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The Effects of Adenosine Antagonists on Distinct Aspects of Motivated Behavior: Interaction with Ethanol and Dopamine Depletion

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The Effects of Adenosine Antagonists on Distinct Aspects of Motivated Behavior: Interaction with Ethanol and Dopamine Depletion Facultat de Ciències de la Salut Departament de Psicologia Bàsica, Clínica i Psicobiologia The effects of adenosine antagonists on distinct aspects of motivated behavior: interaction with ethanol and dopamine depletion. PhD Candidate Laura López Cruz Advisor Dr. Mercè Correa Sanz Co-advisor Dr. John D.Salamone Castelló, May 2016 Als meus pares i germà A Carlos AKNOWLEDGEMENTS This work was funded by two competitive grants awarded to Mercè Correa and John D. Salamone: Chapters 1-4: The experiments in the first chapters were supported by Plan Nacional de Drogas. Ministerio de Sanidad y Consumo. Spain. Project: “Impacto de la dosis de cafeína en las bebidas energéticas sobre las conductas implicadas en el abuso y la adicción al alcohol: interacción de los sistemas de neuromodulación adenosinérgicos y dopaminérgicos”. (2010I024). Chapters 5 and 6: The last 2 chapters contain experiments financed by Fundació Bancaixa-Universitat Jaume I. Spain. Project: “Efecto del ejercicio físico y el consumo de xantinas sobre la realización del esfuerzo en las conductas motivadas: Modulación del sistema mesolímbico dopaminérgico y su regulación por adenosina”. (P1.1B2010-43). Laura López Cruz was awarded a 4-year predoctoral scholarship “Fornación de Profesorado Universitario-FPU” (AP2010-3793) from the Spanish Ministry of Education, Culture and Sport. (2012/2016). TABLE OF CONTENTS ABSTRACT ...................................................................................................................1 RESUMEN .....................................................................................................................3 GENERAL INTRODUCTION ......................................................................................5 OBJECTIVES.................................................................................................................25 CHAPTERS: CHAPTER 1: The impact of caffeine on the behavioral effects of ethanol related to abuse and addiction: a review of animal studies .................................................27 CHAPTER 2: Differences between the nonselective adenosine receptor antagonists caffeine and theophylline in motor and mood effects: Studies using medium to high doses in animal models. ...............................................................75 CHAPTER 3: Effect of caffeine and ethanol coadministration on social preference and recognition in mice: role of different adenosine receptors. ............................107 CHAPTER 4: Motivation for social interaction and impact of anxiety levels in A2A receptor KO mice: involvement of anterior cingulate and amygdala. ..................141 CHAPTER 5: Does caffeine have a therapeutic role in depression?: relevance for the treatment of motivational symptoms. ..............................................................171 CHAPTER 6: Caffeine reverses the shift in preference from high to low effort reinforcing activities induced by dopamine depletion: relation to DARPP32 phosphorylation patterns. ......................................................................................211 CONCLUSIONS ..........................................................................................................241 APPENDICES: APPENDIX 1: Impact of high doses of caffeine on acute and sensitized motor activity induced by ethanol in mice. .........................................................................................247 APPENDIX 2: Behavioral manipulations for the validation of the 3-choice running wheel T-maze ...............................................................................................................265 APPENDIX 3: Dopamine depletion reduces preference for activity-based reinforcers in mice with low but not high experience of exercise: relation to DARPP-32 phosphorylation patterns. .............................................................................................277 The effects of adenosine antagonists on distinct aspects of motivated behavior: interaction with ethanol and dopamine depletion. ABSTRACT Adenosine is a neuromodulator in the central nervous system (CNS) that interacts with other neurotransmitters and with some substances like alcohol, which elevates the adenosinergic tone. It has been shown that increases in adenosine levels produce sedation and fatigue, two behavioral effects that can have an impact on other more complex processes such as anxiety or motivation. Adenosine acts on different receptors, being adenosine A1 and A2A receptors the most relevant for their presence and mechanism of action in specific brain areas involved in the modulation