343
Brain Research, 598 (1992) 343-348 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00
BRES 25465
Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion V6ronique Deroche, Pier Vincenzo Piazza, Paola Casolini, Stefania Maccari, Michel Le Moal and Herr6 Simon Psychobiologie des Comportements Adaptatifs, INSERM U259, Universit~ de Bordeaux II, Domaine de Carreire, Bordeaux (France) (Accepted 15 September 1992)
Key words: Addiction; Sensitization; Stress; Corticosterone; Amphetamine; Morphine; Locomotor activity
Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated restraint stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.
Stressful experiences appear to have a strong influence on susceptibility to drug taking in various animal models of intravenous 54 and oral 33 drug self-administration (SA). For example social isolation 1'5,16'47, competition in the colony 3°, immobilization49, repeated tail-pinch 38 and prenatal stress it increase the propensity to self-administer psychostimulants a n d / o r opioids. Repeated stress not only increases the propensity to drug-taking, but also augments the psychomotor effects of psychostimulants and opioids (for review see refs. 24 and 43). Several observations indicate that this phenomenon defined as stress-induced behavioral sensitization or cross-sensitization is also related to the propensity to drug seeking 27. Firstly, an increased responsiveness of mesolimbic dopaminergic (DA) neurons has been correlated with cross-sensitization 24,43, and these same neurons are also thought to be a substrate of drug reinforcing properties 14,25,55. Secondly, animals that are spontaneously predisposed to
develop amphetamine self-administration, like sensitized subjects, have a higher psychomotor and DA response to psychostimulants2°,37,4°,45. Thirdly, there is an enhanced vulnerability to drug seeking in animals in which behavioral sensitization is induced by other means than stress, such as repeated psychostimulant injections38. Comprehension of the mechanisms underlying stress-induced behavioral sensitization may therefore throw more light on the biological bases of addiction. In this study, we analyzed the involvement of stressinduced corticosterone secretion, the principal glucocorticoid in the rat, in the sensitization of the locomotor response to two addictive drugs: amphetamine and morphine. Glucocorticoid secretion from the adrenal gland represents one of the principal adaptive responses to stress 32,48. These hormones have numerous actions on the brain 1°'31,34, and they have also been reported to modify the activity of the mesocorticolimbic dopaminergic system 13,44. In addition to these gen-
Correspondence: P.V. Piazza, INSERM U259, Rue Camille Saint SaChs, 33077 Bordeaux Cedex, France. Fax: (33) 56 96 68 93.
344 eral considerations, more specific observations point to an involvement of corticosterone in the modulation of responses to addictive drugs. (1) Repeated corticosterone administration, in the same way as repeated stress, sensitizes the locomotor response to amphetamine 12, while behavioral sensitization to cocaine or cross-sensitization between stress and cocaine are reduced by pretreatment with CRH antiserum s'9. (2) Corticosterone influences the individual sensitivity to amphetamine. Thus, the higher the individual's corticosterone level at the time of amphetamine injection, the higher is his locomotor response to this drug 39. Furthermore, an acute injection of corticosterone before a session of amphetamine SA induces this behavior in spontaneously resistant animals 39. (3) Opioidmediated behaviors such as morphine-induced eating exhibit a diurnal rhythm which is in phase with the natural corticosterone diurnal rhythm, i.e. the effects of morphine are greater in the nocturnal phase, when corticosterone levels are high. Furthermore, adrenalectomy reduces the feeding induced by morphine, while acute corticosterone replacement restores this response 4. In order to find out whether stress-induced corticosterone secretion may mediate the behavioral sensitization to psychostimulants and opioids observed after repeated stress, we studied the effect of blocking corticosterone secretion on stress-induced sensitization to the psychomotor effects of amphetamine (1.5 m g / k g i.p.) and morphine (2 m g / k g s.c.). We compared the effects of restraint stress in sham-operated animals and in animals adrenalectomized and implanted with corticosterone pellets that release the hormone within the range of basal physiological levels. Animals submitted to this treatment are not deprived of the basic metabolic functions of the hormone, but are not able to increase secretion in response to stress. Plasma corticosterone levels were measured in both groups under basal conditions and after restraint stress. Male Sprague-Dawley rats (260-280 g b. wt.) were housed 4 to a cage with ad libitum access to food and water. A constant dark-light cycle (on 06.00 h, off 20.00 h) was maintained in the animal house, and temperature (22°C) and humidity (60%) were controlled. D-Amphetamine sulfate and morphine sulfate were dissolved in saline solution (0.9% NaC1), which was also used as control substance. Adrenalectomy was performed via the dorsal route (under ether anesthesia), and at the same time one solid corticosterone pellet was implanted subcutaneously in order to liberate a continuous and stable level of the hormone in the basal physiological range 35.
