BRAIN RESEARCH

ELSEVIER
Brain Research 724 (1996) 251-255

Short communication

Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced sensitization of the locomotor response to cocaine
Michela Marinelli, Michel Le Moal, Pier Vincenzo Piazza *
Psychobiologie des Comportements Adaptatifs, INSERM U 259, Uniuersit~ de Bordeaux 11, Domaine de Carreire, Rue Camille Saint-Sa~ns, 33077 Bordeaux, France

Accepted 5 March 1996

Abstract

Several data indicate that a blockade of stress-induced corticosterone secretion prevents the development of the stress-induced sensitization of the behavioral effects of drugs of abuse. In this report we investigated if an acute blockade of corticosterone secretion could reverse stress-induced sensitization once it is already established. Food restriction (90% of initial body weight) was used as stressor. Corticosterone secretion was blocked by the corticosterone synthesis inhibitor metyrapone (100 mg/kg). After 8 days of food restriction, animals received an injection of metyrapone and 3 h later they were tested either for the locomotor response to cocaine or for the corticosterone secretion in response to stress (restraint, 30 min). Neither metyrapone nor food restriction had any effect on the locomotor response to a saline injection. In contrast, food-restricted animals, compared to ad libitum-fed controls, showed a higher locomotor response to cocaine and higher corticosterone levels. Treatment with metyrapone totally abolished these effects. Food-restricted animals, receiving a single injection of metyrapone, did not differ from ad libitum-fed controls for both locomotor response to cocaine and corticosterone secretion. Metyrapone treatment also similarly reduced the response to cocaine and corticosterone secretion in ad libitum-fed controls. In conclusion, this study provides further evidence that the enhancement in drug effects produced by stress depends on an increase in corticosterone levels. Since stress-induced sensitization is considered one of the conditions predisposing to drug abuse, the present results might have implications for the treatment of addiction.
Keywords: Corticosterone;Cocaine; Metyrapone; Stress-inducedsensitization;Food restriction;Locomotor response; Psychomotor effects

Life experiences, and in particular exposure to stressful situations, increase the sensitivity to the psychomotor and reinforcing properties of drugs of abuse (for review see [24,37,38,43]). In particular, different stressors enhance both the locomotor response to psychostimulant drugs and the propensity to develop oral or intravenous self administration [1,3,11,13,14,18,20,26,33,36,44,51]. Recent studies suggest that the development of stressinduced enhancement of drug effects, a phenomenon known as behavioral sensitization, is mediated by stress-induced corticosterone secretion (for review see [38]). Treatment precluding stress-induced corticosterone secretion, as for example adrenalectomy or a chronic treatment with the corticosterone synthesis inhibitor metyrapone, blocks the development of the sensitization induced by several stres-

* Corresponding author. Fax: (33) 5696-6893; E-maih piervincenzo.piazza@bordeaux.inserm.fr 0006-8993/96/$15.00 1996 Elsevier Science B.V. All rights reserved Pll S0006-8993(96)00309-5

sors, such as restraint, social isolation and food restriction [12-15,40,48]. In parallel, in intact rats, repeated corticosterone administration itself produces effects similar to repeated stress and thus induces the development of a sensitization of the locomotor [16] and reinforcing effects of psychostimulant drugs [39]. In this report the influence of corticosterone on stressinduced behavioral sensitization was further investigated. Specifically, we examined whether an a c u t e blockade of corticosterone synthesis could reverse stress-induced sensitization once its development had already occurred. For this purpose, we examined the effects of an acute treatment with metyrapone on the locomotor response to cocaine of animals in which behavioral sensitization had been induced by a period of food restriction. Food restriction was used as a stressor because it powerfully increases both corticosterone secretion [4] and the psychomotor and reinforcing effects of psychostimulants [6-8,10,12,14,34,48]. The effects of metyrapone on corticosterone secretion were also investigated.

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Male Sprague-Dawley rats (Iffa-Credo, Lyon, France) weighing 2 8 0 - 3 0 0 g were used. Animals were individually housed with ad libitum access to food and water unless otherwise specified. A 12:12 light-dark cycle (lights off at 12 pm) was maintained in the animal room, and temperature (22C) and humidity (60%) were kept constant. Animals were allowed at least one week to acclimatize to the animal room before starting any manipulation. Metyrapone (Sigma) was dissolved in a solution of distilled water containing 7% of Tween 80 which was also used as vehicle solution. Metyrapone was administered s.c. at a dose of 100 m g / k g in a 2 m l / k g volume. This dose was used because we have shown previously that a similar treatment significantly decreases stress-induced corticosterone secretion [40]. Cocaine HC1 (CoopEration Pharmaceutique Fran~aise, France) was dissolved in 0.9% NaC1 solution and injected i.p. at a dose of 10 m g / k g in a volume of 1 m l / k g . Locomotor activity was measured in circular corridors (10 cm wide and 70 cm in diameter) equipped with four equally-spaced photoelectric beams located along the perpendicular axis of the apparatus. Since the locomotor response to novelty and sensitivity to the psychomotor effects of psychostimulants are correlated [21,35], we ensured a homogeneous distribution of this factor throughout the different experimental groups. For this purpose, one week prior to any other experimental manipulation, all animals were tested for their locomotor response to novelty over 2 h. Rats were then evenly distributed among the different experimental groups according to their activity score.

