Brain Research, 584 (1992) 309-313
309
© 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00
BRES 25275
Repeated corticosterone administration sensitizes the locomotor response to amphetamine V6ronique Deroche, Pier Vincenzo Piazza, Stefania Maccari, Michel Le Moal and Herv6 Simon Laboratoire de Psychobiologie des Comportements Adaptatifs INSERM U259, Universit~de Bordeaux II, Bordeaux (France) (Accepted 14 April 1992)
Key words: Sensitization; Amphetamine; Stress; Corticosterone; Locomotor activity
Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50/~g/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states.
Life-events, especially repeated exposure to stressful situations, may induce long-lasting modifications in biological and behavioral reactivity 2. Among these stress-induced changes, the increase in the behavioral and biochemical responses to psychostimulants has been the subject of numerous studies 4'33. The stress-induced increase in the reactivity to psychostimulants, appearing as a cross-sensitization 4, is interesting for at least two reasons. Firstly, it has been proposed as an animal model of psychostimulant p s y c h o s i s 11'33, since a symptomatology of this type may be triggered in psychostimulant users by stressful events 33. Secondly, it has been associated with an increase in individual predisposition to drug-seeking 27'29. For example, animals receiving repeated tail-pinch stress have a higher locomotor response to amphetamine as well as a higher intake of this drug during self-administration (SA) 28. The association of changes in the psychomotor and reinforcing properties of psychostimulants is in line with the notion that the reinforcing effects of these drugs are related to their psychomotor action 32'41.
One of the main biological responses to stress is the activation of the hypothalamic-pituitary-adrenal axis (HPA), which ultimately leads to the secretion of glucocorticoids 23'26. Stress-induced corticosterone secretion could be responsible, at least in part, for the increase in the reactivity to psychostimulants induced by stress. Several observations point to an involvement of the HPA axis and these hormones in the response to psychostimulants: (1) behavioral sensitization to amphetamine or cross-sensitization between stress and amphetamine are reduced by pretreatment with CRH antiserum7'8. (2) Glucocorticoids have numerous actions on the brain, and in particular they seem to modify the activity of the mesocorticolimbic dopaminergic s y s t e m 9'12'34'38, which is thought to mediate the locomotor and reinforcing effects of psychostimulants 17'32'42. (3) Corticosterone, the major glucocorticoid in the rat, influences the individual response to amphetamine. Thus, the higher the corticosterone level at the time of amphetamine injection, the higher is the locomotor response of the animal to this drug 29'3°.
Correspondence: P.V. Piazza, INSERM U259, Rue Camille Saint Sa~ns, 33077 Bordeaux Cedex, France. Fax: (33) (56) 96-68-93.
310 Furthermore, an acute injection of corticosterone before a session of amphetamine SA increases the reinforcing effects of this drug 3°. In order to test if increases in corticosterone levels may augment the reactivity to psychostimulant, we studied the effect of two different paradigms of corticosterone administration on the locomotor response to amphetamine. In the first, corticosterone was administered as a stress procedure (tail-pinch, 15 days, one session per day), which has been found to increase the p s y c h o m o t o r and the reinforcing properties of amphetamine 2s. The animals received an intraperitoneal (i.p.) injection of corticosterone (1.5 m g / k g ) instead of one tail pinch session. In the second, corticosterone (50 ~ g / m l ) was dissolved in the drinking water, which was given to the animals between 7.00 p.m. and 8.00 a.m. for a period of 15 days. Plasma corticosterone levels were measured after both procedures, and compared with levels induced by stress. Fifty-six male S p r a g u e - D a w l e y rats (Iffa-Credo, Lyon, France) (280-300 g body weight) were used. The animals were individually housed with ad libitum access to food and water. A constant dark-light cycle (on 6.00 h, off 20.00 h) was maintained in the animal house under controlled temperature (22°C) and humidity (60%). D-Amphetamine sulfate was dissolved in saline (0.9% NaCI) which was also used as control substance. Corticosterone-21-hemisuccinate ( A G R A R , Italy), was used in all the experiments, and doses were expressed as corticosterone base. Locomotor activity was tested in a circular corridor (170 cm long and 10 cm wide). Four photoelectric cells placed at the 2 perpendicular axes detected overall locomotor activity. Animals were injected with saline first and then with amphetamine (1 m g / k g ) after a 2-h habituation period in the circular corridor. Locomotor activity induced by each injection was recorded over 10-min intervals for a period of 2 h. Sixteen animals were implanted with an intracardiac catheter for blood sampling. Under chloral hydrate (150 m g / k g i.p.) anesthesia, the catheter (Silastic) was first inserted in the right auricle through the external jugular vein, passed under the skin and exited in the mid-scapular region. Plasma corticosterone concentrations were measured by a radiocompetitive binding assay method after extraction into dichloromethane 25. In the first experiment, 38 rats were divided into 4 groups. The first (n = 9) received an injection of corticosterone (1.5 m g / k g i.p.) dissolved in saline (0.9% NaCI) at 9 a.m. every day for 15 days. The second one (n = 9) received an identical sequence of saline injections. To check that the effects of corticosterone were
