Opposite effects on hippocampal corticosteroid receptors induced by stimulation of β and α1 noradrenergic receptors

Pergamon

03064522(94)00620-2

Neuroscience Vol. 66, No. 3, pp. 539-545, 1995 Elsevier Science Ltd Copyright 0 1995 IBRO Printed in Great Britain. All rights reserved 0306-4522/95 $9.50 + 0.00

OPPOSITE EFFECTS ON HIPPOCAMPAL CORTICOSTEROID RECEPTORS INDUCED BY STIMULATION OF fl AND al NORADRENERGIC RECEPTORS M. KABBAJ, P. V. PIAZZA,

H. SIMON, M. LE MOAL and S. MACCARI*

Laboratoire de Psychobiologie des Comportements Adaptatifs, INSERM U259, Universite de Bordeaux II, Rue Camille Saint Sdns, 33077 Bordeaux Cedex, France Abstract&Central corticosteroid receptors play an important role in the regulation of the secretion of corticosterone. Although these receptors are thought to be regulated by circulating levels of corticosterone, there is evidence for direct neural control. For example, it has been shown that noradrenergic lesions can both increase and decrease corticosteroid receptors depending on the brain structure involved. In the present study, we investigated the role of different noradrenergic receptors in the rat, by examining the effect of the acute administration of agonists and antagonists of /l and a, noradrenergic receptors on hippocampal type I and type II corticosteroid receptor levels. The effects of these drugs were studied in adrenalectomized animals whose plasma levels of corticosterone were maintained in the physiological range by implantation of corticosterone pellets. Our results show that the /l receptor agonist salbutamol (5 mg/kg) increased the number of type I and type II hippocampal corticosteroid receptors. This effect was blocked by the j receptor antagonist propranolol (Smg/kg), which had no effect on its own. In contrast, the a, receptor agonist phenylephrine (1OOpg) reduced the number of type I and type II corticosteroid receptors, whereas the a, receptor antagonist prazosin (0.5mg/kg) increased type I receptors. The effect of prazosin was attributed to an increase in the relative /I tonus resulting from blockade of a, receptors. Its effect was reversed by the simultaneous injection of the g receptor antagonist propranolol. In conclusion, our results show that noradrenergic transmission can have both a facilitatory and an inhibitory action on central corticosteroid receptors by acting respectively on B and a, noradrenergic receptors. Since noradrenergic neurons and the hypothalamo-pituitary-adrenal axis are known to be involved in various psychopathological conditions, these results may be relevant to treatment for dysregulation of corticosterone secretion.

The activity of the hypothalamo-pituitary-adrenal (HPA) axis, culminating in the secretion of adrenal steroids, is an important adaptive response to physical and psychological stimuli.” Indeed, modifications of HPA axis activity, especially an attenuated corticosteroid feedback control, have been observed in various neuropsychiatric disorders such as depression3~39~40and Alzheimer’s disease,” as well as during aging, 2*36,4749 although the mechanisms underlying the neuroendocrine abnormalities in these conditions are still largely unknown. Changes in the functional state of central corticos-

teroid receptors may account for at least some of

*To whom correspondence should be addressed. EDTA, ethylenediaminetetra-acetate; HPA, hypothalamopituitary-adrenal; NA, noradrenergic; phenylephrine, 4- [2 - (methylamino)ethy] - I ,2- benzeneprazosin, (l-[4-amino-6,7-dimethoxy-2-quinadiol; zolinyll-4-[2-furanylcarbonyl] piperazine) hydrochloride; propranolol, R(+)-[(1-methylethyl)amino]-3-(lnapthalenyloxy)-2-propranol hydrochloride; RU 28362, 17fi-dihydroxy-6-methyl17a - (1 -propynyl)-androsta1,4,6-trien-3-one; salbutamol, (I-[(t-butylamino) methyl]-4-hydroxy-m -xylene- 1,l ‘-diol).