The pellets contained 50 mg of corticosterone adjusted to 100 mg with cholesterol. Following surgery, NaCI (0.9%) was added to the drinking water of the animals. The restraint procedure began 4 days after adrenalectomy. Animals were placed for 30 min in a tubular plastic cylinder (25 cm long, 7 cm internal diameter). The efficacy of the corticosterone substitutive therapy was checked in 16 animals. Eight rats were adrenalectomized, while the others were sham-operated. After 4 days recovery, the animals were submitted to the 30-rain restraint procedure. Three blood samples (100 pA each) were withdrawn from the tail vein, the first one within the first minute of restraint, the other two 30 and 120 min after the beginning of the stress procedure. Samples were collected in heparinized tubes and stored at - 2 0 ° C until assay. Plasma corticosterone was measured by a radiocompetitive binding assay after extraction into dichloromethane 36. 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. After 2 h habituation to the apparatus, the animals were injected with saline first, and with either amphetamine (1.5 m g / k g i.p.) or morphine (2 m g / k g s.c.) 1 h afterwards. Locomotor activity induced by each injection was recorded over 10-min intervals for 1 h after the saline injection, and for 3 h after the amphetamine and morphine injections. In the first experiment, 48 animals were used. Twenty-four rats were adrenalectomized, the others were sham-operated. In each of these 2 groups, half of the animals (n = 12) were submitted to the restraint procedure twice a day for 5 days, the other half (n = 12) were left undisturbed. In order to minimize habituation to restraint, the two daily stress sessions were separated by a variable interval. The first and the second days of stress were consecutive, but the third stress was carried out on day 4. The fourth stress was carried out on day 7, and the fifth stress on day 8. The time of day of the two daily restraint sessions was also varied. However, the interval between the first daily session and the second one was kept constant (5 h). The first restraint session was performed between 09.00 and 12.00 h while the second one was performed between 13.00 and 19.00 h. Four days after the last stress session, all animals were tested for their locomotor reactivity to amphetamine (1.5 m g / k g i.p.). In the second experiment, 48 animals were used. The procedure was identical to that of the first experiment. In this case, instead of an injection of amphetamine, the animals received an injection of morphine (2 m g / k g s.c). The data were subjected to an analysis of variance
345 secretion affected the locomotor response to saline, although both affected the response to amphetamine (Fig. 2). Repeated exposure to restraint stress increased the locomotor reactivity to amphetamine (1.5 mg/kg i.p.), while this effect was abolished by adrenalectomy (ANOVA, Stress × Adrenalectomy interaction, F1,52= 5.2, P < 0.05). In animals with a normal corticosterone response to stress (sham-operated), the locomotor response to amphetamine was higher in the stressed than in the control unstressed animals (F1,28 = 4.25, P < 0.05). In animals in which stress-induced corticosterone secretion was blocked (ADX + pellets groups), there was no difference in locomotor response between the stressed and control animals. Furthermore, there was no difference in the locomotor response to amphetamine between these 2 groups and the sham-operated controls. Similar results were obtained in the second experiment with morphine (Fig. 3). No differences were observed between the 4 experimental groups in the response to saline, whereas differences were observed in the response to morphine (ANOVA, Stress × Adrenalectomy interaction, F1,26= 3.74, P < 0.05). In the sham-operated animals, the locomotor response to morphine was higher in the stressed than in the control rats (F1,14 = 4.68, P < 0.05), while in the ADX + pellets groups there was no difference between the stressed animals and the controls. Again, there was no difference in the locomotor response to morphine between these 2 groups and the sham-operated controls. Our results are in line with reports showing that repeated stress increases the locomotor response to
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(ANOVA) for repeated measures. The adrenalectomized rats implanted with corticosterone pellets had comparable basal plasma corticosterone levels to those of the sham-operated controls. As expected, while the restraint procedure induced a significant increase in plasma corticosterone levels in sham-operated animals, levels remained constant over time in the ADX + pellet group (F1,15 = 11.28, P < 0.01) (Fig. 1). Neither stress nor the blocking of corticosterone
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Fig, 2. Effect of repeated restraint stress on locomotor response to saline (A) and amphetamine (B) in intact and A D X + pellet rats. Repeated restraint (30 rain, twice a day during 5 days) did not affect the locomotor response to saline in sham-operated and A D X + pellet animals. Repeated restraint significantly increased the locomotor response to amphetamine (F1,28 = 4.25, P < 0.05) in sham-operated rats, while it did not modify the locomotor response to amphetamine of the A D X + pellet rats. * P < 0.05.
