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University of Bristol, HWLINE, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
1 Department of Pyschopharmacology, H Lundbeck A/S, Copenhagen, Denmark
(Requests for offprints should be addressed to M S Harbuz; Email: m.s.harbuz{at}bristol.ac.uk)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CRF is the main hypothalamic peptide involved in the release of ACTH from the anterior pituitary (Aguilera 1994). AVP is a weak solo stimulator of ACTH release that can synergistically enhance the actions of CRF upon ACTH release from pituitary corticotrophs (Gillies et al. 1982). However, under chronic stress conditions it has been proposed that AVP can become the major stimulator of the HPA axis and may be important in maintaining the stress response when the pituitary is refractory to CRF (Scaccianoce et al. 1991, Chowdrey et al. 1995, Aguilera & Rabadan-Diehl 2000, Harbuz 2002). Oxytocin (OT) is another peptide produced mainly within the mPVN (Swanson & Sawchenko 1983), but also within the pPVN, that may have a role in the mediation of the stress response (Neumann et al. 2000a,b, Nakashima et al. 2002, Neumann 2002).
Restraint stress is a well documented predominantly psychological stressor (Pare & Glavin 1986, Harbuz & Lightman 1992, Harbuz et al. 1993), that acutely initiates a transient increase in plasma ACTH and corticosterone (the major glucocorticoid in rodents), usually peaking during the course of a 60 min stress exposure. CRF mRNA in the pPVN also increases, at around 3–4 h after the start of stress (Harbuz & Lightman 1989). Within 60 min following the termination of a 60 min restraint stress, plasma levels of corticosterone and ACTH are restored to basal levels and CRF mRNA expression in the PVN gradually returns to basal levels (Harbuz & Lightman 1989). Parvocellular AVP mRNA can also be increased by acute immobilisation stress (Aubury et al. 1999) although such increases do appear to be strain and procedure dependent (Harbuz et al. 1994).
There is a putative role for central serotonin in the coordination of the HPA axis activity under basal and stressed conditions (Dinan 1996, Matheson et al. 1997, Jorgensen et al. 1998, Chaouloff 2000, Jorgensen et al. 2002). Furthermore serotonergic dysfunction is also associated with depression and around 50% of patients diagnosed with depression have hypercortisolaemia and thus have altered basal HPA axis activity (Gibbons 1964, Nemeroff et al. 1984, Young et al. 1991, Graeff et al. 1996, Arborelius et al. 1999, Hatzinger 2000). Whether hypercortisolaemia is a cause or a consequence of depression remains to be determined. However, impaired feedback responses are considered responsible for the HPA axis overdrive in depression (Young et al. 1991). Selective serotonin re-uptake inhibitors (SSRIs) are the drugs of choice for the treatment of depression. SSRIs block the re-uptake activity of the serotonergic transporter leading to an initial increase in synaptic levels of serotonin following acute administration and modulation of serotonergic activity following chronic (repeated) administration (Massand & Gupta 1999, Davis et al. 1999). SSRI treatment can alter activity of the HPA axis (Jensen et al. 1999, 2001, Raap & Van de Kar 1999, Wieczorek et al. 2001). Citalopram and fluoxetine have been shown to acutely stimulate the rodent HPA axis while this stimulation is attenuated in chronically citalopram-treated rats (Jensen et al. 1999, 2001). It is thought that SSRIs may normalize the basal hyperactive HPA axis in depression, possibly via re-establishment of the feedback control (De Bellis et al. 1993, Maes et al. 1995, Raap & Van de Kar 1999) via the increase in mineralocorticoid receptor levels principally in the hippocampus (Pariante et al. 2004). The HPA axis may be an important target for SSRI-induced clinical improvement in patients diagnosed with depression and who demonstrate hypercortisol secretion. However, there is little data available on how SSRI treatment may affect HPA axis responsiveness. Given the wide use of SSRI’s in psychiatry, a better understanding of HPA responsiveness and function following exposure to SSRI’s, may provide an improved knowledge of how SSRI’s may contribute to clinical improvement in various patients. The purpose of these studies was to evaluate the rodent HPA response to acute restraint stress, following acute and chronic treatment with citalopram so as to better understand how a mammalian system may respond to a psychological stressor in the presence of SSRI’s.