Abbreviations:

the observed abnormalities in the functioning of the HPA axis. These receptors have been shown to be an important modulator of HPA axis activity.5,‘0,29 Thus, a decrease in the number of corticosteroid receptors results in an increased corticosterone secretion and vice versa. Two types of central glucocorticoid receptors have been described. Type I (or mineralocorticoid) receptors are mainly distributed in the limbic structures and have higher affinity for glucocorticoids than the type II (or glucocorticoid) receptors, which are widely distributed throughout the brain.43 Corticosteroid receptors respond essentially to changes in plasma corticosterone levels, and adjust their capacity via an auto-regulation mechanism.rO~” However, some reports indicate that corticosteroid receptors may also be under direct neural control. In particular, aminergic neurons appear to have a marked influence on corticosteroid receptors. Manipulations of serotonergic,‘,37*s5 dopaminergic7r8 and noradrenergic (NA)2s~26~28~55 transmission induce changes in corticosteroid receptors that, at least in certain circumstances, appear to be independent of concurrent changes in corticosterone levels. 539

M. Kabbaj et al.

540

In this report, we investigated the influence of NA transmission on corticosteroid receptors, since NA neurons have been shown to exert an important control on HPA axis activity” via afferents to the hippocampus and hypothalamus.34 For example, these neurons are activated during the stress response,21 and are thought to be involved in neuropsychiatric disorders involving dysfunctions of the HPA axis.” The influence of NA systems on corticosteroid receptors is complex. In previous studies, we showed that a lesion of the dorsal and ventral NA bundles in the superior cerebellar peduncle induced an increase in the numbers of type I receptors in the hippocampus26 and type II receptors in the hypothalamus, while the same lesion decreased type I receptors in the amygdala and hypothalamus.28 The present experiments were designed to find out whether the complex influence of NA transmission on corticosteroid receptors could be accounted for by differential regulation by the different NA receptor types. In particular, stimulation of fl and CI,receptors, which activate different second messengers, may have opposite effects on the binding capacity of corticosteroid receptors. Activation of tl, NA receptors may decrease the number of corticosteroid receptors by increasing intracellular calcium content,‘* a condition which has been shown to reduce the binding capacity of corticosteroid receptorsM Activation of /I NA receptors may increase corticosteroid receptors by activating the same phosphorylation process that is known to be required for steroid receptor regulation.6,‘4,3’ The roles of p and tll NA receptors were investigated by assessing the effects, on hippocampal type I and type II corticosteroid receptors, of an acute treatment with specific adrenergic agonists and antagonists. In order to eliminate the possible influence of changes in endogenous corticosterone levels, the drugs were administered to adrenalectomized animals in which corticosterone levels were maintained at physiological levels by corticosterone implants. EXPERIMENTAL PROCEDURES

Experimental

animals and housing conditions

Eighty-three male rats of the Sprague-Dawley strain (Iffa credo, Lyon) were used in these experiments. The animals were housed under controlled lighting (lights on from 06.00 to 20.00) and temperature (23°C). Food and water were available ad libitum. The rats weighed 325 k 25 g at the end of the experiments. Animals were evenly allocated to the experimental groups on the basis of their locomotor responses to novelty. This procedure was adopted because locomotor reactivity to novelty is correlated with the affinity of hippocampal corticosteroid receptors.27 Stereotaxic

implantation

of cannulae and microinjection

Since the a, receptor agonist phenylephrine does not cross the blood-brain barrier,15 this compound was injected intracerebroventricularly (i.c.v.). Rats were anaesthetized with pentobarbital (48 mg/kg, i.p.) and placed in a stereotaxic apparatus (Kopf Instruments) with incisor bar 5.0mm

above the interaural line. The cannulae were implanted unilaterally in the lateral ventricle according to the following coordinates: AP -5.6 mm, L 1.5 mm from bregma, DV