Animals undergoing the food restriction procedure were reduced to 90% of their body weight using the following procedure: on the first day of food restriction all rats received 8 g of food and on each of the following days the daily ration was individually adapted according to the attained body weight so as to reach 90% of the pre-restriction value within 5 - 6 days from the beginning of the restriction period. Animals were then maintained at 90% of their weight for the duration of the experiment by daily adjustments of their ration. Animals not undergoing the food restriction procedure were weighed daily, as were the restricted animals, but were fed ad libitum throughout the experiment. For the assessment of the effects of food restriction and metyrapone on the locomotor response to cocaine, animals fed ad libitum or food restricted (FR) received an injection of either vehicle or metyrapone (METY). Four experimental groups were then constituted: V E H I C L E ( n = 15), V E H I C L E FR (n = 16), M E T Y (n = 15) and M E T Y FR (n = 16). Injections were given at 9.00 h. One hour later the animals were placed in the circular corridor and alter 2 h of habituation, half of the animals received an i.p. injection of saline and the other half of cocaine. Consequently the metyrapone and cocaine injections were spaced by a 3-h period. Locomotor responses were recorded for 2 h over 10-min intervals. To assess the effects of food restriction and metyrapone on corticosterone secretion, ad libitum-fed and food-restricted rats were injected with either metyrapone or vehicle. Four experimental groups (n = 8 each) identical to the ones described above were thus constituted. This time, 3 h

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Fig. 1. Effect of metyrapone (100 m g / k g , s.c.) and food restriction (90% of body weight) on locomotor response to saline (left panel) and cocaine 10 m g / k g i.p. (right panel). Each point represents the mean _+ S.E.M. of the locomotor activity over 10 min. Bars represent the mean _+ S.E.M. of the total locomotor activity over the first hour of testing. Neither metyrapone nor food restriction had any effect on the locomotor response to a saline injection. In contrast, food-restricted animals (VEHICLE FR) showed a higher locomotor response to cocaine than ad libitum-fed controls (VEHICLE) ( P < 0.001). An acute metyrapone injection (100 m g / k g ) 3 h before cocaine totally abolished this effect. Thus food-restricted animals receiving metyrapone (METY FR) showed a lower response to cocaine than animals in the VEHICLE FR group ( P < 0.01) and did not differ from ad libitum-fed controls (VEHICLE). Metyrapone treatment also reduced the response to cocaine in control ad libitum-fed animals (METY vs. VEHICLE, P < 0.05).

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after the vehicle or metyrapone injections, animals were placed in a plastic cylinder (7 cm diameter, 25 cm long) for 30 min, and three 300 /xl blood samples were withdrawn from the tail vein. The first one was taken within 2 rain from the start of the restraint stress period, the second and the third ones 30 and 120 rain later. Blood for corticosterone assay was collected in heparinized tubes and plasma was obtained after centrifugation. Plasma corticosterone was measured by radioimmuno-assay ( R I A kit, ICN Biomedicals) using a highly specific corticosterone antiserum with a detection threshold of 0.1 / x g / 1 0 0 ml. For the statistical analysis of the locomotor response to saline and cocaine injections, locomotor activity scores were submitted to an A N O V A considering the different experimental groups (VEHICLE, V E H I C L E FR, METY, M E T Y FR) as a between factor (Treatment, four levels) and the different time points after the injection as a within factor (Time, 12 levels). Plasma levels of corticosterone were analyzed considering the different treatments as between factor (Treatment, 4 levels) and the time at which the blood samples were withdrawn as within factor (Time, three levels). N e w m a n - K e u l s test was used for post-hoc analysis. Effects of food restriction and metyrapone on the locomotor response to cocaine. F o o d restriction and metyrapone treatments did not modify the locomotor response to saline [Treatment effect F3,28 = 1.98, P > 0.14] (Fig. 1 left panel) but they did affect the locomotor response to cocaine

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Fig. 2. Effect of metyrapone (100 mg/kg, s.c.) and food restriction (90% of body weight) on corticosterone levels. Each value represents the mean _+S.E.M. of plasma corticosterone levels in basal conditions and 30 and 120 rain after restraint stress. Food-restricted animals (VEHICLE FR) showed a higher secretion of corticosterone than ad libitum-fed controls (VEHICLE) (P < 0.01). An acute metyrapone injection 3 h before stress totally abolished this effect. Thus food-restricted animals receiving metyrapone (METY FR) showed a lower corticosterone secretion than animals in the VEHICLE FR group (P < 0.001) and did not differ from ad libitum-fed controls (VEHICLE). Metyrapone treatment also reduced corticosterone secretion in control ad libitum-fed animals (METY vs. VEHICLE, P < 0.05).