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Materials and Methods |
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Adult male Sprague-Dawley rats (Harlan-Olac, Bicester, UK) weighing 200–250 g, were initially housed four to a cage. Following implantation of i.v. and s.c. cannulae rats were assigned to individual cages. Rats had free access to pellet diet and water and were maintained on a 12 h:12 h light:dark cycle with lights on at 0600 h. The room temperature was 21 °C. Studies were commenced at 0830 h. All procedures carried out were in accordance with the Animals (Scientific Procedures) Act 1986.
Drugs
Citalopram (gift from H Lundbeck A/S, Copenhagen, Denmark) was made up in 0.9% sterile saline (vehicle). Other reagents: heparin–saline solution (made up as 50 units/ml); Hypnorm (0.315 mg fentyal and 10 mg fluranisone/ml (Janssen Pharmaceutica, UK); 100 µl/250 g intramuscular (i.m.) injection); Diazepam (1 mg/ml, (Sigma–Aldrich) 250 µl/250 g i.p. injection). Halothane (2–4% gas (INEOS Fluor, Cheshire, UK)).
Surgery
An i.v. cannula for the collection of blood and a s.c. cannula for the administration of citalopram or vehicle were implanted into rats under Hypnorm–Diazepam anaesthesia. Animals were allowed four recovery days following surgery prior to carrying out the experimental protocol.
The Alzet osmotic minipumps held a total volume of 2 ml released over 14 days at 5 µl/h, and were filled with either citalopram (10 mg/kg/day based on a mid experiment weight of rats ~ 250 g) or vehicle solution (0.9% sterile saline). Minipumps were prepared and stored in sterile saline solution for 12 h prior to surgery. Animals were briefly anaesthetized using halothane gas anaesthesia and minipumps were implanted into the dorsal s.c. space. Once recovered, rodents were returned to their home cages and checked every second day.
Experiment 1: a single dose of citalopram and acute restraint stress
A cannula was implanted into each rat on day 0, and on day 4 an initial blood sample (300 µl) was collected from all rats through the i.v. cannula (zero minute blood sample). Immediately after collection of this basal sample, citalopram or vehicle were administered through the s.c. cannula and half of the citalopram treated rats and half of the vehicle treated rats were restrained for 60 min in clear plastic circular restrainers (10 cm in length by 6 cm diameter – these allowed small forward and reverse movements but no rotation). The remaining rats were kept in their home cages throughout the experiment. Further blood samples were collected from all rats at 15 (100 µl), 30 (300 µl), 45 (100 µl), 60 (300 µl) and 240 (100 µl) min following the onset of restraint or respective non-stress period (in control rats). Blood samples were kept on wet ice during the collection, centrifuged (3200 g/10 min/4 °C) and plasma stored at –20 °C. Following collection of the final blood sample at 240 min, rats were decapitated and brains were collected and frozen on dry ice.
Experiment 2: chronic citalopram and acute restraint stress
Minipumps were implanted into rats on day 0 and on day 11 rats had i.v. and s.c. cannulae fitted as described previously. On day 14, all rats had an initial i.v. blood sample (300 µl) collected at time 0 min. Half of the rats fitted with minipumps containing citalopram and half of the vehicle infusion rats were exposed to a 60 minute restraint and the remaining rats were retained in their home cages through the experiment. Subsequent blood samples were collected at 30 and 60 min (300 µl). Blood samples were kept on wet ice during the collection. At 240 min, rats were decapitated and brains were collected and frozen on dry ice.
Radioimmunoassay
Analysis of the plasma hormones corticosterone and ACTH was undertaken using in house radioimmunoassays (RIA). ACTH peptide was initially extracted from plasma using C18 Sep-Pak cartridges (Millipore, Watford, UK) prior to RIA (Jessop et al. 1989). Plasma concentrations of ACTH were not measured at all time points because of the relatively greater volume of blood required for the ACTH assay. The ACTH assay is specific for ACTH (1–39) in normal rat plasma, as previously determined by high performance liquid chromatography (HPLC) (Jessop et al. 1989). There is no evidence for detection of higher molecular weight forms or smaller proopiomelanocortin (POMC) peptide products such as 
-MSH. Plasma corticosterone was measured directly from plasma (5 µl in 500 µl assay buffer) with antiserum provided by G Makara (Institute of Experimental Medicine, Budapest, Hungary). The corticosterone assay as previously detailed by Harbuz et al. 1992. Intra- and inter-assay variations were all less than 12%.
