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Behavioral, Physiological and Pharmacological Approaches in Rats UNIVERSIDAD DE GRANADA PROGRAMA DE DOCTORADO EN BIOMEDICINA EXPERIMENTAL STUDIES ON FRUSTRATION: BEHAVIORAL, PHYSIOLOGICAL AND PHARMACOLOGICAL APPROACHES IN RATS TESIS DOCTORAL PRESENTADA POR: Ana María Jiménez García Graduada en Psicología, para optar al grado de: DOCTORA POR LA UNIVERSIDAD DE GRANADA (Con la mención de Doctor Internacional) UNIVERSIDAD DE GRANADA Facultad de Medicina Departamento de Farmacología e Instituto de Neurociencias Directores: CRUZ MIGUEL CENDÁN MARTÍNEZ IGNACIO MORÓN HENCHE Editor: Universidad de Granada. Tesis Doctorales Autor: Ana María Jiménez García ISBN: 978-84-1306-621-9 URI: http://hdl.handle.net/10481/63826 La realización de esta Tesis ha sido posible gracias a un contrato del Plan de Garantía Juvenil (Junta de Andalucía) y a una beca y contrato a través de la Fundación General Universidad de Granada. Además de la financiación de nuestro grupo de investigación por la Junta de Andalucía (grupo CTS-109), por fondos del Programa Operativo FEDER de Andalucía (proyecto B-CTS-422-UGR18), Ministerio de Ciencia e Innovación (proyectos SAF2013-47481P y SAF2016-80540-R), y Laboratorios Esteve. A mi sobrinita Alicia, Index Introduction 1. Effect of previous experiences on the emotional response.................................... 1 1.1. Animal models of frustration ......................................................................... 5 1.2. Successive negative contrast .......................................................................... 6 2. Physiological basis of frustration ........................................................................ 13 2.1. Frustration, pain and anxiety ........................................................................ 13 2.2. Drug effects in Successive negative contrast ............................................... 20 3. Sigma-1 receptor.................................................................................................. 26 3.1. General description and structure ................................................................. 26 3.2. Subcellular and anatomical distribution ....................................................... 27 3.3. The pharmacology of sigma-1 receptor ....................................................... 28 3.4. Actions of sigma-1 receptors in several states or pathologies ..................... 29 Rationale, hypothesis and goals 1. Rationale .............................................................................................................. 39 2. Hypothesis and goals ........................................................................................... 40 Material and methods 1. Experimental animals .......................................................................................... 46 2. Animal models of frustration ............................................................................... 46 2.1. Instrumental Successive Negative Contrast ................................................. 46 2.2. Consummatory Successive Negative Contrast ............................................. 49 3. Animal models to assess pain sensitivity ............................................................ 51 3.1. Von Frey test ................................................................................................ 51 3.2. Hargreaves test ............................................................................................. 52 4. Drugs and drug administration ............................................................................ 54 5. Data Analysis ....................................................................................................... 57 Results and Discussion 1. Experiment 1. Previous experiences induce differential responses in Instrumental Successive Negative Contrast procedure in rats. ........................................................ 60 2. Experiment 2. Frustration induces hypoalgesia. .................................................. 63 2.1. Mechanical hypoalgesia induced by reward devaluation ................................. 63 2.2. Heat hypoalgesia induced by reward devaluation ............................................ 66 2.3. Discussion about the hypoalgesia data ............................................................. 68 3. Experiment 3. Role of sigma-1 receptors ligands on the frustration induced by the consummatory Successive Negative Contrast procedure ..................................... 73 3.1. Effects of sigma-1 receptor antagonists ........................................................... 74 3.2. Effects of sigma-1 receptors agonists............................................................... 80 3.3. Discussion of the effects of sigma-1 ligands .................................................... 85 Conclusions 1. Specific conclusions ............................................................................................ 92 2. General conclusions ............................................................................................. 92 Resumen 1. Antecedentes, hipótesis y objetivos ..................................................................... 96 1.1. Antecedentes ................................................................................................ 96 1.2. Hipótesis y objetivos .................................................................................... 98 2. Materiales y métodos ......................................................................................... 100 2.1. Animales de experimentación .................................................................... 100 2.2. Modelos animales para inducir frustración ................................................ 101 2.3. Modelos animales para medir la percepción del dolor ............................... 104 2.4. Fármacos .................................................................................................... 106 2.5. Análisis estadísticos ................................................................................... 107 3. Resultados y discusión ...................................................................................... 107 3.1. Experimento 1: Influencia de las experiencias previas en la respuesta emocional .............................................................................................................. 107 3.2. Experimento 2: Hipoalgesia inducida por la devaluación de recompensas 109 3.3. Experimento 3: Papel de los receptores sigma-1 en la devaluación de recompensas .......................................................................................................... 110 4. Conclusiones ...................................................................................................... 113 4.1. Conclusiones específicas ............................................................................ 114 4.2. Conclusión general ..................................................................................... 114 Bibliographic References ......................................................... 116 Abbreviations ............................................................................ 136 List of publications ................................................................... 140 List of figures Figure 1. Theorical representation of Successive Negative Contrast .............................. 6 Figure 2. Instruments used typically in Consummatory Successive Negative Contrast and in instrumental Successive Negative Contrast. .......................................................... 7 Figure 3. Representation of typical results obtained in a Consummatory Successive Negative Contrast. ............................................................................................................ 8 Figure 4. Figure represents the mean licks per session during the days and considering the type of the devaluation.............................................................................................. 12 Figure 5. The image represents the activation map of negative affect, pain and cognitive control measured by a PET procedure. ........................................................................... 15 Figure 6. PET neuroimaging in a block of reward task. ................................................ 16 Figure 7. Drug Effectiveness Ratio in Consummatory Successive Negative Contrast.. 25 Figure 8. Neuroimaging of sigma 1 receptor activity in repose and after [11C]SA4503 administration.. ............................................................................................................... 28 Figure 9. Link between psychological stress and cellular stress. .................................. 31 Figure 10. Formula for calculating the Drug Effectiveness Ratio.. ............................... 50 Figure 11. Procedure of von Frey Test. The von Frey filaments are exposed above the photograph. ..................................................................................................................... 51 Figure 12. Formula for pain withdrawal value. ............................................................. 52 Figure 13. Mean latency to reach the goal-box on each session in Experiment 1.. ....... 60 Figure 14. Von Frey test: mean (±SEM) sucrose consumption (ml) during the last preshift session (16) and either session 17 or 18 depending on the groups.................... 64 Figure 15. Threshold force (g) for paw withdrawal in the von Frey test during baseline sessions and either 5 or 300 min after sessions 17 or 18, depending on the groups. ..... 65 Figure 16. Hargreaves
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