due to repeated exposure to the hormone, the other two groups of animals (n = 10 each) received only one intraperitoneal injection of either saline or corticosterone (1.5 mg/kg). Five days after the last injection, all the groups were tested for their locomotor response to amphetamine (1 m g / k g i.p.). The effect of an acute injection of corticosterone at this dose on plasma levels of this hormone was studied in a further group of animals (n = 16). Half of the animals received an injection of corticosterone solution (1.5 m g / k g i.p.) at 9 a.m., the other half received, at the same time, an injection of saline. Thirty minutes later blood samples were withdrawn from the tail vein from both groups of rats. In the second experiment, 18 rats were divided into 2 groups (n = 9 each). The first received corticosterone dissolved in the drinking water at a concentration of 50 ~ g / m l . Corticosterone solution was available between 7 p.m. and 8 a.m., while water was available for the rest of the day. The second group, received water throughout the day. This treatment lasted 15 days and after 5 days washout both groups were tested for amphetamine-induced locomotor activity. The effect of oral corticosterone administration on plasma corticosterone levels was studied in another group of animals (n = 6). Rats in this group were implanted with an intracardiac catheter for blood sampiing. At the same time the animals were adrenalectomized and implanted subcutaneously with solid corticosterone pellets designed to deliver a continuous and stable amount of this hormone in the physiological range of diurnal basal levels. The solid pellets contained 12.5 mg of corticosterone adjusted to 100 mg with cholesterol. This procedure was adopted to avoid the potential bias of an increased secretion of corticosterone induced by manipulation during blood sampiing. One week after the surgical intervention, these animals received corticosterone in the drinking water as described above. Six 500-~1 blood samples were withdrawn from the catheter for corticosterone assay. The first sample was withdrawn at 7 a.m. immediately before the administration of the corticosterone solution. The other 4 were sampled at 2-h intervals with the last one taken at 9 a.m. A further group of animals (n = 10) was used to compare the increase in corticosterone plasma levels induced by these treatments with those observed during stress. The rats in this group were implanted with an intracardiac catheter, and after 1 week of recovery they were exposed to a novel environment, represented by the circular corridor described above. Blood samples were withdrawn from the catheter immediately before, and 30 min after exposure to the novel environment.
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The data were subjected to an analysis of variance (ANOVA) for repeated measures. Repeated intraperitoneal administration of corticosterone increased the locomotor response to amphetamine (Fig. 1). While the locomotor response to saline solution in the corticosterone-treated animals did not differ from that of controls (Fig. 1A), the two groups showed a significant difference (ANOVA, injection × time interaction, F1],]76 = 1.92, P < 0.03) in locomotor response to amphetamine (Fig. 1B). The corticosterone-treated animals exhibited a higher locomotor response to amphetamine during the first hour after the injection (El,16 = 4.06, P < 0.05) (Fig. 1B, inset). In contrast to repeated corticosterone administration, a single injection of the hormone did not significantly affect the locomotor response to amphetamine 5 days later. However, corticosterone-treated animals tended to have an increased response to amphetamine (control = 516 + 132; corticosterone = 607 + 81) cumulated over the first hour of the test (Ft,18 = 0.32; P = 0.57). Administration of corticosterone at the dose used in this experiment significantly increased plasma levels of this hormone (Fig. 2A). Thirty minutes after the injection, the corticosterone-treated animals had significantly higher levels than the saline-treated rats (FL~ 4 = 14.4, P < 0.005). Levels attained those observed 30 min after exposure to novelty stress. Administration of corticosterone in the drinking water also increased the locomotor response to amphetamine (Fig. 3). Thus, corticosterone-treated animals did not differ from controls in locomotor response to saline injection (Fig. 3A), while the two groups showed a significant difference (ANOVA, Injection x Time interaction, Fl1,176 = 2.368, P < 0.01) in the loco-
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Fig. 1. Effect of repeated intraperitoneal corticosterone injections on locomotor response to saline (A) and amphetamine (B). Corticosterone treatment (1.5 m g / k g , o n c e a day for 15 days) did not modify the locomotor response to saline, whereas it increased the locomotor response to amphetamine (FI1,176 = 1.92, P < 0.05). In the inset, locomotor activity is cumulated over 60 min. * = P < 0.05.