-3.1 mm from the skull. After one week of recovery, the rats were infused i.c.v. with 5.~1 of either a solution of phenylephrine (100 pg) or vehicle (injectable solution). The solution was injected slowly (3.5 min) through an injection cannula that was left in place for 2min to allow for drug diffusion. One hour later, the animals were killed and the brains removed. Adrenalectomy

and corticosterone

replacement

treatment

All the animals were adrenalectomized via the dorsal approach and implanted subcutaneously with solid corticosterone pellets, which produced stable corticosterone levels (6 + 0.9 ~g/tOO ml) in the diurnal physiological range. Each pellet contained 60 mg of corticosterone 21-hemisuccinate (Agar, Rome) adjusted to 100 mg with cholesterol. During the dark period, the animals also received 50pg/ml of corticosterone 21-hemisuccinate in 0.5% NaCl in their drinking water. This was designed to induce a similar increase in corticosterone levels (12 + 0.4 pg/iOO ml) to that observed in the nocturnal period. For the phenylephrine experiment, adrenalectomy and implantation of pellets were carried out at the same time as the cannulation. Plasma corticosterone was measured by a radiocompetitive binding assay after extraction in dichloromethane.35 Drug administration

The drugs used for this experiment were: the c(, receptor agonist phenylephrine (100 pg); the a, receptor antagonist prazosin (0.5 mg/kg); the /3 receptur agonist salbutamol (5 mg/kg); the B receptor antagonist propranolol(5 mg/kg). All drugs were obtained from Sigma. They were dissolved in injectable solution and administered one week after surgery. Phenylephrine was injected i.c.v., while all the other compounds were injected intraperitoneally (i.p.). The animals were killed 1 h after injection of the G(,compounds and 3 h after injection of the fi NA drugs. When propranolol and salbutamol were injected concomitantly, salbutamol was injected 1 h after propranolol, and the animals were killed 2 h after the salbutamol injection. When propranolol and prazosin were injected concomitantly, prazosin was injected 2 h after propranolol and the animals were killed 1 h after the prazosin injection. This last experiment was designed to evaluate interactions between the two NA receptor types. Given that some behavioural effects of c(, receptor antagonists have’been attributed to the relative increase in /J tonus resulting from a, receptor blockade,45 the above-mentioned doses of NA drugs and the time of killing were chosen to be compatible with their behavioural effects.‘s~33 Type I and type II corticosteroid

receptor assays

The hippocampus was rapidly dissected and frozen on dry

ice. Tissues were stored at - 80°C until receptor assay. The binding characteristics of cytosolic type I and type II corticosteroid receptors of the hippocampus were determined from the tissue of one rat. In order to eliminate endogenous corticosterone, an exchange assay was used for both type I and type II corticosteroid receptors, as described previously.7,8 The tissue was homogenized in 2 ml of ice-cold buffer (30 mM Tris, pH adjusted to 7.4 with 6 N HCl, 1 mM EDTA, 10 mM sodium molybdate and 10% glycerol) and centrifuged (105,OOOg,20 min in a Beckman TLlOO ultracentrifuge) at 4°C. Endogenous, unbound steroids were removed from the soluble fraction by passing the samples twice through LH-20 columns equilibrated with buffer (10 mM Tris, 2 mM EDTA, 10 mM sodium molybdate and 2.3 mM b-mercaptoethanol). For the type I receptor assay, aliquots of cytosol (140~1) were incubated with tritiated corticosterone ([‘Hlcorticosterone, 101.6 Ci/mM; New England Nuclear) over a concentration range of 0.625-20 nM

