Influence of social stress on the rewarding effects os cocaine
- Autores: Sandra Montagud Romero
- Directores de la Tesis: Marta Rodríguez Arias (dir. tes.), José Miñarro López (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2016
- Idioma: español
- Tribunal Calificador de la Tesis: Olga Valverde Granados (presid.), Antonio Vidal Infer (secret.), Vincenzo De Feo (voc.)
- Materias:
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- Resumen
Social relations are crucial not only for human development, but also for other species that live according to social hierarchies. The environment in which individuals develop is critical due to its impact on wellness, health maintenance and survival (Kessler et al., 2010). Another key factor in maintaining human homeostasis and health is the stress response. This response depends on the interaction between the environment and the activity of some regulatory body systems, such as the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis (HPA) (Stratakis and Chrousos 1995). Different types of stress (physical or psychological) can induce qualitatively varied behavioral patterns and physiological responses. In recent years, several studies have focused on the phenomenon of social and psychological stress and its consequences (i.e. Miczek et al., 2008; Rodríguez-Arias et al., 2013). Nowadays, people experience stress daily due to the social environments in which they operate, which has negative behavioral and psychological consequences, both immediate and long-term.
Stress is one of the main risk factors involved in substance abuse and addiction. Addiction is a chronic multifactorial relapsing disorder resulting from an interaction of biological and environmental aspects (Ellenbroek et al., 2005; Enoch, 2006). Research has demonstrated that stress is a risk factor for the initiation, maintenance and escalation of drug consumption (Logrip et al., 2011; Sinha et al., 2011; Koob, 2012). There is a close association between brain systems involved in addiction and stress, as environmental stressors can cause long-term changes in the brain's rewarding system function, inducing phenomena such as relapse. Activation of the stress system seems to be crucial for the negative emotional state induced by dependence, which drives drug-seeking through negative reinforcement mechanisms (Koob, 2010).
It is important to emphasize the high prevalence of cocaine consumption worldwide, as it is the second most consumed illegal drug in Europe, after cannabis. Cocaine use is a health problem with serious social and economic consequences (EMCDDA, 2015) affecting not only drug addicts, but also their families and social environment. Knowledge of the neurobiological basis of addiction allows prevention and treatment strategies to be improved. As ethical reasons rule out performing studies in human subjects, animal models are a vital tool for experimental research.
To date, studies performed in animal models have focused on evaluating the immediate or short-term neurobiological and physiological consequences of stress. However, only a few works have studied the long-term consequences or the influence of these neuroadaptations in subsequent drug intake (e.g. Burke and Miczek, 2014). Social and emotional stressors are the main triggers of the stress response in humans, which explains the translational importance of this research in animals. In animal procedures, social defeat stress is a naturalistic model of stress that involves an agonistic encounter between conspecifics and is thought to represent a stressor of ecological and ethological validity in mice (Tornatzky and Miczek, 1993). Rodents expose to social defeat stress show physiological and behavioral changes (de Groot et al., 1999; Lumley et al., 1999; Keeney et al., 2001; Griebel et al., 2002; García-Pardo et al., 2015). Moreover, it has been repeatedly demonstrated that exposure to different procedures of social defeat increases the reinforcing effects of different types of psychostimulant drugs, including cocaine and amphetamine. Most studies have used the intravenous self-administration (SA) paradigm (Miczek et al., 2008; Neisewander et al., 2012), and almost all have employed only adult rodents, with few reports having addressed the issue in adolescents (e.g. Burke et al., 2011). Adolescence is a period of enhanced vulnerability to drug abuse because the brain has not yet matured (Rodríguez-Arias and Aguilar, 2012). Consumption of drugs of abuse and exposure to different negative environmental conditions are especially harmful at this stage of life.
As commented on above, most of the studies that have evaluated the effects of social stress on cocaine reward have employed the SA procedure. Conditioned place preference (CPP) is the most widely used paradigm to measure the association between environmental cues and drug reinforcement (Aguilar et al., 2013). The SA and CPP models provide a complete evaluation of the rewarding effects of drug of abuse, as they allow us to measure the role of both motivation and environmental cues. CPP, on the other hand, has rarely been used in studies of social stress (McLaughlin et al., 2006).