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Fig. 2. Plasma corticosterone levels after intraperitoneal (i.p.) (A) or oral (p.o.) (B) corticosterone administration. The injection of corticosterone (1.5 mg/kg i.p.) led to a similar increase in plasma corticosterone levels to those induced by exposure to novelty stress. The intake of corticosterone in drinking water (50 / z g / m l ) significantly increased plasma corticosterone levels overnight (F5,25 = 9.23, P < 0.001). Levels returned to basal values by the morning. The dotted line represents the mean increase in plasma corticosterone levels 30 min after exposure to a novelty stress, and the shaded area represents the S.E.M. * = P < 0.05; * * = P < 0.01.
motor response to amphetamine (Fig. 3B). The corticosterone-treated animals had a higher locomotor response to amphetamine during the first hour after the injection (El,16 = 3.88, P < 0.05) (Fig. 3B, inset). Corticosterone administration in the drinking water significantly increased (F5~25 = 9.23, P < 0.001) the overnight plasma concentration of the hormone (Fig. 2B). The increase induced by this treatment was similar to that induced by stress 28. The peak level (14.1 + 2 . 3 / z g / 1 0 0 ml) was observed 2 h after exposure to the corticosterone solution (9 p.m.). Corticosterone levels were still elevated 8 h later (3 a.m.) (Ft, s = 12.29,
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Fig. 3. Effect of repeated oral corticosterone administration on locomotor response to saline (A) and amphetamine (B). Corticosterone treatment ( 5 0 / z g / m l in drinking water for 15 days) did not alter the locomotor response to saline, whereas it increased the locomotor response to amphetamine (Fi1,176 ~ 2.368, P < 0.01). In the inset, locomotor activity is cumulated over 60 min. * = P < 0.05.
312 P < 0.01), returning to basal levels (2.9 _+ 1.3 /xg/100 ml) by the morning (9 a.m.). Our results show that repeated corticosterone administration increases the locomotor response to an acute injection of amphetamine. Interestingly, at the doses used in both experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those observed after stress. Thus, corticosterone secretion could be a mechanism by which repeated stress increases the behavioral response to psychostimulants 4'33. Furthermore, as described for stress 3"28, the effect of corticosterone seems to bring about long-lasting neural modifications. The increase in the locomotor response to amphetamine was detectable 5 days after the end of the treatment. Glucocorticoids may modulate neural activity via two types of receptor: the classical intracellular receptors (Type I and Type II) 5'9 or the membrane receptors recently described in amphibians 26. Intracellular receptors, which induce slow gene-mediated effects 9, may account for the long-lasting modifications observed in our experiments. Thus, it has been shown that the glucocorticoid effects on gene expression, which occur with a delay of at least 15 min to several hours 24, may persist weeks after disappearance of the glucocorticoid, and are sometimes irreversible during development 9. A neuronal mechanism mediating the action of glucocorticoids on amphetamine-induced behaviors could involve an increased reactivity of aminergic, particularly dopaminergic (DA) neurons to psychostimulants. This idea is supported by various lines of evidence. Firstly, mesolimbic D A neurons are thought to be a principle substrate of amphetamine-induced locomotor activity 17,32. Secondly, D A neurons have glucocorticoids receptors ~5, and glucocorticoids may increase the release of DA 34'38. Thirdly, an increased release of dopamine in response to amphetamine, observed after repeated stress or amphetamine injections 4°, is associated with a higher behavioral response to this drug 4'33. However, the action of corticosterone on other transmitter systems, such as serotoninergic (5-HT) and GABAergic neurons, may account for the observed effect on the locomotor response to amphetamine. Both these systems may influence locomotor activity 32'35 and glucocorticoids have been reported to modify the binding capacity of 5-HT 6'1°'22 and G A B A receptors 2°'21'37. The increased locomotor response to amphetamine induced by repeated corticosterone treatment supports the idea that glucocorticoids are involved in the determination of the propensity to amphetamine self-administration 29 as well as in some psychiatric disturbances 14'16. It has been shown that a higher locomotor response to amphetamine is associated with an en-