of mood and motivational processes such as striatum, prefrontal cortex and amygdala. Caffeine is a worldwide consumed methylxanthine that acts as a non-selective adenosine A1/A2A receptor antagonist. This drug is generally consumed to reduce fatigue and increase alert. More recently, caffeine, at high concentrations, is combined with alcoholic beverages under the popular belief that can counteract some of the sedative and impairing effects of ethanol. The knowledge about how high levels of caffeine can affect complex motivated behaviors such alcohol abuse, or social interaction patterns is limited, and potential side effects such as increases in anxiety and motor impairments can modulate them. Thus, the first part of the present dissertation (Chapters 1-4), reviews the literature on caffeine-ethanol interaction, and addresses the impact of high doses of caffeine on anxiety and how they can modulate social interaction patterns in animal models. High doses of caffeine are studied also in interaction with moderate doses of ethanol that had demonstrated to produce anxiolysis. In order to provide evidence about a potentially selective mechanism of action on adenosine A1 or on A2A receptors, other selective and non-selective adenosine antagonists and A2A receptor KO mice are also used. On the other hand, A1 and A2A receptors have been proposed as therapeutical targets for the treatment of motivational impairments such as psychomotor retardation and fatigue observed in some psychopathologies such as depression. Mesolimbic dopamine (DA) is involved in the regulation of the activational component of motivation and DA depletion or antagonism has shown to impair this aspect of motivation in effort-based decision making tasks, shifting preferences from high effort/high reward options to low 1 effort/low reward options. Adenosine A1 and A2A are colocalized with DA D1 and D2 receptors respectively in striatal areas and they interact in antagonistic way at the cellular and also the behavioral level. Several selective adenosine antagonists have shown to revert the anergia-like effect induced by DA impairments. However, the therapeutical impact of caffeine on those impairments has not been widely explored. Thus, in Chapters 5-6 the impact of caffeine on depression is reviewed, and its potential on effort-based decision-making tasks in animal models is studied after the administration of a DA depleting agent. Cellular markers activated after adenosine and DA receptor interactions were analyzed in order to elucidate the mechanism of action. 2 Efecto de los antagonistas de adenosina en diferentes componentes de la conducta motivada: estudios de interacción con alcohol y con disminución en los niveles de dopamina. RESUMEN La adenosina es un neuromodulador del Sistema Nervioso Central (SNC) que interactúa con otros neurotransmisores y otras sustancias como el alcohol, el cual incrementa los niveles de adenosina. Se ha demostrado que estos incrementos adenosinérgicos producen sedación y fatiga, dos efectos conductuales que pueden tener impacto en procesos como la ansiedad o la motivación. La adenosina actúa en diferentes receptores, siendo los A1 y los A2A los más relevantes por su presencia y mecanismo de acción en áreas cerebrales involucradas en la modulación de procesos emocionales y motivacionales como el estriado, el córtex prefrontal y la amígdala. La cafeína es una metilxantina ampliamente consumida que actúa como antagonista no selectivo de los receptores A1/A2A de adenosina. Esta droga es generalmente consumida para reducir la fatiga e incrementar los niveles de alerta. Recientemente, la cafeína a dosis altas, se ingiere junto a bebidas alcohólicas bajo la creencia popular de que esta metilxantina puede compensar los efectos sedativos e intoxicantes del alcohol. El conocimiento acerca de cómo altas concentraciones de cafeína pueden afectar directamente aspectos complejos de conductas motivadas como el abuso de alcohol o la interacción social, es limitado, y además estas conductas pueden verse moduladas también por los efectos secundarios asociados a la cafeína, como es el incremento de ansiedad y las alteraciones motoras. En este sentido, la primera parte de esta tesis (Capítulos 1-4), revisa la literatura relacionada con la interacción cafeína-alcohol, y explora el impacto de dosis altas de cafeína en ansiedad y como estas sustancias pueden modular la interacción social en modelos animales. Con el objetivo de conocer el mecanismo de acción selectivo de la cafeína sobre los receptores de adenosina A1 o A2A, se estudian también otros antagonistas selectivos y no selectivos de los receptores de adenosina, así como animales KO para los receptores de adenosina A2A. Por otra parte, los receptores A1 y A2A, se han propuesto como dianas terapéuticas para el tratamiento de alteraciones motivacionales como el enlentecimiento motor y la fatiga observadas en algunas psicopatologías como
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