and in cortical synaptosomes [3]. Changes in the function of neurotransmitters in the mesolimbic system, and specifically in the NAc, have been attributed to the pathophysiology and therapy of depression [37]. Recent evidence from our laboratory has shown that the sst1 receptor subtype present in the nucleus accumbens regulates the release of somatostatin and acts as an autoreceptor [34]. In the ventral pallidum, a nucleus that influences the physiology of the NAc, somatostatin activation of sst1 and sst2 receptors reduces rat locomotor activity [19]. These studies suggest that somatostatin’s presence in brain nuclei with known involvement in affective behaviors may have an impact in normal or pathological brain function, such as depression. Chronic antidepressant treatment has been used as a paradigm to study this conjecture. Earlier studies from our laboratory [12] showed that chronic administration of DMI resulted in an increase in [125 I]-Tyr11 -somatostatin binding sites, and an exaggerated somatostatin-induced increase in dopamine levels exclusively in the NAc [25]. These data suggested an up regulation of somatostatin receptor binding sites, possibly due to a monoamine induced attenuation of somatostatin release, since DMI inhibits the reuptake of dopamine, serotonin (5-HT), and norepinephrine (NE). The present in vivo data do not support this hypothesis, since chronic DMI administration resulted in an increase in somatostatin levels. Similarly, chronic administration of the selective 5-HT reuptake inhibitor citalopram was also found to increase somatostatin levels in the NAc. Data from the literature have shown that repeated administration of two other serotonin reuptake inhibitors, clomipramine and zimelidine, was found to result in a wide spread reduction in somatostatin levels in brain tissues (the NAc was not mentioned), whereas imipramine had no effect [16]. In addition, long-term treatment with a serotonin synthesis inhibitor resulted in an elevation of somatostatin levels in brain tissues, suggesting that somatostatin is under the negative control of serotonin [15]. In another study, a reduction of somatostatin levels in the NAc and the striatum was observed after 4 h of administration of a single dose of citalopram (same dose as in the present study), while chronic citalopram administration resulted in a decrease of somatostatin and its mRNA only in the striatum [27]. The investigators suggested a reduction in the biosynthesis of the peptide. The results from the above mentioned studies [15,16,27] appear to be contradictory to the present data. In all studies, somatostatin tissue levels were measured and a reduction was observed. One could suggest that this decrease in tissue levels could be due to an increase in somatostatin release, in agreement with the present findings. However, direct comparisons can only be made with the Prosperini et al. study [27]. While the conditions employed for the chronic treatment group were not identical, similarities were present (citalopram, 10 mg/kg, i.p. twice daily, 14 days [27], citalopram, 20 mg/2 ml/kg, i.p.) once daily for 21 days, present study). However, these investigators do not report any changes in somatostatin-like immunoreactivity in the NAc.

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The present study provides for the first time in vivo evidence in the awake animal that the antidepressants, desipramine and citalopram, when administered i.p. chronically influence somatostatin levels in a positive manner. This increase in somatostatin levels may have ramifications on the pharmacological actions of the antidepressants, since the levels of somatostatin were reported to be attenuated in the cerebrospinal fluid of depressed patients [11]. While there is no direct evidence that somatostatin or its agonists are efficacious as antidepressants, somatostatin may act indirectly to influence other neurotransmitter systems known to be instrumental in the pathophysiology and therapeutics of depression, such as the norepinephrine, dopamine or serotonin systems. The mechanism underlying the increase in somatostatin levels is not evident. There are reports suggesting NE–somatostatin interactions. Somatostatin receptors are present in the locus coeruleus either in the vicinity of NE-containing cell bodies or on NE containing cells, suggesting somatostatin’s ability to control locus coeruleus physiology [9]. Also, in the hippocampus, somatostatin receptors have been localized presynaptically on noradrenergic nerve terminals [18]. These studies provide evidence on how somatostatin receptor activation may influence NE release rather than how increased levels of NE could affect the release of somatostatin that would provide an explanation for the present findings. The presence of the NE transporter (NET) in the NAc has been reported and its role in dopamine clearance has been established [6]. Therefore, blockade of NET by chronic DMI treatment may result in chronic increases in dopamine levels in the NAc. Studies examining the effect of dopamine on somatostatin release have been reported. In the striatum, acute administration of dopamine ligands had no effect on somatostatin release [33]. However, other studies suggested an inhibitory or a stimulatory role of dopamine on somatostatin release in the same nucleus [1,31,32]. Due to the above discrepancies as to the effect of the acute administration of dopamine on somatostatin levels, it is difficult to hypothesize what consequences would chronic dopamine levels have on somatostatin release. Regarding 5-HT, the NAc receives a dense serotoninergic innervation [14] and is rich in 5-HT receptors [2]. While numerous reports have supported 5-HT’s influence on the dopamine system in the striatum and the NAc [8,7], very few reports have addressed 5-HT–somatostatin interactions [27]. It becomes apparent that future studies should focus directly on the (a) acute effects of serotonin and (b) chronic effects of both serotonin and dopamine on somatostatin release in the NAc. The present data showing statistically significant differences in somatostatin levels in the two antidepressant treatment groups suggest a larger serotonin influence on the somatostatin system. However, further investigations are necessary to substantiate this finding. One may question whether the two antidepressants interact directly with the somatostatinergic system. DMI does not compete for [125 I] Tyr11 somatostatin binding in rat cortical membranes [30] nor does it affect [125 I] Tyr11 somatostatin affin-

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