hanced propensity to self-administer this drug2'( This association is observed in certain vulnerable individuals 27, or when self-administration behavior is induced experimentally by repeated stress 2'~ or repeated amphetamine administrations 2s (amphetamine sensitization). Furthermore, spontaneously vulnerable animals or animals in which the propensity has been induced by stress have a longer release of corticosterone in response to environmental stimulation 3°. Thus an increase in corticosterone secretion, either spontaneously present in certain individuals or stress-induced in others, may predispose an individual to psychostimulantseeking behavior by enhancing the response to psychostimulants. E n h a n c e d responsiveness to amphetamine may also be indicative of a higher susceptibility to psychological disturbances. In view of the observed relationships between affective or cognitive disturbances and stress L13,3j, repeated stress could enhance the risk of psychopathologies via an exaggerated secretion of glucocorticoids. It is of interest in this respect that manic-depressive symptoms and even psychosis has been observed in patients with Cushing's syndrome or those receiving prolonged corticosteroid treatment t4,16,18,19,39. In conclusion, our results show that stress-induced corticosterone secretion may be one of the biological mechanisms mediating the increased sensitivity to psychostimulants. Furthermore, they throw some light on possible mechanisms of the psychiatric side effects of chronic glucocorticoid treatment. This work was supported by l'Institut National de la Sant~ et de la Recherche M6dicale (INSERM) and l'Universit~ de Bordeaux II. REFERENCES 1 Anisman, H. and Zacharko, R.M., Depression: the predisposing influence of stress, BehaL,. Brain Sci., 5 (1982) 89-137. 2 Antelman, S.M., Stressor-induced sensitization to subsequent stress: implications for the development and treatment of clinical disorders. In P.W. Kalivas (Eds.), New York, Academic Press, Sensitization in the Central Nert;ous System, 1988, pp. 227-259. 3 Antelman, S.M. and Eichler, A.J., Persistent effects of stress on dopamine-related behaviors: clinical implications. In E. Usdin, I.J. Kopin and J. Barchas (Eds.), Catecholamines: Basic and Clinical Frontiers, Pergamon, New York, 1979, pp. 1579-1761. 4 Antelman, S.M., Eichler, A.J., Black C.A. and Kocan, D., Interchangeability of stress and amphetamine in sensitization, Science, 207 (1980) 329-331. 5 Arriza, J.L., Weinberger, C., Cerelli, G., Glaser, T.M., Handelin, B.L., Housman, D.E. and Evans, R.M., Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoidreceptor, Science, 237 (1987) 268-275. 6 Biegon, A., Rainbow, T.C. and McEwen, B.S., Corticosterone modulation of neurotransmitter receptors in rat hippocampus: a quantitative autoradiographic study, Brain Res., 332 (1985) 309314. 7 Cole, B.J., Cador, M., Stinus, L., Rivier, C., Rivier, J., Vale, W., Le Moal, M. and Koob. G.F., Critical role of the hypothalamic
313 pituitary adrenal axis in amphetamine-induced sensitization of behavior, Life Sci., 47 (1990) 1715-1720. 8 Cole, B.J., Cador, M., Stinus, L., Rivier, J., Vale, W., Koob, G.F. and Le Moal, M., Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization, Brain Res., 512 (1990) 343-346. 9 De Kloet, E.R., Brain corticosteroid receptor balance and homeostatic control, Frontiers Neuroendocrinol., 12 (1991) 95-164. 10 De Kloet, E.R., Sybesma, H. and Reul, J.M.H.M., Selective control by corticosterone of serotonin 1 receptor capacity in raphe-hippocampal system, Neuroendocrinology, 42 (1986) 513521. 11 Ellison, G.D. and Eison, M.A., Continuous amphetamine intoxication: an animal model of the acute psychotic episode, Psychol. Med., 13 (1983) 751-762. 12 Faunt, J.E. and Crocker, A.D., Adrenocortical hormone status affects responses to dopamine receptor agonists, Eur. J. Pharmacol., (1988) 255-261. 13 Field, T.M., Mc Cabe, P.M. and Schneiderman, N., In L. Erlbaum (Eds.), Stress and Coping, Hillsdale, NJ, 1984. 14 Hall, R.C.W., Popkin, M.K., Stickney, S.K. and Gardner E.R., Presentation of steroid psychoses, J. Neru. Ment. Dis., 167 (1979) 229-236. 15 H~irfstrand, A., Fuxe, K., Cintra, A., Agnati, L.F., Zini, I., Wikstr6m, A.C., Okret, S., Yu, Z.Y., Goldstein, M., Steinbuch, H., Verhofstad, A. and Gustafsson, J.A., Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain, Proc. Natl. Acad. Sci. U.S.A., 83 (1986) 9779-9783. 16 Holsboer, F., Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity, Eur. Arch. Psychiatr. Neurol. Sci., 238 (1989) 302-322. 17 Kelly, P.H., Seviour, P. and Iversen, S.D., Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum, Brain Res., 94 (1975) 507-522. 18 Krieger, D.T., Physiopathology of Cushing's disease, Endocrinol. Rev., 4 (1983) 22-53. 19 Ling, M.H.M., Perry P.J. and Tsuang, M.T., Side effects of corticosteroid therapy, Arch. Gen. Psychiatry, 38 (1981) 471-477. 20 Majewska, M.D., Antagonist-type interaction of glucocorticoids with the GABA receptor-coupled chloride channel, Brain Res., 418 (1987) 377-382. 21 Majewska, M.D., Harrison, N.L., Schwartz, R.D., Barker, J.L. and Paul, S.M., Steroid hormone metabolites are barbiturate-like modulators of the GABA receptors, Science, 232 (1986) 10041007. 22 Martire, M., Pistritto, G. and Preziosi P., Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus, J. Neural Transm., 78 (1989) 109-120. 23 McEwen, B.S., De Kloet, E.R. and Rost~ne, W., Adrenal steroid receptors and action in the nervous system, Physiol. Rev., 66 (1986) 1121-1188. 24 Mosher, K.M., Young, D.A. and Munck, A., Evidence for irreversible, actinomycin D-sensitive, and temperature-sensitive steps following binding of cortisol to glucocorticoid receptors and preceding effects on glucose metabolism in rat thymus cells, J. Biol. Chem., 246 (1971) 654-659. 25 Murphy, B.E.P., Some studies of the protein binding of steroids and their application to the routine micro- and ultramicro-measurement of various steroids in body fluids by competitive protein-binding radioassay, J. Clin. Endocrinol. Metab., 27 (1967) 973-990.