In situ hybridisation
Brain slices (12 µm) of PVN were prepared using a cryostat (c.f. Figure 27 in Paxinos & Watson 1998) and mounted onto gelatin-coated slides. Oligo probe in situ hybridization (ISH), as described previously by Harbuz & Lightman (1989), was used to analyze parvocellular CRF mRNA, parvocellular AVP mRNA and magnocellular OT mRNA in the PVN. The oligo probes have been previously characterized (OT and AVP, Young et al. 1986a and CRF, Young et al. 1986b). The specific activities (d.p.m./mol) of the oligo probes were: experiment 1: CRF (1.54x1019), AVP (6.71x1018) and OT (4.53x1018); experiment 2: CRF (4.45x1018), AVP (3.30x1018) and OT (1.11x1019).
Statistics and data analysis
Data are represented as the mean ± S.E.M. For radioimmunoassay data a two-way analysis of variance (ANOVA) was used followed by the Fisher’s PLSD post-hoc test (Statview 5.0, SAS Institute Inc., NC, USA). For ISH data autoradiographic images (Examples of similar images are shown in Kinoshita et al. 2000) of probe bound to target mRNA were analyzed using an image analysis system (Image NIH 6.12, National Institute of Health, Bethesda, MD, USA) and values were calibrated according to the autoradiographic images of C-14 standards (co-exposed with the samples on the same film). For each rat, two sections of PVN per slide/probe were measured. To distinguish parvocellular AVP from magnocellular AVP mRNA, data was generated using a threshold function as described by Kinoshita et al.(2000). In our previous paper (Kinoshita et al. 2000) we compared the threshold method with the grain-counting method that is more usually applied to studies of the parvocellular AVP system. We were able to demonstrate the effectiveness of the threshold method despite the penumbra of signal surrounding the magnocellular region. Although there is a chance that by increasing the background this may result in increased false negatives, we were able to demonstrate quite subtle differences in signal comparing the two methods. We are entirely confident that a positive result using the threshold technique, because of the potential risk of false negatives, means that any significant changes are likely to be physiologically relevant. ISH data was statistically compared using one-way ANOVA followed by Fisher’s PLSD post hoc test. ISH data is presented as a percentage of the saline control group.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Corticosterone data Basal levels of corticosterone were 35 ± 10 ng/ml prior to drug administration and restraint and these levels did not alter significantly within the saline control group throughout the experiment (Fig. 1A
). In saline treated rats, restraint stress was able to induce significant elevations in plasma corticosterone between 15 and 45 min into the 60 min restraint procedure compared with saline treated control rats. A single s.c. injection of 5 mg/kg citalopram was able to significantly increase plasma corticosterone levels in non-restrained rats from 15 min following administration until 45 min compared with saline control rats, with levels comparable to those in saline treated restrained rats. In the combined citalopram and restraint treatment group, citalopram induced a prolonged corticosterone response to restraint stress with corticosterone levels remaining significantly increased compared with non-stressed controls, citalopram treated and saline treated restrained rats at 45 and 60 min. Corticosterone levels returned to basal levels in all groups by 240 min.
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). ACTH was significantly increased in saline treated restrained rats compared with saline treated control rats. Citalopram alone was not found to significantly elevate plasma ACTH levels at 30 min following administration of drug. However, citalopram treated restrained rats had significantly elevated levels of ACTH at 30 min and these levels remained elevated at 60 min.
mRNA data Brains were collected and frozen 4 h after the start of the experiment on the sample day, therefore all mRNA data is representative of this time point. Parvocellular AVP mRNA was not significantly altered by citalopram treatment or by acute restraint stress. However, in the combined treatment group AVP mRNA was significantly enhanced in the pPVN (Fig. 2A). Parvocellular CRF mRNA was significantly enhanced by restraint and by the combined treatment but was unaffected by acute citalopram treatment (Fig. 2B). Magnocellular OT mRNA was enhanced by restraint or citalopram, with no enhanced effects resulting from the combined treatment (Fig. 2C).
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Corticosterone data Chronic administration of citalopram (10 mg/kg/day) for 14 days did not affect the basal levels of corticosterone (35 ± 10 ng/ml) and there were no significant differences in corticosterone levels, in any of the rats, prior to restraint on day 14 (Fig. 3A). Neither saline nor citalopram infusion altered basal levels of corticosterone throughout the experiment. Restraint stress increased plasma corticosterone levels in saline treated rats and the corticosterone response to acute restraint stress was not affected by chronic citalopram treatment.