346 psychostimulants (for review see refs. 24, 27 and 43), and with the only report 28 to our knowledge, describing a similar effect for opiates. Our results show that blocking stress-induced corticosterone secretion abolishes the stress-induced cross-sensitization to both psychostimulants and opioids. The suppression of cross-sensitization by blocking stress-induced corticosterone secretion extends observations pointing to an involvement of the hypothalamo-pituitary-adrenal (HPA) axis in this phenomenon. For example, we have recently shown that repeated corticosterone treatment, like repeated stress, sensitizes the locomotor response to psychostimulants 12. Furthermore, the stress-induced sensitization to cocaine is abolished by administration of CRH antiserum 9. Stress-induced corticosterone secretion could, therefore, be one mechanism mediating stress-induced sensitization. Corticosterone may influence sensitization by an action on DA neurons. An increase in reactivity of these neurons to both psychostimulants and opioids is thought to be a main biological substrate of stress-induced sensitization 24'43. Mesolimbic dopaminergic neurons possess corticosteroid receptors TM, and glucocorticoids have been reported to stimulate dopamine release 44'51. Furthermore, we have recently found that stress-induced corticosterone secretion modulates stress-induced dopamine release (unpublished results). Compared to intact animals, animals lacking the corticosterone stress response (ADX + pellet), exhibit a reduced stress-induced dopamine release in the nucleus accumbens, while an acute injection of corticos-
terone together with the stress restores the DA response in the ADX + pellet group. Other neurotransmitters, such as opioids and excitatory amino acids, may also be involved in the action of corticosterone on sensitization processes. For instance. stress-induced sensitization to morphine is blocked by antagonists of Fz-opioids receptors 22 and behavioral sensitization to amphetamine and cocaine is blocked by antagonists of excitatory amino acid 2~ receptors. Furthermore, corticosterone seems to stimulate both opiold and glutamatergic transmission. For example, corticosterone potentiates the effects of enkephalins on hippocampal slices 5z and stimulates the expression of the preproenkephalin rnRNA in the striatum 6'7'2t and in the adrenal medulla. Furthermore, glucocorticoids stimulate the enzyme glutamine synthetase, and have been reported to increase the availability of glutamate in the synaptic cleft 46'5°. Cross-sensitization between the response to stress and drugs has been used as evidence to support a role for sensitization processes in the etiology of the paranoid symptomatology encountered in some drug abusers 3'41. Furthermore, repeated stress has been shown to enhance liability to some affective and cognitive disturbances 2'15'42. Our results lend support to an involvement of corticosterone secretion in stress-precipitated psychopathologics. This notion is supported by the psychiatric disturbances commonly observed in patients with excess glucocorticoid secretion, such as in Cushing's disease 19'26, and in some patients receiving glucocorticoid therapy 17,29,53. In animals, stress-induced sensitization has been
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Fig. 3 Effect of repeated restraint stress on locomotor response to saline (A) and morphine (B) in intact and A D X + p e l l e t rats. Repeated restraint (30 min, twice a day during 5 days) did not affect the locomotor response to saline in the sham-operated and A D X + p e l l e t animals. Repeated restraint significantly increased the locomotor response to morphine in the sham-operated animals (Fl,14 = 4.68, P < 0.05), but not in the A D X + pellet animals. * P < 0.05.
347
associated with an enhanced propensity to self-administer psychostimulants 37'38. The suppression of sensitization by blocking stress-induced corticosterone secretion is in line with reports suggesting that glucocorticolds are involved in the propensity to psychostimulant self-administration. In previous studies, we have shown that glucocorticoids increase the reinforcing properties of amphetamine 39, and that animals spontaneously predisposed to self-administer this drug 39, or in which such predisposition has been induced by stress 3°, have a longer stress-induced corticosterone secretion. Although to our knowledge, relationships between HPA axis activity and individual vulnerability to opioid selfadministration have not yet been established, the resuits presented here suggest that corticosterone secretion may also be involved in the enhancement of the reinforcing properties of opioids induced by stress. In conclusion, our results show that stress-induced corticosterone secretion may mediate, at least in part, stress-induced sensitization. Since stress-induced sensitization appears to be a determinant of the vulnerability to drug seeking, enhanced corticosterone secretion, either spontaneously present in certain individuals, or stress induced in others, may underlie susceptibility to drug abuse.