26 Orchinik, P.V., Murray, T.F. and Moore, F., A corticosteroid receptor in neuronal membranes, Science, 252 (1991) 1848-1851. 27 Piazza, P.V., Demini~re, J.M., Le Moal, M. and Simon, H., Factors that predict individual vulnerability to amphetamine self-administration, Science, 245 (1989) 1511-1513. 28 Piazza, P.V., Demini~re, J.M., Le Moal, M. and Simon, H., Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration, Brain Res., 514 (1990) 22-26. 29 Piazza, P.V., Demini~re, J.M., Maccari, S., Le Moal, M., Morm~de, P. and Simon, H., Individual vulnerability to drug self-administration: action of corticosterone on dopaminergic systems as a possible pathophysiological mechanism. In P. Willner and J. Scheel-Kriiger (Eds), The Mesolimbic Dopamine System: from Motivation to Action, Wiley, Chichester, 1991, pp. 473-495. 30 Piazza, P.V., Maccari, S., Demini~re, J.M., Le Moal, M., Morm~de, P. and Simon, H., Corticosterone levels determine individual vulnerability to amphetamine self-administration, Proc. NatL Acad. Sci. U.S.A., 88 (1991) 2088-2092. 31 Post, R.M., Weiss, S.R.B. and Pert, A., Implications of behavioral sensitization and kindling for stress-induced behavioral change. In P.W. Gold (Eds), Mechanisms of Physical and Emotional Stress, Plenum, New York, 1988, pp. 441-464. 32 Pulvirenti, L., Swerdlow, N.R., Hubner, C.B. and Koob, G.F., The role of limbic-accumbens-pallidal circuitry in the activating and reinforcing properties of psychostimulant drugs. In P. Willner and J. ScheeI-Kruger (Eds.), The Mesolimbic Dopamine System: from Motivation to Action, Wiley, Chichester, 1991, pp. 131-139. 33 Robinson, T.E. and Becker J.B., Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis, Brain Res. Rev., 11 (1986) 157-198. 34 Rothschild, A.J., Langlais, P.J., Schatzberg, A.F., Miller, M.M., Saloman, M.S., Lerbinger, J.E., Cole, J:O. and Bird, E.D., The effect of single acute dose of dexamethasone on monoamine and metabolites levels in the rat brain, Life Sci., 36 (1985) 2491-2505. 35 ScheeI-Kliiger, J., Magelund, G. and Olianas, M.C., Role of GABA in the striatal output system: Globus pallidus, nucleus entopeduncularis, substantia nigra and nucleus subthalamicus. In Di Chiara and Gessa (Eds.), GABA and the Basal Ganglia, Raven, New York, 1981, pp. 165-186. 36 Selye, H., Stress. The physiology and the pathology of exposure to stress, Acta Medica Publication, Montreal, 1950. 37 Sutanto, W., Handelmann, G., De Bree, F. and De Kloet, E.R., Multifaceted interaction of corticosteroids with the intracellular receptors and with membrane GABA-A receptor complex in the rat brain, J. Neuroendocrinol., 1 (1989) 243-247. 38 Versteeg, D.H.G., Van Zoest, I. and De Kloet, E.R., Acute changes in dopamine metabolism in the medial basal hypothalamus following adrenalectomy, Experientia, 40 (1983) 112-114. 39 Von Zerssen, D., Mood and behavioral changes under corticosteroid therapy. In T.M. Itel, G., Laudahn and W.M. Hermann (Eds.), Psychotropic Action of Hormones, New York Spectrum, 1976, pp. 195-214. 40 Wilcox, R.A., Robinson, T.E. and Becker, J.B., Enduring enhancement in amphetamine-stimulated striatal dopamine release in vitro produced by prior exposure to amphetamine or stress in vivo, Eur. J. Pharmacol., 124 (1986) 375-376. 41 Wise, R.A. and Bozarth, M.A., A psychomotor stimulant theory of addiction, PsychoL Rev., 94 (1987) 469-492. 42 Wise, R.A. and Rompre, P.P., Brain dopamine and reward, Annu. Rev. Psychol., 40 (1989) 191-225.
309
© 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00
BRES 25275
Repeated corticosterone administration sensitizes the locomotor response to amphetamine V6ronique Deroche, Pier Vincenzo Piazza, Stefania Maccari, Michel Le Moal and Herv6 Simon Laboratoire de Psychobiologie des Comportements Adaptatifs INSERM U259, Universit~de Bordeaux II, Bordeaux (France) (Accepted 14 April 1992)
Key words: Sensitization; Amphetamine; Stress; Corticosterone; Locomotor activity
Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50/~g/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states.