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). Basal levels of ACTH were maintained in the saline and citalopram control groups throughout the experiment. Restraint stress increased plasma ACTH levels in saline treated rats. However, the ACTH response to restraint was suppressed at 30 min in rats treated for 14 days with citalopram.
mRNA data Brains were collected 4 h after the start of the study on the sample collection day, therefore all mRNA data is representative of this time point. AVP mRNA was increased in the pPVN in rats following 14 days of citalopram infusion and in the citalopram-restraint group compared with saline infused controls (Fig. 4A). Restraint stress did not alter AVP mRNA levels compared with their saline controls. CRF mRNA was significantly increased by restraint stress in saline infused rats. Chronic citalopram treatment did not enhance basal CRF mRNA compared with saline infused controls nor did it alter the CRF mRNA response to restraint as there was no significant difference between saline-restraint and citalopram-restraint rats (Fig. 4B). Magnocellular OT mRNA was enhanced by acute restraint stress in both saline-infused and citalopram-infused rats (Fig. 4C). Chronic citalopram alone had no effect on OT mRNA.
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Discussion |
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Plasma corticosterone and ACTH were transiently increased in rats in response to acute restraint stress as demonstrated previously (Harbuz et al. 1993, Viau et al. 1993, Harbuz et al. 1994). A single injection of citalopram (5 mg/kg) increased plasma levels of corticosterone as shown by Jensen et al.(1999) using a higher dose (10 mg/kg) of citalopram. At 5 mg/kg, citalopram was able to elevate basal plasma corticosterone to comparable levels induced by restraint stress. However, at 5 mg/kg, citalopram had no effect on plasma ACTH, at least at the 30 minute time point in ‘non-stressed’ rats. This would suggest that ACTH release, in response to 5 mg/kg citalopram, has either a response with a shorter duration or exhibits a response with lower amplitude than that stimulated by 10 mg/kg of citalopram. The dose of citalopram used in this study (5 mg/kg) was chosen to prevent maximal stimulation of the HPA axis by citalopram, in order that a combined response to restraint and citalopram could be clearly distinguished from solo treatments. At this dose (5 mg/kg), citalopram was not found to further enhance the levels of corticosterone induced by restraint stress (during the peak restraint-induced stimulation of corticosterone), but was found to prolong the increase in plasma corticosterone induced by restraint stress. The combined action of citalopram and restraint stress also resulted in sustained increases in ACTH.
Parvocellular AVP mRNA was not induced by acute restraint stress alone. It has previously been reported that increases in AVP mRNA in response to restraint stress are strain dependent with CFY rats but not Sprague-Dawley rats having an increase in AVP mRNA in the pPVN (Harbuz et al. 1994). AVP was also not affected by a single injection of citalopram when given alone, but the combined treatment of restraint and citalopram did enhance AVP mRNA in the pPVN. Therefore citalopram may be able to prolong the acute corticosterone and ACTH response to restraint via an AVP-mediated pathway, which would be an interesting consideration for future studies. The possibility that citalopram when combined with restraint is able to stimulate AVP-associated pathways is intriguing due to the hypothesis that under chronic stimulatory conditions AVP can become the dominant PVN neuropeptide regulating the HPA axis (Aquilera 1994, Harbuz 2002).
Paraventricular OT mRNA was increased in both restrained and citalopram treated rats which may reflect enhanced plasma OT levels following a single dose of an SSRI (Uvnas-Moberg et al. 1999) and in both plasma and the PVN, following exposure to acute stress (Neumann 2002). The combined treatment of restraint and citalopram was however not able to further enhance OT mRNA in the PVN. OT is proposed to have a complex interaction with the HPA axis that varies under basal and stressed conditions. It is claimed that OT may increase the ACTH response to various acute stressors (Neumann et al. 2000a) and may have a potential role in the long term mediation of the HPA axis following withdrawal of a stressor (Nakashima et al. 2002). Conversely, OT may also provide a basal HPA axis regulatory or inhibitory role in rodents (Neumann et al. 2000b). However, Nakashima et al.(2002) found that the intracerebral injection of an OT receptor antagonist did not alter the plasma ACTH level at the end of a single stress. Rather, it presented an effect 2 days after the withdrawal of a single immobilisation stress, suggesting a more involved role for AVP, over OT, in this immediate prolonged activation of the HPA axis evoked by the combined treatment of restraint stress and citalopram. It would seem that OT can provide a homeostatic cue to stimulate or regulate the activity of the axis depending on the level of HPA axis stimulation.