This work was supported by l'Institut National de la Sant6 et de la Recherche M6dicale (INSERM), l'Universit6 de Bordeaux II and le Conseil R6gional d'Aquitaine.
1 Alexander, B.K., Coambs, R.B. and Hadaway, P.F., The effect of housing and gender on morphine self-administration in rats, Psychopharmacology, 58 (1978) 175-179. 2 Anisman, H. and Zacharko, R.M., Depression: the predisposing influence of stress, Behav. Brain Sci., 5 (1982) 89-137. 3 Antelman, S.M., Stressor-induced sensitization to subsequent stress: implications for the development and treatment of clinical disorders. In P.W. Kalivas (Ed.), Sensitization in the Central Nervous System, Academic Press, New York, 1988, pp. 227-259. 4 Bhakthavatsalam, P. and Leibowitz, S.F., Morphine-elicited feeding: diurnal rhythm, circulating corticosterone and macronutrient selection, Pharrnacol. Biochem. Behav., 24 (1986) 911-917. 5 Bozarth, M.A., Murray, A. and Wise, R.A., Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats, Pharmacol. Biochem. Behav., 33 (1989) 903-907. 6 Chap, H.M. and McEwen, B.S., Glucocorticoid regulation of preproenkephalin messenger ribonucleic acid in the rat striatum, Endocrinology, 126 (1990) 3124-3130. 7 Chap, H.M. and McEwen, B.S., Giucocorticoid regulation of neuropeptide mRNAs in the rat striatum, Mol. Brain Res., 9 (1991) 307-311. 8 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 pituitary adrenal axis in amphetamine-induced sensitization of behavior, Life Sci., 47 (1990) 1715-1720. 9 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.
10 De Kloet, E.R., Brain corticosteroid receptor balance and homeostatic control, Front. Neuroendocrinol., 12 (1991) 95-164. 11 Demini~re, J.M., Piazza, P.V., Guegan, G., Abrous, N., Maccari, S., Le Moal, M. and Simon, H., Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers, Brain Res., 586 (1992) 135-139. 12 Deroche, V., Piazza, P.V., Maccari, S., Le Moal, M. and Simon, H., Repeated corticosterone administration sensitizes the locomotor response to amphetamine, Brain Res., 584 (1992) 309-313. 13 Faunt, J.E. and Crocker, A.D., Adrenocortical hormone status affects responses to dopamine receptor agonists, Eur. J. Pharmacol., (1988) 255-261. 14 Fibiger, H.C. and Phillips, A.G., Mesocorticolimbic dopamine systems and reward. In P.W. Kalivas and C.B. Nemeroff (Eds.), The mesocorticolimbic dopamine system, Ann. N.Y. Acad. Sci., 537 (1988) 206-215. 15 Field, T.M., McCabe, P.M. and Schneiderman, N. In L. Erlbaum (Ed.), Stress and Coping, Hillsdale, New Jersey, 1984. 16 Hadaway, P.F., Alexander, B.K., Coambs, R.B. and Beyerstein, B., The effect of housing and gender on preference for morphine-sucrose solutions in rats, Psychopharmacology, 66 (1979) 87-91. 17 Hall, R.C.W., Popkin, M.K., Stickney, S.K. and Gardner, E.R., Presentation of steroid psychoses, J. Nerv. Ment. Dis., 167 (1979) 229-236. 18 H~irfstrand, A., Fuxe, K., Cintra, A., A4~nati, 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. USA, 83 (1986) 9779-9783. 19 Holsboer, F., Psychiatric implications of altered limbic-hypothalamo-pituitary-adrenocortical activity, Eur. Arch. Psychiat. Neurol. Sci., 238 (1989) 302-322. 20 Hooks, M.S., Jones, G.H., Smith, A.D., Neill, D.B. and Justice Jr., J.B., Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine, Synapse, 9 (1991) 121-128. 21 Inturrisi, C.E., Branch, A,D., Robertson, H.D., Howells, R.D., Franklin, S.O., Shapiro, J.R., Calvano, S.E. and Yoburn, B.C., Glucocorticoid regulation of enkephalins in cultured rat adrenal medulla, Mol. Endocrinol., 2 (1988) 633-640. 22 Kalivas, P.W. and Abhold, R., Enkephalin release into the ventral tegmental area in response to stress: modulation of mesocorticolimbic dopamine, Brain Res., 414 (1987) 339-348. 