Life-events, especially repeated exposure to stressful situations, may induce long-lasting modifications in biological and behavioral reactivity 2. Among these stress-induced changes, the increase in the behavioral and biochemical responses to psychostimulants has been the subject of numerous studies 4'33. The stress-induced increase in the reactivity to psychostimulants, appearing as a cross-sensitization 4, is interesting for at least two reasons. Firstly, it has been proposed as an animal model of psychostimulant p s y c h o s i s 11'33, since a symptomatology of this type may be triggered in psychostimulant users by stressful events 33. Secondly, it has been associated with an increase in individual predisposition to drug-seeking 27'29. For example, animals receiving repeated tail-pinch stress have a higher locomotor response to amphetamine as well as a higher intake of this drug during self-administration (SA) 28. The association of changes in the psychomotor and reinforcing properties of psychostimulants is in line with the notion that the reinforcing effects of these drugs are related to their psychomotor action 32'41.
One of the main biological responses to stress is the activation of the hypothalamic-pituitary-adrenal axis (HPA), which ultimately leads to the secretion of glucocorticoids 23'26. Stress-induced corticosterone secretion could be responsible, at least in part, for the increase in the reactivity to psychostimulants induced by stress. Several observations point to an involvement of the HPA axis and these hormones in the response to psychostimulants: (1) behavioral sensitization to amphetamine or cross-sensitization between stress and amphetamine are reduced by pretreatment with CRH antiserum7'8. (2) Glucocorticoids have numerous actions on the brain, and in particular they seem to modify the activity of the mesocorticolimbic dopaminergic s y s t e m 9'12'34'38, which is thought to mediate the locomotor and reinforcing effects of psychostimulants 17'32'42. (3) Corticosterone, the major glucocorticoid in the rat, influences the individual response to amphetamine. Thus, the higher the corticosterone level at the time of amphetamine injection, the higher is the locomotor response of the animal to this drug 29'3°.
Correspondence: P.V. Piazza, INSERM U259, Rue Camille Saint Sa~ns, 33077 Bordeaux Cedex, France. Fax: (33) (56) 96-68-93.
310 Furthermore, an acute injection of corticosterone before a session of amphetamine SA increases the reinforcing effects of this drug 3°. In order to test if increases in corticosterone levels may augment the reactivity to psychostimulant, we studied the effect of two different paradigms of corticosterone administration on the locomotor response to amphetamine. In the first, corticosterone was administered as a stress procedure (tail-pinch, 15 days, one session per day), which has been found to increase the p s y c h o m o t o r and the reinforcing properties of amphetamine 2s. The animals received an intraperitoneal (i.p.) injection of corticosterone (1.5 m g / k g ) instead of one tail pinch session. In the second, corticosterone (50 ~ g / m l ) was dissolved in the drinking water, which was given to the animals between 7.00 p.m. and 8.00 a.m. for a period of 15 days. Plasma corticosterone levels were measured after both procedures, and compared with levels induced by stress. Fifty-six male S p r a g u e - D a w l e y rats (Iffa-Credo, Lyon, France) (280-300 g body weight) were used. The animals were individually housed with ad libitum access to food and water. A constant dark-light cycle (on 6.00 h, off 20.00 h) was maintained in the animal house under controlled temperature (22°C) and humidity (60%). D-Amphetamine sulfate was dissolved in saline (0.9% NaCI) which was also used as control substance. Corticosterone-21-hemisuccinate ( A G R A R , Italy), was used in all the experiments, and doses were expressed as corticosterone base. Locomotor activity was tested in a circular corridor (170 cm long and 10 cm wide). Four photoelectric cells placed at the 2 perpendicular axes detected overall locomotor activity. Animals were injected with saline first and then with amphetamine (1 m g / k g ) after a 2-h habituation period in the circular corridor. Locomotor activity induced by each injection was recorded over 10-min intervals for a period of 2 h. Sixteen animals were implanted with an intracardiac catheter for blood sampling. Under chloral hydrate (150 m g / k g i.p.) anesthesia, the catheter (Silastic) was first inserted in the right auricle through the external jugular vein, passed under the skin and exited in the mid-scapular region. Plasma corticosterone concentrations were measured by a radiocompetitive binding assay method after extraction into dichloromethane 25. In the first experiment, 38 rats were divided into 4 groups. The first (n = 9) received an injection of corticosterone (1.5 m g / k g i.p.) dissolved in saline (0.9% NaCI) at 9 a.m. every day for 15 days. The second one (n = 9) received an identical sequence of saline injections. To check that the effects of corticosterone were