Plasma OT levels have previously been shown to be increased by chronic citalopram treatment (Uvnas-Moberg et al. 1999) however, our data demonstrates that OT mRNA levels were not increased by chronic citalopram as they had been for acute citalopram. This would suggest that paraventricular OT mRNA increases are only induced during early SSRI treatment and increased plasma levels of OT are seen during the early to mid-phase of SSRI treatment. This elevation in plasma OT may aid the SSRI-induced modulations that are involved in the therapeutic action of these antidepressants.
Chronic infusion of citalopram for 14 days, did not alter basal plasma corticosterone or ACTH levels on day 14 under non-stressed conditions confirming previous data (Jensen et al. 1999). The corticosterone response to acute restraint stress was unaffected by chronic citalopram treatment. However, the ACTH response was suppressed in rats treated chronically with citalopram. This apparent lack of ACTH response at 30 min despite a corticosterone response to restraint in rodents exposed to citalopram for 14 days may indicate that the adrenal glands of rats treated chronically with citalopram may be sensitive to low levels of ACTH, an observation which needs to be confirmed. Reports of dissociations between plasma ACTH and corticosterone concentrations are not uncommon in the literature (Dohanics et al. 1990, Larsen et al. 1994, Dallman et al. 2002), but these dissociations have not been systematically investigated, to our knowledge, to date. Such studies, including those that may consider the potential dissociation between cortisol and ACTH in depressed patients treated with SSRIs would be of considerable interest and would be worthy of further study.
Infusion of citalopram for 14 days increased parvocellular AVP mRNA but not parvocellular CRF mRNA suggesting that citalopram may be working through a vasopressinergic mechanism in these rats. CRF mRNA may have initially been enhanced during the early stages of SSRI treatment, as demonstrated by Wieczorek et al.,(2001). Our data demonstrate a slight but non-significant increase in CRF mRNA in the PVN of citalopram treated rats compared with saline controls, suggesting that the CRF mRNA response to citalopram is attenuated following prolonged exposure, but that AVP mRNA expression is enhanced. This potential switch in the regulatory mechanism of the HPA axis, by citalopram, may be critical for the clinical effectiveness of SSRI treatment. Although our data provide evidence for an involvement of AVP, this evidence is on the basis of changes in AVP mRNA and not peptide release. Further studies would be required to confirm this possibility. An increase in AVP has been noted in depression (Scott & Dinan 2002) and this may contribute to anxiety-related or depressive symptoms in patients as antagonists for the V1b receptor have been shown to have potential antidepressant and anxiolytic effects in rodents (Serradeil-Le Gal et al. 2003, Wigger et al. 2004).
Although we have reported a SSRI-induced increase in parvocellular AVP mRNA, SSRIs have been reported to reduce the vasopressin hyper-drive in high-anxiety bred rats (Keck et al. 2003). SSRIs may therefore target the vasopressin system to normalise the ratio of CRF to AVP and re-establish CRFR1 function at the pituitary level in depressed patients. However, in ‘non-depressed’ rats, the SSRI-induced increase in AVP during chronic treatment may represent an alternate SSRI-mediated event that may contribute to an alteration in the way the HPA axis is able to respond to acute stress.
It is generally recognized that in response to repeated/chronic stress AVP is critical in sustaining corticotroph responsiveness in the presence of elevated blood glucocorticoid levels and that this is reflected by an increase in AVP receptors (Aguilera & Rabadan-Diehl 2000). In adjuvant-induced arthritis it has been shown that CRF mRNA is decreased, while AVP mRNA is increased in the pPVN in the face of increased levels of plasma corticosterone and that these changes are reflected by similar changes in mature CRF and AVP peptide release into the hypophysial portal blood (Chowdrey et al. 1995). There is also evidence that various stress paradigms can induce increases in AVP mRNA and heteronuclear RNA (hnRNA), despite the increase in circulating levels of glucocorticoids (Aguilera & Rabadan-Diehl 2000). Cumulatively, these data suggest that in response to repeated/chronic stress AVP may be a more important regulator of the HPA axis than CRF. Our findings of a preferential action on AVP mRNA suggests SSRIs may operate through such a mechanism.
In conclusion, we have demonstrated that acute and chronic SSRI treatment can impact on the rodent response to acute restraint stress. This would suggest that the HPA axis is affected by SSRI treatments, and that there may be potential involvement of the vasopressin-containing subset of CRF neurons in the pPVN.
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Acknowledgements |
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Funding |
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The work carried out in this paper was funded by the MRC and H Lundbeck A/S, Copenhagen, Denmark.
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References |
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Received 11 March 2005
Accepted 24 March 2005
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