Associations between the angiotensin-converting enzyme insertion/deletion polymorphism and monoamine metabolite concentrations in cerebrospinal fluid
Introduction
Serotonin, dopamine and noradrenaline are monoaminergic neurotransmitters of importance for numerous psychiatric disorders. Measurement of cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA), and the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) has been used in many studies as an indirect way to assess the central turnover of these compounds (Agren, 1980, Asberg and Traskman, 1981). Studies of human twins indicate that CSF levels of 5-HIAA, HVA and MHPG are under both genetic and environmental influence (Oxenstierna et al., 1986). In addition, in rhesus monkeys (Higley et al., 1993) and baboons (Rogers et al., 2004), CSF levels of 5-HIAA, HVA and MHPG are shown to be largely, but not exclusively, determined by genetic factors.
The renin angiotensin system (RAS) appears to exert a complex influence on brain dopaminergic transmission. In rat striatum, where dopaminergic neurons express angiotensin II (Ang II) type 1 (AT1) receptors (Allen et al., 1992), administration of Ang II induces an increase in extracellular levels of dopamine (in the presence of a dopamine reuptake inhibitor), as well as in the formation of the dopamine metabolites HVA and DOPAC, suggesting Ang II to exert mainly a stimulatory influence on dopamine transmission (Jenkins et al., 1997a, Jenkins, 2008). On the other hand, the same authors have shown angiotensin-converting enzyme (ACE) inhibitors, which should reduce the formation of Ang II, to enhance dopamine release and turnover (Jenkins et al., 1997b, Jenkins, 2008), effects that may have a bearing on the mood-lifting (Gard, 2004) and anti-Parkinson (Reardon et al., 2000) actions that have been attributed to these antihypertensive agents. Moreover, in addition to exerting acute effects on dopamine release and turnover, angiotensin II has been reported not only to facilitate the formation of dopaminergic nerve cells (Rodriguez-Pallares et al., 2004), but also to promote oxidative stress-induced degeneration of dopamine neurons (Munoz et al., 2006).
The interaction between angiotensin and serotonin is less well studied. It has however been shown that angiotensin II reduces central serotonin release in rats (Tanaka et al., 2003, Voigt et al., 2005), and that an AT1 receptor antagonist enhances serotonin formation (Jenkins, 2008).
A polymorphism in the ACE gene constituted by an insertion (I)/deletion (D) of 287 nucleotides in intron 16 has been reported to account for about half of the phenotypic variance in serum ACE levels. Subjects homozygous for the long allele (I/I) display the lowest concentrations; subjects homozygous for the short allele (D/D) display the highest; and heterozygous subjects (I/D) display ACE concentrations in between (Rigat et al., 1990). Whereas numerous studies have been published suggesting the ACE I/D polymorphism to be associated with cardiovascular function and dementia (Sayed-Tabatabaei et al., 2006), an increasing body of evidence suggests that it may also be associated with psychiatric conditions such as panic disorder (Olsson et al., 2004), depression (Baghai et al., 2006), schizophrenia (Crescenti et al., 2009) and suicide (Sparks et al., 2009), hence emphasising the importance of possible interactions between RAS and monoaminergic transmission. To our knowledge, no studies have however been published assessing the possible association between the AC I/D polymorphism and endophenotypes reflecting monoaminergic activity.
Prompted i) by the studies suggesting the ACE I/D polymorphism to be associated with serotonin- and dopamine-related psychiatric disorders, ii) by the animal experiments revealing interactions between RAS on the one hand, and serotonin and dopamine transmission on the other and iii) the tentative mood-lifting effect of drugs counteracting angiotensin activity, we deemed it of interest to explore to what extent the ACE I/D polymorphism may influence monoamine metabolite concentrations in lumbar CSF. To this end, we first investigated possible associations between this polymorphism and CSF concentrations of 5-HIAA, HVA and MHPG in a population comprising healthy male subjects. After having found significant associations in this group, we tried to replicate this observation using a sample comprising violent male offenders from which also both CSF and DNA were available. The associations found in the first sample were also present in the second one.
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Ethical considerations
All investigations were carried out in accordance with the Declaration of Helsinki. The Ethics Committee of the Karolinska Hospital, Stockholm, approved the part of the study concerning healthy volunteers, and the Ethics Committee of Göteborg University, Göteborg, approved the part concerning violent offenders. Informed consent was obtained from all participants after the nature of the procedures had been fully explained.
Healthy males
Healthy Caucasian men (n = 46) were recruited predominately among students
Healthy males
There was no significant deviation from the Hardy–Weinberg equilibrium (data not shown). The ACE I/D polymorphism was significantly associated with CSF levels of 5-HIAA (F = 12.4, R2 = 0.22, P = 0.001) and HVA (F = 5.9, R2 = 0.12, P = 0.02), but not MHPG (F = 1.9, R2 = 0.04, P = 0.17) (Table 1). 5-HIAA and HVA concentrations correlated significantly with each other (F = 84.955, R2 = 0.659, P < 0.001). When we correlated ACE I/D with 5-HIAA and controlled for HVA using partial correlation, the correlation remained
Discussion
In the present study, associations were found between the functional ACE I/D polymorphism and CSF levels of 5-HIAA and HVA, respectively, in a group of healthy men. Supporting this association to be genuine, and not accidental, it was replicated in a small group of male violent offenders.
The observed association between ACE I/D and CSF levels of HVA is in line with the notion that ACE modulates dopamine levels (see Introduction). If one assumes ACE activity to be lower in I/I carriers, the
Acknowledgements
This study was supported by the Lundberg Foundation, The Söderberg Foundation, The Bertil Hållsten Foundation, The Swedish Brain Foundation, The Swedish Brain Power Initiative, the Swedish Lundbeck foundation, the Swedish Research Council (8668, 2006-2992, 2006-986), the Wallenberg Foundation and the HUBIN project. Gunilla Bourghardt, Inger Oscarsson, Alexandra Tylec and Kjerstin Lind are gratefully acknowledged for their excellent technical assistance.
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