Affective startle modulation : psychopharmacological studies on the roles of CRF and serotonin in the regulation of emotions

Abstract

Major depression and anxiety disorders are the most prevalent psychiatric disorders. The high co-morbidity and strong overlap in symptoms suggest that neurobiological mechanisms may also overlap. Two neuromodulators have received much attention. First, serotonin: Selective serotonin reuptake inhibitors, which target the serotonin system, are currently pharmacological treatment of choice for both depression and anxiety. Second, corticotropin-releasing factor (CRF), which is a key regulator in the neuroendocrine and behavioural responses to stress., is suggested to play a role in the development of psychiatric illness following chronic stress This thesis focused on one characteristic, which is evident in both depression and anxiety, namely disturbed affect regulation. The acoustic startle response was used to study affect regulation, as this response can be modulated by emotional stimuli: pleasant stimuli attenuate the startle response, whereas aversive stimuli potentiate the startle response. In psychiatric patients, changes in affective startle modulation have already been shown. However, how changes in affective state influence affective startle modulation in rodents has hardly been studied. Therefore, the aims of this thesis were to 1. Evaluate how changes in affective startle influence affective startle modulation in rodents. And 2. Further study the involvement of corticotropin-releasing factor and serotonin in affect regulation. The data presented in this thesis shows that affective startle modulation shows high translational value. Similar to what is seen in depressed patients, emotional numbing is reflected in blunted affective startle modulation in rodent models for affective disorders. In addition, a negative affective state results in exacerbation of specific forms of aversive startle modulation, depending on the manipulation used to induce this negative affective state. A positive affective state, on the other hand, results in attenuation of aversive startle modulation. In this thesis, both a pharmacological and genetic approach were used to modulate CRF and serotonin signalling. The data further underlined the involvement of both neuromodulators in affect regulation first of all, repeated local corticotropin-releasing factor infusion resulted in exacerbation of different types of negative affect (fear or anxiety) later in life, depending on the brain area targeted. This suggests that individual differences in sensitivity of certain brain areas to the effects of CRF, may determine which systems are affected by chronic stress and, consequently, which psychiatric symptoms develop. In addition, deletion of the serotonin transporter resulted in maladaptive fear responses, similar to those seen in panic disorder patients., suggesting that the serotonin transporter may be important in symptom exacerbation in these patients. The high translational value of affective startle models makes these models very useful in studying the brain systems involved in the regulation of affective state. In addition, the studies described in this thesis show that corticotropin-releasing factor and serotonin play an important role in affect regulation