The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

Breg Braak 0 1 3 Jan Booij 0 1 3 Tamira K. Klooker 0 1 3 Rene M. J. van den Wijngaard 0 1 3 Guy E. E. Boeckxstaens 0 1 3 0 R. M. J. van den Wijngaard Tytgat Institute of Liver and Intestinal Research, Academic Medical Center , Amsterdam, The Netherlands 1 J. Booij Department of Nuclear Medicine, Academic Medical Center , Amsterdam, The Netherlands 2 ) Department of Gastroenterology, University Hospital Leuven, Catholic University Leuven , Herestraat 45, Leuven 3000, Belgium 3 G. E. E. Boeckxstaens ( Purpose Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. Methods In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [123I] IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. Results The HV subjects comprised 12 women and 8 men (mean age 31 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 5 years). The FD patients had a lower left plus right average striatal binding potential (BPNP) for the caudate nucleus (p 0 0.02), but not for putamen (p 0 0.15), which in the FD patients was correlated with maximal ingested volume (r 0 0.756, p 0 0.03). The D2R BPNP in the putamen was correlated with nausea (r 0 0.857, p 0 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. Conclusion These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathways. - Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. These symptoms include pain, early satiety, fullness, bloating and nausea, and are usually related to food intake [1]. Dyspeptic patients have increased sensitivity to distension of the proximal stomach [2] and impaired relaxation of the stomach after food intake [3]. However, the underlying mechanisms giving rise to gastric dysfunction and dyspeptic symptoms remain to be unravelled. Stress is generally accepted as an important factor triggering or exacerbating dyspeptic symptoms [4]. In rodents, acute stress has been associated with stress-induced visceral analgesia [5], possibly by interfering with the processing of sensory information in the brain. In the brain, pain, pleasure and motivation (emotional cognitive function) are processed in the mesolimbic system, including the ventral tegmental area, nucleus accumbens and anterior cingulate cortex. In particular because these brain areas are rich in dopamine D2 receptors (D2Rs) and activated by the neurotransmitter dopamine [6], dopaminergic pathways are considered important in the regulation of (visceral) pain [7]. Moreover, stress is known to have a detrimental impact on the normal function of the dopaminergic system [8]. Both acute and chronic stress are able to influence levels of dopamine and dopamine receptor function in rodents. However, the association between changes in the dopaminergic system and visceral pain perception has not been investigated. Another key factor in the regulation of gut physiology, and the interaction with the brain, is the serotonergic (5-HTergic) neurotransmission system. It has been suggested that 5-HT1A receptor hypersensitivity may play a role in FD, which was supported by an increased release of prolactin (PRL) after challenge with buspirone, an agonist of this receptor [9]. However, buspirone is not only an agonist for 5-HT1A receptors, but also a partial antagonist for dopamine D2Rs [10]. Inhibition of D2Rs can stimulate the release of PRL as well. In chronic pain disorders, which are associated with a hypodopaminergic system [11] and are related to FD [12], an increased release of PRL, but not of growth hormone, has been observed after a buspirone challenge test. While the release of growth hormone by buspirone is only mediated by stimulation of the 5-HT1A receptor, is has been suggested that the increased release of PRL is a dopaminergic and not a 5-HT-ergic effect [10]. In addition, in FD, subsequent brain imaging PET studies have shown increased activation of the mesolimbic system (among others in the cingulated cortex) and deactivation of the pregenual anterior cingulate after gastric distension [7, 13]. All these pain-related brain areas are rich in D2Rs and (de)activation of brain areas might correspond to a hypodopaminergic system. Based on the above, we hypothesized that abnormalities in the central dopaminergic system could be involved in the pathogenesis of FD. We therefore first analysed the in vivo expression of central D2Rs using [123I]iodobenzamide ([123I]IBZM) SPECT in FD patients compared to that in age- and gender-matched healthy volunteers (HV) [14]. In addition, the response of the dopaminergic system to an acute, but reversible, dopamine depletion was investigated using the well-validated alpha-methyl-para-tyrosine (AMPT) challenge test [15]. The advantage of this test is, in contrast to buspirone, that AMPT only interferes with the catecholaminergic system. Finally, on a separate day all participants underwent a nutrient drink test to investigate the correlation between maximal ingested volume, evoked symptoms and the central D2Rs. Materials and methods Study population Patients aged 18 to 65 years with a diagnosis of FD as defined by the Rome III criteria [1] were recruited from the gastrointestinal motility unit of the Academic Medical Centre (AMC). Dyspeptic symptoms were scored using the Nepean Dyspepsia Index (NDI) questionnaire [16], a validated method to assess FD symptoms. Based on previous studies, only patients with a NDI score of >25 were included [16, 17]. All patients underwent a careful history, physical examination, upper endoscopy, blood investigation (including thyroid-stimulating hormone, white blood cell count, Creactive protein) and abdominal ultrasonography. The HV subjects, recruited by public advertisement, were included if their NDI score was 5. Subjects with depression, as diagnosed with a score of >50 on the Zung self-rating depression scale [18] and with concomitant diseases, such as diabetes mellitus, epilepsy (...truncated)