22 Chapter 1 REVIEW ETIOPATHOLOGY OF AN The pathophysiology of AN remains unknown. It is unclear whether there is a primary disturbance of appetite, or whether the disturbed appetite is secondary to other phenomena, such as body image disturbance, or anxiety (41). The aetiology of eating disorders is considered multifactorial, with involvement of genetic factors (42-47), neurobiological factors, and temperamental vulnerabilities such as negative emotionality, poor intraceptive awareness, perfectionism and obsessive-compulsive personality traits (43, 48-50), that may interact with environmental factors resulting in an increased risk (41, 51). The neurobiology and neurocircuitries involved in AN are a main focus in today’s AN research. Of particular interest are the brain areas involved in registering the reward value and modulation of reward of food and the motivation to eat, considered to be located within the mesolimbic cortex and striatum (52, 53). Moreover, the brain areas involved in the cognitive control of eating and appetite, located in the dorsolateral prefrontal and parietal cortices may be involved in AN (41, 51). Neurotransmitters Results from positron-emission tomography (PET) studies indicate differences between subjects recovered from AN and healthy subjects in serotonin and dopamine receptor activity, indicating dysregulation of these systems involved in mood, anxiety, appetite and impulse control (41, 54). Several studies showed alterations in the serotonergic (5-HT)-system in AN. For example, Kaye et al. (2009) reported elevated 5-HT metabolite levels, as well as elevated binding potential for postsynaptic 5-HT1a receptors and diminished binding potential for 5-HT2a receptors in recovered AN patients (55-57). In contrast, ill AN patients were shown to have reduced amounts of the major 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA) (41). Finally, it has been found that a dietary-induced reduction of tryptophan, the precursor of serotonin, is associated with decreased anxiety in AN patients (58). Starvation may help AN patients to briefly reduce 5-HT activity and thus give symptom relief. These alterations in 5-HT function may be related to AN symptoms regarding inhibition of appetite, generalized inhibition, anxiety and obsessions through stimulation of 5-HT1a receptors. Several studies showed that ill and recovered AN patients also have altered striatal dopamine (DA) function. Kaye et al. (1999) found reduced levels of DA metabolites in the cerebrospinal fluid in ill and recovered AN patients (59). Frank et al. (2005) found that patients recovered from AN had increased D2/D3 receptor binding potential in the ventral striatum (VS), indicating either increased D2/D3 receptor density or decreased extracellular DA, or both (60). In addition, functional DA D2 receptor gene polymorphisms have been associated with AN (61) and subjects with AN have impaired visual discrimination learning, indicating altered DA neurotransmission
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