Elsevier

Behavioural Brain Research

Volume 177, Issue 2, 27 February 2007, Pages 329-339
Behavioural Brain Research

Research report
Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner

https://doi.org/10.1016/j.bbr.2006.11.015Get rights and content

Abstract

The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy (‘ADX’: surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals. ADX and SHAM operated mice were subjected to repeated injections of cocaine (15.0 mg/kg) or saline for nine consecutive days, followed by a 5-day withdrawal interval and a saline challenge on day 14. All animals were challenged with 7.5 mg/kg cocaine on day 15.

We report that repeated cocaine exposure induced locomotor sensitisation in both strains, while endocrine sensitisation was only observed in the DBA/2 strain. By contrast, cocaine attenuated corticosterone responses in C57BL/6 mice throughout the sensitisation paradigm. We have therefore identified one strain, the DBA/2 strain, that displays parallel sensitisation of cocaine-induced locomotion and -corticosterone secretion. Most interestingly, ADX prevented locomotor sensitisation only in DBA/2 mice, suggesting that behavioural sensitisation depends on the integrity of adrenal function and on secretion of adrenal glucocorticoids in this strain.

The present results demonstrate that adrenal stress hormones facilitate behavioural sensitisation to cocaine in a genotype-dependent manner and suggest that glucocorticoids contribute to strain differences in psychostimulant sensitivity.

Introduction

Behavioural responses to psychostimulant drugs are characterised by a large degree of individual variability, both in humans and laboratory animals [17], [27], [31]. Psychostimulants activate the mesocorticolimbic dopamine system and individual vulnerability to their effects may reflect a given predisposition to dopaminergic psychosis, such as observed in drug addiction, schizophrenia and psychotic depression. Knowledge of factors that enhance vulnerability to psychostimulants will therefore greatly increase our insight in the neurobiology of dopaminergic psychopathologies.

The existence of marked strain differences in responsiveness to drugs such as amphetamine and cocaine has demonstrated that genetic traits contribute to variations in psychostimulant vulnerability. Two inbred mouse strains that have been used frequently to study the psychopharmacology of dopamine are the C57BL/6 and DBA/2 strains. These strains display profound differences in the anatomy and functioning of the mesocorticolimbic dopamine system and in behavioural responsiveness to dopaminergic agonists and addictive drugs (reviewed in [38]). Compared to DBA/2 mice, C57BL/6 mice are more sensitive to amphetamine-induced locomotion and reward and display higher drug-induced dopamine outflow in the nucleus accumbens [6], [11], [49], [50], [53]. Paradoxically, while C57BL/6 mice are also more vulnerable to the rewarding effects of cocaine, they appear less sensitive to cocaine-induced locomotion [28], [47]. Robust differences between the two strains have also been reported for behavioural sensitisation to repeatedly administered psychostimulants, although the magnitude and direction thereof appears to be highly dependent on the design of the sensitisation paradigm [2], [6], [28], [40].

Interestingly, the strain differences in dopaminergic transmission and sensitivity to the rewarding properties of psychostimulants are not stable, but can change under the influence of environmental challenges, pointing towards a role for the neuroendocrine stress system in psychostimulant vulnerability [10], [11], [39], [51]. Indeed, a wealth of data suggests that stress modulates behavioural and neurochemical responses to psychostimulants and other addictive drugs [18], [24], [34], [35], [45].

Stressful stimuli, either physical or mental, induce concomitant activation of the hypothalamus–pituitary–adrenal axis (HPA-axis) and the sympathetic nervous system resulting in release of glucocorticoid hormones and epinephrine from the adrenal glands [13]. Glucocorticoids in particular, have been shown to modulate transmission in the mesocorticolimbic dopamine system and to facilitate behavioural responses to psychostimulants such as locomotor activity, behavioural sensitisation, self-administration and relapse (reviewed in: [25]). Furthermore, corticosterone in the range of stress-induced levels has reinforcing potential and stress can, like drugs of abuse, increase strength of excitatory synapses on midbrain dopaminergic neurons [33], [42]. Strong evidence indicates that the glucocorticoid–dopamine interactions are dependent on activation of the glucocorticoid receptor that is widely distributed throughout the brain and is expressed by the majority of the midbrain dopaminergic neurons [12], [14], [15], [19], [22], [41], [42].

Taken together, these data suggest that variations in HPA-axis responsiveness to stress may contribute to individual differences in psychostimulant vulnerability, as was elegantly addressed by Piazza et al. [36]. In this respect, laboratory mouse or rat strains with differential stress responsivity provide a valuable tool to study the interaction between the neuroendocrine stress system and the mesocorticolimbic dopamine circuit. With respect to the C57BL/6 and DBA/2 inbred strains, few studies have addressed differences in HPA-axis activation and findings are contradictory. In one study, C57BL/6 mice displayed higher peak corticosterone levels in response to novelty, which is in line with our findings (S. Dalm, personal communication), but contradictory to two reports using other stressors and experimental designs [7], [23], [46]. In addition, there may be differences between these strains in psychostimulant-induced HPA-axis activation, but this has to our knowledge not been reported yet. Differences in basal, stress- or psychostimulant-induced glucocorticoid release may however play a prominent role in the observed strain differences in psychostimulant sensitivity.

The present study was designed to test the hypothesis that adrenal stress hormones contribute to strain differences in cocaine sensitivity. The C57BL/6 and DBA/2 mouse strains were used as model for genetic differences in dopamine and HPA-axis function. We have measured behavioural sensitisation to the locomotor stimulant effect of cocaine and, in parallel, corticosterone responses to single and repeated cocaine exposure. In order to show involvement of the adrenal, we have tested whether strain differences persist when the adrenal is surgically removed (adrenalectomy: ‘ADX’) prior to the onset of drug treatment.

Section snippets

Animals

Male C57BL/6 Rj (C57BL/6) and DBA/2 Rj (DBA/2) mice were obtained from Janvier (Le Genest Saint Isle, France) and received in the animal facility at the age of 8 weeks. Mice were housed in groups of four of the same strain in perspex cages (35 cm × 19 cm × 14 cm) with food and water available ad libitum at a 12 h light–dark cycle (lights on: 7 am) in a temperature (21 ± 1 °C) and humidity (55 ± 5%) controlled room. Surgery was performed 2 weeks after arrival in the animal facility. Animals were briefly

Locomotor activity

The effects of ADX on locomotion of C57BL/6 and DBA/2 mice were studied during the different phases of the sensitisation paradigm. Fig. 1A (C57BL/6) and B (DBA/2) depict total distance moved in the four behavioural tests (days 1, 9, 14 and 15) for the treatment groups SHAM/SAL, SHAM/COC, ADX/SAL and ADX/COC.

Discussion

The present data show similarities, but also profound differences, between the C57BL/6 and DBA/2 strains in behavioural and endocrine sensitisation to cocaine. We have identified one strain, the DBA/2 strain, in which repeated cocaine exposure induces sensitisation of both drug-induced locomotion and -corticosterone secretion. Furthermore, only in this strain, behavioural sensitisation was prevented by ADX, suggesting that adrenal hormones facilitate sensitisation to the locomotor stimulant

Acknowledgements

This research was supported by NWO/INSERM/ZON grants 985-10-014 and 985-10-504. We greatfully acknowledge Drs. L. Enthoven and Ing. M. van der Mark for technical support and Dr. O.C. Meijer for critically reading the manuscript.

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