Noradrenergic modulation of corticosteroid receptors (six points for each Scatchard plot) and with a IOO-fold excess of unlabelled RU 28362. Unlabelled RU 28362 was used to displace ]3H]corticosterone from type II receptors. Type II receptor binding was evaluated directly using pure elucocorticoid 13HlRU 28362 (suecific activitv 89 Ciimmol) . over a concentration range of 0.625-20 nM isix points for each Scatchard plot). Binding equilibrium was reached after 22 h at 4°C. This has been shown to be sufhcient for maximal exchange, and binding remains stable over this period. ‘6,30Non-specific binding for the [‘HJcorticosterone binding was determined in the presence of a W-fold excess of unlabelled corticosterone and for [‘H]RU 28362 was assessed in the presence of a 500-fold excess of unlabelled RU 28362. Bound and unbound [‘Hlcorticosterone or [-‘H]RU 28362 were separated on Sephadex LH-20 columns equilibrated with Tris-HCl-EDTA-molybdateglycerol buffer at 4°C using 60 ~1 of the incubates and eluting with 900 ~1 of buffer; 960 ~1 of the eluate containing the bound form was added to 3.6 ml of scintillation fluid (LipolumaR, Lumac) and radioactivity was counted. Protein concentration was determined according to Lowry er ~1.~~using albumin as standard. The apparent maximum binding capacity (g,,, in fmol/mg of proteins) of [‘H]corticosterone or [3H]RU 28362 and the dissociation constants (Kd, in nM) for both types of receptors were evaluated from Scatchard plots.50 jl

.

,

I

,

Statistical analyses

After an analysis of data distribution, the data were subjected to analyses of variance (ANOVA) for repeated measures. Student’s t-test was used for posr hoc comparisons. RESULTS

Injection of /I NA drugs modified the B,,, of both type I and type II corticosteroid receptors [ANOVA treatment effect F(3,27) = 4.517, P = 0.0108; treatment x receptors interaction F(3,27) = 0.888, P = 0.45991, without having any significant effects on their affinity (Table 1). The injection of the /I agonist salbutamol (5 mg/kg, i.p.) increased the B,,,,, of both type I (t-test, P = 0.0256) and type II (t-test, P = 0.0339) receptors. While injection of the /3 antagonist propranolol (5mg/kg, i.p.) by itself had no effect, it totally reversed the effects of salbutamol. Thus, animals injected with both propranolol (5 mg/kg, i.p.) and salbutamol (5 mg/kg, i.p.) had lower levels of corticosteroid receptors (type I, t-test,

541

P = 0.0055; type II, t-test, P = 0.0196) than the animals receiving only salbutamol, and did not differ from controls. The stimulation of CC,NA receptors had opposite effects to those observed after stimulation of /? NA receptors (Table 2). Thus, the injection of the CC, receptor agonist phenylephrine (100 pg, i.c.v.) decreased hippocampal corticosteroid receptors [ANOVA treatment effect F(1,18) = 16.689, P = O.OOOS]to a similar extent for type I and type II receptors [treatment x receptors interaction F(1,18) = 0.892, P = 0.35751. Type I receptors were reduced by -50% [F(1,18) = 5.7, P = 0.0282], and type II receptors by -45% [F(1.18) = 12.871, P = 0.00221. The administration of phenylephrine did not alter the affinity of either type I or type II receptors. The number of type I receptors was found to be higher in the control group for the phenylephrine experiment (i.e. in the rats injected with saline i.c.v.) than peripherally-treated control rats (Table 1 vs Table 2). Given that it has been shown previously that a single acute treatment can cause a long-term increase in corticosteroid receptor numbers,” it is possible that the different surgical procedures in the i.c.v.-treated rats accounts for the above-mentioned difference between the control groups. Injection of the CC, NA receptor antagonist prazosin (0.5 mg/kg, i.p.) modified type I corticosteroid receptors, and the effect appeared to depend on the relative increase in /I NA tonus [ANOVA treatment effect F(2,29) = 3.62, P = 0.03931 (Table 3). Animals receiving prazosin had more hippocampal type I corticosteroid receptors than did the saline-treated controls (t-test, P = 0.0394). This effect was reversed by the concomitant administration of the /I NA receptor antagonist propranolol(5 mg/kg). Thus, the rats injected with both propranolol and prazosin had lower levels of type I corticosteroid receptors than did the rats injected with prazosin alone (t-test, P = 0.0316), and did not differ from the salinetreated controls. None of these treatments modified the B_ of type II receptors or the affinity of either type I or type II receptors (Table 3).