23 Kalivas, P.W., Duffy, P. and Barrow, J., Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes, J. Pharrnacol. Exp. Ther., 251 (1989) 378-387. 24 Kalivas, P.W. and Stewart, J., Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity, Brain Res. Rev., 16 (1991) 223-244. 25 Koob, G.F. and Bloom, F.E., Cellular and molecular mechanisms of drug dependence, Science, 242 (1989) 715-723. 26 Krieger, D.T., Physiopathology of Cushing's disease, Endocrinol. Rev., 4 (1983) 22-53. 27 Le Moal, M. and Simon, H., Mesocorticolimbic dopamine network: functional and regulatory roles, Physiol. Rev., 71 (1991) 155 -234. 28 Leyton, M. and Stewart, J., Preexposure to foot-shock sensitizes the locomotor response to subsequent systemic morphine and intra-nucleus accumbens amphetamine, Pharmacol. Biochem. Behav., 37 (1990) 303-310. 29 Ling, M.H.M., Perry, P.J. and Tsuang, M.T., Side effects of corticosteroid therapy, Arch. Gen. Psychiatry, 38 (1981) 471-477. 30 Maccari, S., Piazza, P.V., Demini~re, J.M,, Lemaire, V., Morm~de, P., Simon, H., Angelucci, L. and Le Moal, M., Life events-induced decrease of type I corticosteroid receptors is associated with a decrease of corticosterone feedback and an increase of the vulnerability to amphetamine self-administration, Brain Res., 547 (1991) 7-12. 31 Majewska, M.D., Steroids and brain activity. Essential dialogue between body and mind, Biochem. Pharmacol., 36 (1987) 37813788.
348 32 McEwen, B.S., De Kloet, E.R. and Rost~ne, W., Adrenal steroid receptors and action in the nervous system, Physiol. Rel,,., 66 (1986) 1121-1188. 33 Meisch, R.A. and Carroll, M.E., Oral drug self-administration: drugs as reinforcers. In M.A. Bozarth (Ed.), Methods of Assessing the Reinforcing Properties of Abused Drugs, Springer, New York, 1987, pp. 143-161). 34 Meyer, J.S., Biochemical effects of corticosteroids on neural tissues, Physiol. Rev., 65 (1985) 946-1020. 35 Meyer, J.S., Micco, D.J., Stephenson, B.S., Krey, L.C. and McEwen, B.S., Subcutaneous implantation method for chronic glucocorticoid replacement therapy, Physiol. Beha~,., 22 (1979) 867-870. 36 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. 37 Piazza, P.V., Demini6re, J.M., Le Moal, M. and Simon, H., Factors that predict individual vulnerability to amphetamine self-administration, Science, 245 (1989) 1511-1513. 38 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. 39 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. USA, 88 (1991) 2088-2092. 40 Piazza, P.V., Roug6-Pont, F., Deminib~re, J.M., Kharouby, M., Le Moal, M. and Simon, H., Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration, Brain Res., 567 (1991) 169-174. 41 Post, R.M., Rubinow, D.R. and Ballenger, J.C., Conditioning, sensitization and kindling: implications for the course of affective illness. In R.M. Post and J.C. Ballenger (Eds.), Neurobiology of Mood Disorders, Williams and Wilkins, Baltimore, 1984, 432-466. 42 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 (Ed.), Mechanisms of Physical and Emotional Stress, Plenum, New York, 1988, pp. 441-464.
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Brain Research, 598 (1992) 343-348 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00
BRES 25465
Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion V6ronique Deroche, Pier Vincenzo Piazza, Paola Casolini, Stefania Maccari, Michel Le Moal and Herr6 Simon Psychobiologie des Comportements Adaptatifs, INSERM U259, Universit~ de Bordeaux II, Domaine de Carreire, Bordeaux (France) (Accepted 15 September 1992)
Key words: Addiction; Sensitization; Stress; Corticosterone; Amphetamine; Morphine; Locomotor activity
Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated restraint stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.
