Research reportAdrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner
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.
Reference (53)
- et al.
Chronic stress induces strain-dependent sensitization to the behavioral effects of amphetamine in the mouse
Pharmacol Biochem Behav
(1992) - et al.
Circulating adrenal hormones are not necessary for the development of sensitization to the psychomotor activating effects of amphetamine
Brain Res
(1995) - et al.
Exposure to repeated, intermittent d-amphetamine induces sensitization of HPA axis to a subsequent stressor
Neuropsychopharmacology
(2002) - et al.
Behavioral and biochemical changes monitored in two inbred strains of mice during exploration of an unfamiliar environment
Physiol Behav
(1990) - et al.
Parallel strain-dependent susceptibility to environmentally-induced stereotypies and stress-induced behavioral sensitization in mice
Physiol Behav
(1997) - et al.
Stress promotes major changes in dopamine receptor densities within the mesoaccumbens and nigrostriatal systems
Neuroscience
(1998) - et al.
Effects of immobilization stress on dopamine and its metabolites in different brain areas of the mouse: role of genotype and stress duration
Brain Res
(1988) - et al.
Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine
Eur J Pharmacol
(1996) - et al.
Conditioned release of corticosterone by contextual stimuli associated with cocaine is mediated by corticotropin-releasing factor
Brain Res
(1998) - et al.
Individual differences in drug dependence in rats: the role of genetic factors and life events
Eur J Pharmacol
(2005)
Kinetics of glucocorticoid response to restraint stress and/or experimental influenza viral infection in two inbred strains of mice
J Neuroimmunol
Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain
Neuroscience
Sensitization of amphetamine-stereotypy reduces plasma corticosterone: implications for stereotypy as a coping response
Behav Neural Biol
Increased motor response to cocaine administration following recovery from chronic corticosterone treatment in the rat
Eur Neuropsychopharmacol
Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration.
Brain Res
The role of stress in drug self-administration
Trends Pharmacol Sci
A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants.
Brain Res Brain Res Rev
Psychopharmacology of dopamine: the contribution of comparative studies in inbred strains of mice
Prog Neurobiol
Role of genotype in the adaptation of the brain dopamine system to stress
Neurosci Biobehav Rev
Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons
Neuron
Stressor- or drug-induced sensitization of the corticosterone response is not critically involved in the long-term expression of behavioural sensitization to amphetamine
Neuroscience
Intermittent cocaine exposure causes delayed and long-lasting sensitization of cocaine-induced ACTH secretion in rats
Eur J Pharmacol
Stress-induced relapse to heroin and cocaine seeking in rats: a review.
Brain Res Brain Res Rev
Mouse strain differences in plasma corticosterone following uncontrollable footshock
Pharmacol Biochem Behav
Locomotor stimulant effects of cocaine and novel cocaine analogs in DBA/2J and C57BL/6J inbred mice
Pharmacol Biochem Behav
Opposite genotype-dependent mesocorticolimbic dopamine response to stress
Neuroscience
Cited by (34)
CRF<inf>1</inf> receptor-deficiency increases cocaine reward
2017, NeuropharmacologyEither the dorsal hippocampus or the dorsolateral striatum is selectively involved in consolidation of forced swim-induced immobility depending on genetic background
2014, Neurobiology of Learning and MemoryCitation Excerpt :Thus, strain differences in susceptibility to shift to dorsal striatal learning under stress could depend on different sensitivity to the central effects of corticosterone. Indeed, in comparison with B6, D2 mice are characterized by higher sensitivity to the effects of stress hormones on brain plasticity, higher susceptibility to the amnesic effects of post-training administration of exogenous corticosterone and by a higher number of hippocampal GRs (Cabib et al., 1996; de Jong, Oitzl, & de Kloet, 2007; de Jong, Steenbergen, & de Kloet, 2008; Patacchioli et al., 1990). Impaired learning of classic hippocampus-dependent tasks by D2 mice is associated with reduced markers of hippocampal plasticity (Ambrosini, Mariucci, Tantucci, Van Hooijdonk, & Ammassari-Teule, 2005; Gerlai, 1998; Menard, Valastro, Martel, Martinoli, & Massicotte, 2004; Passino, Middei, Restivo, Bertaina-Anglade, & Ammassari-Teule, 2002; Podhorna & Brown, 2002; Restivo et al., 2006; Sung et al., 2008).
The extra-adrenal effects of metyrapone and oxazepam on ongoing cocaine self-administration
2014, Brain ResearchCitation Excerpt :Surprisingly, however, adrenalectomized rats continued to self-administer cocaine, contrary to the effects of adrenalectomy on the acquisition of cocaine self-administration (Goeders and Guerin, 1996a) whereby cocaine-naive rats did not learn to self-administer cocaine across a range of doses. Surgical adrenalectomy has also been demonstrated to decrease the sensitization of locomotor responses to cocaine (De Jong et al., 2007; De Jong and de Kloet, 2009; Marinelli et al., 1997; Prasad et al., 1996, 1998; Przegaliński et al., 2000) and the escalation of cocaine self-administration and stress-induced reinstatement (Deroche et al., 1997; Graf et al., 2011; Mantsch et al., 2008). These data support the theory that stressful stimuli may potentiate the ability of other drug-related stimuli to induce relapse to cocaine-seeking behavior in both rodents and humans (Buffalari and See, 2009; Feltenstein and See, 2006; Mantsch et al., 2014; Piazza et al., 1996; Preston and Epstein, 2011; Shalev et al., 2003).
Reconceptualizing in a dual-system model the effects of prenatal cocaine exposure on adolescent development: A short review
2011, International Journal of Developmental NeuroscienceCitation Excerpt :The threshold level of corticosterone is necessary for the establishment of self-administration of cocaine (Goeders, 2002). Initiation of behavioral sensitization to cocaine was blocked by adrenalectomy (de Jong et al., 2007). Adult rats with early separation experience demonstrated a lower density of DA transporters in the NAc and an enhanced DA response to both cocaine administrations and stress, adding to the concept of cross-sensitization between these two systems (Brake et al., 2004).