Table 1. Effects of /I noradrenergic drugs on hippocampal corticosteriod receptors Type II

Type 1 B max

Saline Salbutamol Propranolol Propranolol + Salbutamol

Kd

1.39 f. 0.20 61 rf: 6.05 86 k 6.32* 1.46kO.11 74 + 5.92 1.29 + 0.10 55 f 11.333 1.087 + 0.06

B mx

259 f 311 f 299 f 253 +

16.06 13.03* 15.71 25.05.t

Kd

0.75 f 0.61 + 0.71 f 0.77 +

0.09 0.07 0.07 0.18

Characterization of hippocampal type I and type II corticosteriod receptors after treatment with the /l receptor agonist salbutamol (5mg/kg, i.p.). /I receptor antagonist propranolol(5 mg/kg, i.p.), and simultaneous injection of salbutamol and propranolol. The /l receptor agonist salbutamol increased the B,,,,, (fmol/mg of proteins) of both type I and type II corticosteriod receptors, while the concomitant administration of the /I receptor antagonist propranolol reversed this effect. Propranolol by itself had no significant effect. *P < 0.05 vs saline; tP < 0.05 vs salbutamol; $P -C 0.01 vs salbutamol.

542

M. Kabbaj

et al.

Table 2. Effects of a, noradreneraic agonists on hiDDocamDa1corticosteriod receDtors Type

Saline Phenylephrine

172 &-17.09 115 k 16.71*

Type II

1

BInill

B mm

Kd

1.71 * 0.12 1.42 + 0.14

Kd

281 + 14.68 193 f 19.72**

0.76 + 0.13 0.76+0.13

Characterization of hippocampal type I and type II corticosteriod receptors after treatment with the a, receptor agonist phenylephrine (100 pg, i.c.v.). PhenyleDhrine induce a decrease in both tvne I and type II hippocampal corticosteriod receptors. *P cO.05; **P< 0.01. IL

DISCUSSION

Our results show that CL,and /3 NA receptor stimulation has opposite effects on hippocampal corticosteroid receptors. Thus, an acute treatment with the #?receptor agonist salbutamol increased the number of type I and type II corticosteroid receptors, whereas injection of the c(, receptor agonist phenylephrine decreased it. There was evidence for an interaction between these two receptors, and the overall number of hippocampal corticosteroid receptors may therefore depend on the relative weight of these two opposite controls. For example, blockade of CL,NA receptors by prazosin appeared to increase the level of corticosteroid receptors by enhancing the relative stimulation of /I receptors. Given that the effect of prazosin was completely reversed by the concomitant blockade of /I NA receptors by propranolol, this interaction between CIand fi NA tonus is in agreement with the blockade by propranolol of the inhibitory effects of prazosin on food intake observed in pygmy goats.4s Our findings indicate that noradrenaline exerts a control on corticosteroid receptors independently of concomitant changes in circulating corticosterone levels. Thus, NA drugs modified central corticosteroid receptors despite the fact that plasma corticosterone levels were maintained at a constant level by implantation of corticosterone pellets after adrenalectomy. These findings are consistent with the direct influence of neurotransmitters on corticosteroid receptors described by various groups. For example, it has been shown that antidepressant drugs increase type II mRNA in primary culture of rat brain neurons3* and type II immunoreactivity.20 Reserpine, Table 3. Effects of a, noradrenergic