[Treatment effect, F3,26 = 10.94, P < 0.001] (Fig. 1 right panel) in a time-dependent manner [Treatment Time interaction, F33,286 = 5.1, P < 0.01]. As Fig. 1 shows, food restriction increased the locomotor response to cocaine (VEHICLE F R vs. VEHICLE, P < 0.001) and metyrapone treatment reversed this effect. Thus animals in the M E T Y F R group showed a lower locomotor response than animals in the V E H I C L E F R group ( P < 0.01), but did not differ from animals in the V E H I C L E group. Metyrapone treatment also reduced the response to the drug in control animals ( M E T Y vs. VEHICLE, P < 0.05). Effects of food restriction and metyrapone on corticosterone secretion. F o o d restriction and metyrapone treatment significantly modified plasma corticosterone levels [Treatment effect, F3,28 = 8.54, P < 0.001] and this effect was independent from time following restraint stress [Treatment X Time interaction, F6,56 = 1.4, P > 0.23]. The effects of these treatments on corticosterone levels paralleled those observed on the locomotor response to cocaine. Overall, as Fig. 2 shows, food restriction significantly increased plasma levels of corticosterone (VEHICLE FR vs. VEHICLE, P < 0.01) and metyrapone treatment reversed this effects. Thus, the M E T Y F R group showed lower levels of corticosterone than V E H I C L E FR rats ( P < 0.001) but did not differ from the V E H I C L E group. Furthermore, metyrapone also decreased corticosterone secretion in control rats. Thus, animals in the M E T Y group showed lower levels of the hormone than animals in the V E H I C L E group ( P < 0.05). The results of this study indicate that the enhancement in the psychomotor activating effects of cocaine produced by a chronic stress can be reversed by an acute reduction of corticosterone secretion. Animals subjected to food restriction showed an enhanced sensitivity to the psychomotor activating effects of cocaine and an enhanced corticosterone secretion. The acute administration of the corticosterone synthesis inhibitor metyrapone reversed these effects. Thus food-restricted animals treated with metyrapone showed the same amount of cocaine-induced locomotor activity and corticosterone secretion as ad libiturn-fed control rats. This parallel between corticosterone secretion and locomotor response to cocaine is also supported by the results obtained in control rats. Acute blockade of corticosterone secretion in control, ad libitum-fed rats, also decreased the psychomotor effect of cocaine, and this effect was accompanied by a significant reduction in plasma corticosterone levels. Despite the effects on cocaine-induced locomotion and corticosterone secretion, neither food restriction nor metyrapone treatments had any effect on locomotor activity produced by an injection of saline. This suggests that the effects of these treatments on cocaine-induced activation are not due to a non-specific action on motor abilities. These results confirm and extend previous findings indicating that the enhancement in drug effects induced by stress depends on an increase in circulating levels of corticosterone.

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The mechanism by which corticosterone increases the response to cocaine is still not clear. In recent studies, we determined that the effect of corticosterone is not due to changes in cocaine pharmacokinetics. Neither metyrapone treatment, corticosterone administration, or adrenalectomy had any effect on brain levels of cocaine [30,31]. Furthermore, sensitivity to behavioral effects of psychostimulants is equally controlled by corticosterone when psychostimulant drugs are either injected systemically or directly in relevant brain areas [12,29]. Corticosterone could modify stress-induced sensitization to psychostimulants by acting directly on the neural substrates that mediate sensitization of the psychomotor and reinforcing effects of cocaine. In this respect the mesencephalic dopaminergic neurons are good candidates. An enhancement of the response of these neurons to psychostimulants is considered the main neural substrate of sensitization (for review see [24,45,46]). Several data support an interaction between glucocorticoids and dopamine in behavioral sensitization. Dopaminergic neurons express glucocorticoid receptors [19] and an increase in glucocorticoid levels seems able to increase dopaminergic activity. These hormones inhibit DA reuptake [17], reduce dopamine catabolism [47,54] and increase extracellular concentrations of dopamine [22,41]. In parallel, a reduction of glucocorticoids increases DA catabolism [5] and blocks the sensitization-induced increase in the dopaminergic response to cocaine [48]. Of course, dopaminergic systems do not operate in isolation and corticosterone could act through many other neuronal substrates such as GABA, 5-HT, excitatory amino acids and opioids. Glucocorticoids have been shown to modify the activity of these neurotransmitters [2,9,27,28,32,49,52,53] which, in turn, can modulate dopamine-dependent behaviours [23,25,42,50]. In conclusion, the increase in the effects of cocaine produced by a chronic stress can be reversed by an acute pharmacological inhibition of corticosterone secretion. This study provides further evidence that the enhancement in drug effects produced by stress depends on an increase in corticosterone levels. Since stress-induced sensitization is considered one of the conditions predisposing to drug abuse, the present results might have implications for the treatment of addiction.

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Acknowledgements This work was supported by Institut National de la Sant6 et de la Recherche M6dicale (INSERM), Universit6 de Bordeaux II, Conseil Rdgional d'Aquitaine, P61e M~dicament d'Aquitaine, Minist~re de la Recherche et de FEnseignement Sup&ieur. We thank Dr. T.E. Robinson for helpful comments on an earlier version of this manuscript.

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