The cerebellum on cocaine. Plasticity, metaplasticity and environmental enrichment effects
- Autores: Dolores Vázquez Sanromán
- Directores de la Tesis: Marta Miquel Salgado-Araujo (dir. tes.)
- Lectura: En la Universitat Jaume I ( España ) en 2014
- Idioma: inglés
- Tribunal Calificador de la Tesis: Marcello Solinas (presid.), Carla Sanchis Segura (secret.), Daniela Carulli (voc.)
- Materias:
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- Resumen
Despite the enormous progress having been made during the last decade in the knowledge about the molecular and cellular mechanisms of drug addiction there are still many gaps and unenlightened points that need to be elucidated. It is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity alterations in those cortico-striatal-limbic circuits that follow a ventral-dorsal pattern with increasing drug administrations (Everitt and Robbins 2005; Corbit et al., 2012; Willuhn et al 2012; Murray et al 2013). However, very few studies have dealt with brain territories beyond the cortico-striatal-limbic networks. Even though growing evidence confirms the involvement of the cerebellum in drug-related alterations, this structure has been traditionally dismissed in the addiction field (Miquel et al., 2009). The present research aims to contribute to the understanding of the circuits that support long-lasting drug-dependent plasticity modifications underlying the addictive phenotype. Here, we present an extensive investigation on cocaine-induced cerebellar plasticity with different treatment and environmental conditions. We have approached cerebellar plasticity by evaluating several molecular parameters related to BDNF as well as ¿FosB mechanisms. Thus, our assessment includes BDNF, its P75 and TrkB receptors, the plasminogen activator tpA, ¿FosB and GluR2 AMPA subunites. Likewise, we have analysed cocaine effects on structural plasticity in Purkinje neurons. One of the most relevant and important aspects of the present research is the unprecedented evaluation of cocaine effects on the cerebellar perineuronal nets, a cartilage-like of extracellular matrix structure that enwraps the perikaryon of several neurons and which may create restrictive conditions for the emergence of new synaptic contacts (Brucker et al., 1993; Grimpe and Silver 2002; Carulli et al., 2005, 2006; 2013; Soleman et al., 2013). This approach, scarcely explored so far, opens further avenues of research in the investigation of drug-induced metaplasticity.
It is important to highlight that the research we addressed here is correlational and thus the findings should be framed taking into account this approach. Even though we are aware that future causal research is required, still an exhaustive description of cocaine effects on cerebellar plasticity was needed, due to the fact that there are very few data about the effects of cocaine in the cerebellum.
This doctoral thesis contains four different articles arranged in two different chapters. The first chapter includes two studies describe the effects of a cocaine treatment protocol that induces sniffing sensitization on cerebellar plasticity mechanisms. Thus, in the first one: The cerebellum on cocaine: Brain Derived Neurotrophic Factor, ¿FosB, structural plasticity and metaplasticity, we explored the effects of cocaine administration followed by a one drug free week and then a seventh cocaine injection. In the second article: Cocaine-dependent molecular and structural plasticity in the cerebellum after a long withdrawal period, we used the same cocaine treatment protocol but we extended the duration of the drug free period up to one month. Remarkably, the consequences of cocaine administration on cerebellar plasticity depend on the length of the drug free period.
Environmental factors may play a critical role in determining the sensitivity to drug response (Shina, 2001, Goeders, 2002, Solinas et al., 2010) and to some extent may compete with drugs for neuroplasticity mechanisms or even counteract drug effects. Enriched environments have been used in order to standardize environmental influences on brain and behaviour. Therefore, in the second chapter of this doctoral thesis we investigated the effects of drug-environment interactions on cerebellar neuroplasticity by comparing two experimental settings: a standard condition, where five animals either share the same housing and where no more stimulation was provided (STE) or an enriched environment with major sensory, motor, cognitive and social stimulation (EE). In the first and already published article of this second chapter, we evaluated the consequences of different EE durations on cerebellar BDNF expression: The effects of enriched environment on BDNF expression in the mouse cerebellum depending on the length of exposure. Next, in the last paper: Enriched environment impact on cocaine-induced cerebellar plasticity: Who arrived first matters, we analysed drug-environment interactions in two different situations: on the one hand, when EE exposure occurs before and during drug administration (concomitant EE); on the other hand, when cocaine is administered under STE conditions and then the animals are switched to an EE (subsequent EE). Strikingly, cocaine effects on cerebellar plasticity were modulated by environmental conditions in a very selective way.
Finally, we conclude this thesis with a section where summarized findings, strengths and pitfalls as well as a working model for future research are provided. References can be found at the end of each article and after the general discussion section.