a cathecholaminergic depleting agent, has been found to decrease both type I and type II receptors in adrenalectomized rat.23 Mitchell et ~1.~~ have also reported that serotonin regulates type II corticosteroid receptors in hippocampal cell cultures. The mechanism by which activation of /I and tl, NA receptors has opposite effects on corticosteroid receptors remain to be elucidated. However, a differential activation of phosphorylationdephosphorylation processes by the two types of NA receptors could be involved, as these processes are known to modulate steroid receptor function. Activation of /l NA receptors by noradrenaline could increase corticosteroid receptor levels by stimulating protein kinase A. This cytoplasmic enzymer8 phosphorylates corticosteroid receptorsTs2 turning them into an inactive form,6,‘4,31which leads to an increase in binding capacity. Noradrenaline may have opposite effects on corticosteroid receptors via tl, receptors, since their activation stimulates phospholipase C. Activation of this enzyme leads to an increase in intracellular Ca2+ content,” which has been shown to reduce the binding capacity of corticosteroid receptors.& An alternative explanation is that the noradrenaline could have interfered with the translocation of the corticosterone-receptor complex into the nucleus. In fact, it has been shown that an NA lesion reduces the number of nuclear corticosteroid receptors” and increases the number of these receptors in the cytosol. 25,26Furthermore, noradrenaline could alter the corticosteroid receptors’ mRNA expression. In fact, it has been shown that a central NA lesion decreases type I but not type II corticosteroid receptor mRNA in hippocampal subfields. However, other mechanisms, such as an action of

antagonists receptors

corticosteriod

Type II

Type 1 Saline Prazosin Prazosin + propranolol

on hippocampal

Bmax

Kd

60 + 4.78 84 + 8.70* 55 f 9.86t

0.99 + 0.08 1.19 kO.06 1.10 +0.15

[email protected] 254 & 20.32 263 + 10.62 287 + 28.50

Kd 0.61 + 0.06 0.59 rf:0.07 0.80 rt 0.20

Characterization of hippocampal type I and type II corticosteriod receptors after treatment with the LX,receptor antagonist prazosin (0.5mg/kg, i.p.) and the b receptor antagonist proranolol (5 mg/kg, i.p.). Prazosin increased the number of type I receptors in the hippocampus, but had no influence on the number of type II receptors. The concomitant injection of propranolol reversed the effect of prazosin. *P i 0.05 vs saline; tP < 0.05 vs prazosin.

Noradrenergic modulation of corticosteroid

noradrenaline on exitatory amino acids, which are known to regulate corticosteroid receptors,*’cannot be ruled out. Stimulation of ai and fl NA receptors has also been shown to have opposite effects on the activity of the HPA axis. A single injection of an TV,agonist induces an increase in corticotropin-releasing hormone’9~42 and adrenocorticotropic hormones3 secretion, while a single injection of a @ agonist decreases release of these peptides. 42Our fIndings suggest that the modification of central corticosteroid receptors by NA drugs is an early process in a cascade of changes culminating in a shift in the activity of the HPA axis. Thus, an increase or a decrease in the functional state of corticosteroid receptors results in a decrease or an increase in the activity of the HPA axis, respectively. A mechanism of this kind may account for the recent results of Reul and co-workerqM who demonstrated that chronic treatment with the antidepressant amitriptyline attenuates the activity of the HPA axis

receptors

543

and increases the number of type I and type II corticosteroid receptors.

CONCLUSION

Our results indicate that activation of ~1,and /? NA receptors influences central corticosteroid receptors and may thus have a significant effect on corticosterone secretion. NA drugs may therefore be of value in therapeutic strategies designed to treat the glucocorticoid hypersecretion resulting from a disruption in feedback control, which is observed in certain psychopathological states,‘*i3and in individuals who are vulnerable to drug self-administration.” study was supported by the Instide la Sante et- de la Recherche l&&ale fINSERh41.the Universit6of Bordeaux II and the Conseil Regional d’Aquitaine. We thank Roussel-UCLAF for providing RU 28362. Acknowledgements-This

tut National

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