due to repeated exposure to the hormone, the other two groups of animals (n = 10 each) received only one intraperitoneal injection of either saline or corticosterone (1.5 mg/kg). Five days after the last injection, all the groups were tested for their locomotor response to amphetamine (1 m g / k g i.p.). The effect of an acute injection of corticosterone at this dose on plasma levels of this hormone was studied in a further group of animals (n = 16). Half of the animals received an injection of corticosterone solution (1.5 m g / k g i.p.) at 9 a.m., the other half received, at the same time, an injection of saline. Thirty minutes later blood samples were withdrawn from the tail vein from both groups of rats. In the second experiment, 18 rats were divided into 2 groups (n = 9 each). The first received corticosterone dissolved in the drinking water at a concentration of 50 ~ g / m l . Corticosterone solution was available between 7 p.m. and 8 a.m., while water was available for the rest of the day. The second group, received water throughout the day. This treatment lasted 15 days and after 5 days washout both groups were tested for amphetamine-induced locomotor activity. The effect of oral corticosterone administration on plasma corticosterone levels was studied in another group of animals (n = 6). Rats in this group were implanted with an intracardiac catheter for blood sampiing. At the same time the animals were adrenalectomized and implanted subcutaneously with solid corticosterone pellets designed to deliver a continuous and stable amount of this hormone in the physiological range of diurnal basal levels. The solid pellets contained 12.5 mg of corticosterone adjusted to 100 mg with cholesterol. This procedure was adopted to avoid the potential bias of an increased secretion of corticosterone induced by manipulation during blood sampiing. One week after the surgical intervention, these animals received corticosterone in the drinking water as described above. Six 500-~1 blood samples were withdrawn from the catheter for corticosterone assay. The first sample was withdrawn at 7 a.m. immediately before the administration of the corticosterone solution. The other 4 were sampled at 2-h intervals with the last one taken at 9 a.m. A further group of animals (n = 10) was used to compare the increase in corticosterone plasma levels induced by these treatments with those observed during stress. The rats in this group were implanted with an intracardiac catheter, and after 1 week of recovery they were exposed to a novel environment, represented by the circular corridor described above. Blood samples were withdrawn from the catheter immediately before, and 30 min after exposure to the novel environment.
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The data were subjected to an analysis of variance (ANOVA) for repeated measures. Repeated intraperitoneal administration of corticosterone increased the locomotor response to amphetamine (Fig. 1). While the locomotor response to saline solution in the corticosterone-treated animals did not differ from that of controls (Fig. 1A), the two groups showed a significant difference (ANOVA, injection × time interaction, F1],]76 = 1.92, P < 0.03) in locomotor response to amphetamine (Fig. 1B). The corticosterone-treated animals exhibited a higher locomotor response to amphetamine during the first hour after the injection (El,16 = 4.06, P < 0.05) (Fig. 1B, inset). In contrast to repeated corticosterone administration, a single injection of the hormone did not significantly affect the locomotor response to amphetamine 5 days later. However, corticosterone-treated animals tended to have an increased response to amphetamine (control = 516 + 132; corticosterone = 607 + 81) cumulated over the first hour of the test (Ft,18 = 0.32; P = 0.57). Administration of corticosterone at the dose used in this experiment significantly increased plasma levels of this hormone (Fig. 2A). Thirty minutes after the injection, the corticosterone-treated animals had significantly higher levels than the saline-treated rats (FL~ 4 = 14.4, P < 0.005). Levels attained those observed 30 min after exposure to novelty stress. Administration of corticosterone in the drinking water also increased the locomotor response to amphetamine (Fig. 3). Thus, corticosterone-treated animals did not differ from controls in locomotor response to saline injection (Fig. 3A), while the two groups showed a significant difference (ANOVA, Injection x Time interaction, Fl1,176 = 2.368, P < 0.01) in the loco-
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Fig. 1. Effect of repeated intraperitoneal corticosterone injections on locomotor response to saline (A) and amphetamine (B). Corticosterone treatment (1.5 m g / k g , o n c e a day for 15 days) did not modify the locomotor response to saline, whereas it increased the locomotor response to amphetamine (FI1,176 = 1.92, P < 0.05). In the inset, locomotor activity is cumulated over 60 min. * = P < 0.05.