Stressful experiences appear to have a strong influence on susceptibility to drug taking in various animal models of intravenous 54 and oral 33 drug self-administration (SA). For example social isolation 1'5,16'47, competition in the colony 3°, immobilization49, repeated tail-pinch 38 and prenatal stress it increase the propensity to self-administer psychostimulants a n d / o r opioids. Repeated stress not only increases the propensity to drug-taking, but also augments the psychomotor effects of psychostimulants and opioids (for review see refs. 24 and 43). Several observations indicate that this phenomenon defined as stress-induced behavioral sensitization or cross-sensitization is also related to the propensity to drug seeking 27. Firstly, an increased responsiveness of mesolimbic dopaminergic (DA) neurons has been correlated with cross-sensitization 24,43, and these same neurons are also thought to be a substrate of drug reinforcing properties 14,25,55. Secondly, animals that are spontaneously predisposed to
develop amphetamine self-administration, like sensitized subjects, have a higher psychomotor and DA response to psychostimulants2°,37,4°,45. Thirdly, there is an enhanced vulnerability to drug seeking in animals in which behavioral sensitization is induced by other means than stress, such as repeated psychostimulant injections38. Comprehension of the mechanisms underlying stress-induced behavioral sensitization may therefore throw more light on the biological bases of addiction. In this study, we analyzed the involvement of stressinduced corticosterone secretion, the principal glucocorticoid in the rat, in the sensitization of the locomotor response to two addictive drugs: amphetamine and morphine. Glucocorticoid secretion from the adrenal gland represents one of the principal adaptive responses to stress 32,48. These hormones have numerous actions on the brain 1°'31,34, and they have also been reported to modify the activity of the mesocorticolimbic dopaminergic system 13,44. In addition to these gen-
Correspondence: P.V. Piazza, INSERM U259, Rue Camille Saint SaChs, 33077 Bordeaux Cedex, France. Fax: (33) 56 96 68 93.
344 eral considerations, more specific observations point to an involvement of corticosterone in the modulation of responses to addictive drugs. (1) Repeated corticosterone administration, in the same way as repeated stress, sensitizes the locomotor response to amphetamine 12, while behavioral sensitization to cocaine or cross-sensitization between stress and cocaine are reduced by pretreatment with CRH antiserum s'9. (2) Corticosterone influences the individual sensitivity to amphetamine. Thus, the higher the individual's corticosterone level at the time of amphetamine injection, the higher is his locomotor response to this drug 39. Furthermore, an acute injection of corticosterone before a session of amphetamine SA induces this behavior in spontaneously resistant animals 39. (3) Opioidmediated behaviors such as morphine-induced eating exhibit a diurnal rhythm which is in phase with the natural corticosterone diurnal rhythm, i.e. the effects of morphine are greater in the nocturnal phase, when corticosterone levels are high. Furthermore, adrenalectomy reduces the feeding induced by morphine, while acute corticosterone replacement restores this response 4. In order to find out whether stress-induced corticosterone secretion may mediate the behavioral sensitization to psychostimulants and opioids observed after repeated stress, we studied the effect of blocking corticosterone secretion on stress-induced sensitization to the psychomotor effects of amphetamine (1.5 m g / k g i.p.) and morphine (2 m g / k g s.c.). We compared the effects of restraint stress in sham-operated animals and in animals adrenalectomized and implanted with corticosterone pellets that release the hormone within the range of basal physiological levels. Animals submitted to this treatment are not deprived of the basic metabolic functions of the hormone, but are not able to increase secretion in response to stress. Plasma corticosterone levels were measured in both groups under basal conditions and after restraint stress. Male Sprague-Dawley rats (260-280 g b. wt.) were housed 4 to a cage with ad libitum access to food and water. A constant dark-light cycle (on 06.00 h, off 20.00 h) was maintained in the animal house, and temperature (22°C) and humidity (60%) were controlled. D-Amphetamine sulfate and morphine sulfate were dissolved in saline solution (0.9% NaC1), which was also used as control substance. Adrenalectomy was performed via the dorsal route (under ether anesthesia), and at the same time one solid corticosterone pellet was implanted subcutaneously in order to liberate a continuous and stable level of the hormone in the basal physiological range 35.