The principal aim of the experiments presented in this doctoral thesis was to characterize how social stress exposure modifies the rewarding effects of cocaine and to further our knowledge of the neurobiological substrates of these effects. To do this, we studied the effect of acute social defeat (ASD) stress on the rewarding effects of cocaine using the CPP procedure. We also evaluated if the effect of ASD differed when experienced during adolescence rather than in adulthood.
In a second phase, we used the CPP and SA procedures to assess the long-lasting effects of repeated social defeat (RSD) stress during adolescence on the rewarding effects of cocaine. Again, we explored if these long-lasting effects differed when social stress was experienced in adolescence versus adulthood.
Once we had characterized the effects of ASD and RSD on cocaine reward, we set out to detect the vulnerability factors affecting these effects. We determined the influence of a personality trait – impulsivity - in a study performed at the Department of Psychology of Tufts University (USA), during a 6-month stay in the prestigious laboratory directed by Professor K.A. Miczek. Furthermore, during my stay, we analyzed the role of corticotrophin releasing factor (CRF) in the response to stress and its influence on cocaine-seeking after a period of forced abstinence. In another study, we also evaluated genetic differences with respect to aggression, and how experience modifies the agonistic response depending on the strain of the mice used.
In a final phase of the study, we aimed to unveil some of the mechanisms underlying the effects of social defeat on cocaine reward. Firstly, we determined the role of dopamine (DA) neurotransmission in the long-lasting effects of RSD on the rewarding effects of cocaine. We used pharmacological tools as well as measured D1R and D2R levels in the cortex and hippocampus. Once this role had been determined, we performed a further study to explore how social defeat modifies control of the DA pathway. To do this, we assessed DA transcription factors, such as Nurr and Pitx3, and the role of (brain-derived neurotrophic factor) BDNF, which can in turn modify the function of DA neurons.
As a second putative mechanism, we explored the implication of the epigenetic changes induced by social defeat and how they are related to an increase in cocaine reward. After measuring alterations of histone acetylation provoked by RSD, we analyzed the effects of the histone acetyltransferase (HAT) and histone deacetylase (HDAC) inhibitors, administered before RSD, on cocaine-induced CPP.
In the last few years, many reports have highlighted neuroinflammatory processes as constituting the basis of mental disorders such as depression or schizophrenia. However, little is known regarding the neuroinflammatory process in response to stress. As a first and pioneering study in this field, we evaluated how exposure to RSD during adolescence alters the blood-brain barrier (BBB), which is highly affected by the neuroinflammation response.
Overall, our results expand our knowledge about the influence of social defeat on cocaine effects. The effects of social defeat stress on the CPP induced by cocaine vary depending on the social stress procedure used (ASD or RSD) and the age of the animals when it is experienced. However, RSD augments the rewarding effects of cocaine, independently of whether stress is suffered during adolescence or adulthood. These effects can be modulated by genetics, which modify the response to defeat and are influenced by personality traits such as impulsivity.
We also throw new light on the role of DA neurotransmission in the effects of RSD on cocaine reward. Both D1R and D2R are involved in these effects, although D1R seems to be more implicated. Social defeat also modifies the transcription factors that regulate DA gene expression, thus highlighting adolescence as a more sensitive period. Alterations of DA neurotransmission could modulate the increased expression in BDNF via ERK/CREB or other pathways, which in turn would mediate neuroplastic changes in brain areas related to reward.
In addition, our results show for the first time that adolescent mice exposed to RSD undergo significant changes in BBB structure, indicating that social defeat increases BBB permeability, probably through alterations in structural proteins. Furthermore, using the RSD paradigm, we show, also for the first time, that the epigenetic changes induced by social stress are associated with an increase in the rewarding and reinstating effects of a threshold dose of cocaine in the CPP paradigm that can be blocked by the inhibition of HAT enzyme.
Advances in knowledge surrounding the neurobiological substrates implicated in the effects of social stress on the rewarding effects of cocaine are likely to contribute to the development of pharmacological and behavioral strategies for the treatment of drug addiction.