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motor response to amphetamine (Fig. 3B). The corticosterone-treated animals had a higher locomotor response to amphetamine during the first hour after the injection (El,16 = 3.88, P < 0.05) (Fig. 3B, inset). Corticosterone administration in the drinking water significantly increased (F5~25 = 9.23, P < 0.001) the overnight plasma concentration of the hormone (Fig. 2B). The increase induced by this treatment was similar to that induced by stress 28. The peak level (14.1 + 2 . 3 / z g / 1 0 0 ml) was observed 2 h after exposure to the corticosterone solution (9 p.m.). Corticosterone levels were still elevated 8 h later (3 a.m.) (Ft, s = 12.29,
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312 P < 0.01), returning to basal levels (2.9 _+ 1.3 /xg/100 ml) by the morning (9 a.m.). Our results show that repeated corticosterone administration increases the locomotor response to an acute injection of amphetamine. Interestingly, at the doses used in both experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those observed after stress. Thus, corticosterone secretion could be a mechanism by which repeated stress increases the behavioral response to psychostimulants 4'33. Furthermore, as described for stress 3"28, the effect of corticosterone seems to bring about long-lasting neural modifications. The increase in the locomotor response to amphetamine was detectable 5 days after the end of the treatment. Glucocorticoids may modulate neural activity via two types of receptor: the classical intracellular receptors (Type I and Type II) 5'9 or the membrane receptors recently described in amphibians 26. Intracellular receptors, which induce slow gene-mediated effects 9, may account for the long-lasting modifications observed in our experiments. Thus, it has been shown that the glucocorticoid effects on gene expression, which occur with a delay of at least 15 min to several hours 24, may persist weeks after disappearance of the glucocorticoid, and are sometimes irreversible during development 9. A neuronal mechanism mediating the action of glucocorticoids on amphetamine-induced behaviors could involve an increased reactivity of aminergic, particularly dopaminergic (DA) neurons to psychostimulants. This idea is supported by various lines of evidence. Firstly, mesolimbic D A neurons are thought to be a principle substrate of amphetamine-induced locomotor activity 17,32. Secondly, D A neurons have glucocorticoids receptors ~5, and glucocorticoids may increase the release of DA 34'38. Thirdly, an increased release of dopamine in response to amphetamine, observed after repeated stress or amphetamine injections 4°, is associated with a higher behavioral response to this drug 4'33. However, the action of corticosterone on other transmitter systems, such as serotoninergic (5-HT) and GABAergic neurons, may account for the observed effect on the locomotor response to amphetamine. Both these systems may influence locomotor activity 32'35 and glucocorticoids have been reported to modify the binding capacity of 5-HT 6'1°'22 and G A B A receptors 2°'21'37. The increased locomotor response to amphetamine induced by repeated corticosterone treatment supports the idea that glucocorticoids are involved in the determination of the propensity to amphetamine self-administration 29 as well as in some psychiatric disturbances 14'16. It has been shown that a higher locomotor response to amphetamine is associated with an en-
hanced propensity to self-administer this drug2'( This association is observed in certain vulnerable individuals 27, or when self-administration behavior is induced experimentally by repeated stress 2'~ or repeated amphetamine administrations 2s (amphetamine sensitization). Furthermore, spontaneously vulnerable animals or animals in which the propensity has been induced by stress have a longer release of corticosterone in response to environmental stimulation 3°. Thus an increase in corticosterone secretion, either spontaneously present in certain individuals or stress-induced in others, may predispose an individual to psychostimulantseeking behavior by enhancing the response to psychostimulants. E n h a n c e d responsiveness to amphetamine may also be indicative of a higher susceptibility to psychological disturbances. In view of the observed relationships between affective or cognitive disturbances and stress L13,3j, repeated stress could enhance the risk of psychopathologies via an exaggerated secretion of glucocorticoids. It is of interest in this respect that manic-depressive symptoms and even psychosis has been observed in patients with Cushing's syndrome or those receiving prolonged corticosteroid treatment t4,16,18,19,39. In conclusion, our results show that stress-induced corticosterone secretion may be one of the biological mechanisms mediating the increased sensitivity to psychostimulants. Furthermore, they throw some light on possible mechanisms of the psychiatric side effects of chronic glucocorticoid treatment. This work was supported by l'Institut National de la Sant~ et de la Recherche M6dicale (INSERM) and l'Universit~ de Bordeaux II. REFERENCES 1 Anisman, H. and Zacharko, R.M., Depression: the predisposing influence of stress, BehaL,. Brain Sci., 5 (1982) 89-137. 2 Antelman, S.M., Stressor-induced sensitization to subsequent stress: implications for the development and treatment of clinical disorders. In P.W. Kalivas (Eds.), New York, Academic Press, Sensitization in the Central Nert;ous System, 1988, pp. 227-259. 3 Antelman, S.M. and Eichler, A.J., Persistent effects of stress on dopamine-related behaviors: clinical implications. In E. Usdin, I.J. Kopin and J. Barchas (Eds.), Catecholamines: Basic and Clinical Frontiers, Pergamon, New York, 1979, pp. 1579-1761. 4 Antelman, S.M., Eichler, A.J., Black C.A. and Kocan, D., Interchangeability of stress and amphetamine in sensitization, Science, 207 (1980) 329-331. 5 Arriza, J.L., Weinberger, C., Cerelli, G., Glaser, T.M., Handelin, B.L., Housman, D.E. and Evans, R.M., Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoidreceptor, Science, 237 (1987) 268-275. 6 Biegon, A., Rainbow, T.C. and McEwen, B.S., Corticosterone modulation of neurotransmitter receptors in rat hippocampus: a quantitative autoradiographic study, Brain Res., 332 (1985) 309314. 7 Cole, B.J., Cador, M., Stinus, L., Rivier, C., Rivier, J., Vale, W., Le Moal, M. and Koob. G.F., Critical role of the hypothalamic
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