The pellets contained 50 mg of corticosterone adjusted to 100 mg with cholesterol. Following surgery, NaCI (0.9%) was added to the drinking water of the animals. The restraint procedure began 4 days after adrenalectomy. Animals were placed for 30 min in a tubular plastic cylinder (25 cm long, 7 cm internal diameter). The efficacy of the corticosterone substitutive therapy was checked in 16 animals. Eight rats were adrenalectomized, while the others were sham-operated. After 4 days recovery, the animals were submitted to the 30-rain restraint procedure. Three blood samples (100 pA each) were withdrawn from the tail vein, the first one within the first minute of restraint, the other two 30 and 120 min after the beginning of the stress procedure. Samples were collected in heparinized tubes and stored at - 2 0 ° C until assay. Plasma corticosterone was measured by a radiocompetitive binding assay after extraction into dichloromethane 36. 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. After 2 h habituation to the apparatus, the animals were injected with saline first, and with either amphetamine (1.5 m g / k g i.p.) or morphine (2 m g / k g s.c.) 1 h afterwards. Locomotor activity induced by each injection was recorded over 10-min intervals for 1 h after the saline injection, and for 3 h after the amphetamine and morphine injections. In the first experiment, 48 animals were used. Twenty-four rats were adrenalectomized, the others were sham-operated. In each of these 2 groups, half of the animals (n = 12) were submitted to the restraint procedure twice a day for 5 days, the other half (n = 12) were left undisturbed. In order to minimize habituation to restraint, the two daily stress sessions were separated by a variable interval. The first and the second days of stress were consecutive, but the third stress was carried out on day 4. The fourth stress was carried out on day 7, and the fifth stress on day 8. The time of day of the two daily restraint sessions was also varied. However, the interval between the first daily session and the second one was kept constant (5 h). The first restraint session was performed between 09.00 and 12.00 h while the second one was performed between 13.00 and 19.00 h. Four days after the last stress session, all animals were tested for their locomotor reactivity to amphetamine (1.5 m g / k g i.p.). In the second experiment, 48 animals were used. The procedure was identical to that of the first experiment. In this case, instead of an injection of amphetamine, the animals received an injection of morphine (2 m g / k g s.c). The data were subjected to an analysis of variance
345 secretion affected the locomotor response to saline, although both affected the response to amphetamine (Fig. 2). Repeated exposure to restraint stress increased the locomotor reactivity to amphetamine (1.5 mg/kg i.p.), while this effect was abolished by adrenalectomy (ANOVA, Stress × Adrenalectomy interaction, F1,52= 5.2, P < 0.05). In animals with a normal corticosterone response to stress (sham-operated), the locomotor response to amphetamine was higher in the stressed than in the control unstressed animals (F1,28 = 4.25, P < 0.05). In animals in which stress-induced corticosterone secretion was blocked (ADX + pellets groups), there was no difference in locomotor response between the stressed and control animals. Furthermore, there was no difference in the locomotor response to amphetamine between these 2 groups and the sham-operated controls. Similar results were obtained in the second experiment with morphine (Fig. 3). No differences were observed between the 4 experimental groups in the response to saline, whereas differences were observed in the response to morphine (ANOVA, Stress × Adrenalectomy interaction, F1,26= 3.74, P < 0.05). In the sham-operated animals, the locomotor response to morphine was higher in the stressed than in the control rats (F1,14 = 4.68, P < 0.05), while in the ADX + pellets groups there was no difference between the stressed animals and the controls. Again, there was no difference in the locomotor response to morphine between these 2 groups and the sham-operated controls. Our results are in line with reports showing that repeated stress increases the locomotor response to
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(ANOVA) for repeated measures. The adrenalectomized rats implanted with corticosterone pellets had comparable basal plasma corticosterone levels to those of the sham-operated controls. As expected, while the restraint procedure induced a significant increase in plasma corticosterone levels in sham-operated animals, levels remained constant over time in the ADX + pellet group (F1,15 = 11.28, P < 0.01) (Fig. 1). Neither stress nor the blocking of corticosterone
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Fig, 2. Effect of repeated restraint stress on locomotor response to saline (A) and amphetamine (B) in intact and A D X + pellet rats. Repeated restraint (30 rain, twice a day during 5 days) did not affect the locomotor response to saline in sham-operated and A D X + pellet animals. Repeated restraint significantly increased the locomotor response to amphetamine (F1,28 = 4.25, P < 0.05) in sham-operated rats, while it did not modify the locomotor response to amphetamine of the A D X + pellet rats. * P < 0.05.
346 psychostimulants (for review see refs. 24, 27 and 43), and with the only report 28 to our knowledge, describing a similar effect for opiates. Our results show that blocking stress-induced corticosterone secretion abolishes the stress-induced cross-sensitization to both psychostimulants and opioids. The suppression of cross-sensitization by blocking stress-induced corticosterone secretion extends observations pointing to an involvement of the hypothalamo-pituitary-adrenal (HPA) axis in this phenomenon. For example, we have recently shown that repeated corticosterone treatment, like repeated stress, sensitizes the locomotor response to psychostimulants 12. Furthermore, the stress-induced sensitization to cocaine is abolished by administration of CRH antiserum 9. Stress-induced corticosterone secretion could, therefore, be one mechanism mediating stress-induced sensitization. Corticosterone may influence sensitization by an action on DA neurons. An increase in reactivity of these neurons to both psychostimulants and opioids is thought to be a main biological substrate of stress-induced sensitization 24'43. Mesolimbic dopaminergic neurons possess corticosteroid receptors TM, and glucocorticoids have been reported to stimulate dopamine release 44'51. Furthermore, we have recently found that stress-induced corticosterone secretion modulates stress-induced dopamine release (unpublished results). Compared to intact animals, animals lacking the corticosterone stress response (ADX + pellet), exhibit a reduced stress-induced dopamine release in the nucleus accumbens, while an acute injection of corticos-
terone together with the stress restores the DA response in the ADX + pellet group. Other neurotransmitters, such as opioids and excitatory amino acids, may also be involved in the action of corticosterone on sensitization processes. For instance. stress-induced sensitization to morphine is blocked by antagonists of Fz-opioids receptors 22 and behavioral sensitization to amphetamine and cocaine is blocked by antagonists of excitatory amino acid 2~ receptors. Furthermore, corticosterone seems to stimulate both opiold and glutamatergic transmission. For example, corticosterone potentiates the effects of enkephalins on hippocampal slices 5z and stimulates the expression of the preproenkephalin rnRNA in the striatum 6'7'2t and in the adrenal medulla. Furthermore, glucocorticoids stimulate the enzyme glutamine synthetase, and have been reported to increase the availability of glutamate in the synaptic cleft 46'5°. Cross-sensitization between the response to stress and drugs has been used as evidence to support a role for sensitization processes in the etiology of the paranoid symptomatology encountered in some drug abusers 3'41. Furthermore, repeated stress has been shown to enhance liability to some affective and cognitive disturbances 2'15'42. Our results lend support to an involvement of corticosterone secretion in stress-precipitated psychopathologics. This notion is supported by the psychiatric disturbances commonly observed in patients with excess glucocorticoid secretion, such as in Cushing's disease 19'26, and in some patients receiving glucocorticoid therapy 17,29,53. In animals, stress-induced sensitization has been
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Fig. 3 Effect of repeated restraint stress on locomotor response to saline (A) and morphine (B) in intact and A D X + p e l l e t rats. Repeated restraint (30 min, twice a day during 5 days) did not affect the locomotor response to saline in the sham-operated and A D X + p e l l e t animals. Repeated restraint significantly increased the locomotor response to morphine in the sham-operated animals (Fl,14 = 4.68, P < 0.05), but not in the A D X + pellet animals. * P < 0.05.
347
associated with an enhanced propensity to self-administer psychostimulants 37'38. The suppression of sensitization by blocking stress-induced corticosterone secretion is in line with reports suggesting that glucocorticolds are involved in the propensity to psychostimulant self-administration. In previous studies, we have shown that glucocorticoids increase the reinforcing properties of amphetamine 39, and that animals spontaneously predisposed to self-administer this drug 39, or in which such predisposition has been induced by stress 3°, have a longer stress-induced corticosterone secretion. Although to our knowledge, relationships between HPA axis activity and individual vulnerability to opioid selfadministration have not yet been established, the resuits presented here suggest that corticosterone secretion may also be involved in the enhancement of the reinforcing properties of opioids induced by stress. In conclusion, our results show that stress-induced corticosterone secretion may mediate, at least in part, stress-induced sensitization. Since stress-induced sensitization appears to be a determinant of the vulnerability to drug seeking, enhanced corticosterone secretion, either spontaneously present in certain individuals, or stress induced in others, may underlie susceptibility to drug abuse.
This work was supported by l'Institut National de la Sant6 et de la Recherche M6dicale (INSERM), l'Universit6 de Bordeaux II and le Conseil R6gional d'Aquitaine.
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