In Vivo Association Between Alcohol Intoxication, Aggression, and Serotonin Transporter Availability in Nonhuman Primates

Heinz, Andreas; Higley, J. Dee; Gorey, Julia G.; Saunders, Richard C.; Jones, Douglas W.; Hommer, D.; Zajicek, Kristin B.; Suomi, Stephen J.; Lesch, Klaus‐Peter; Weinberger, Daniel R.; Linnoila, Markku

doi:10.1176/ajp.155.8.1023

Cited by 165 publications

(125 citation statements)

References 37 publications

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“…Accordingly, from our findings 5-HIAA and 5-HTT gene polymorphism I Kishida et al that there is higher 5-HIAA concentration in patients with the S/S genotype, it is reasonable to assume reduction of 5-HTT density, resulting in increased extracellular serotonin concentration owing to low activity of serotonin reuptake. This hypothesis is supported by previous studies among non-human primates (Heinz et al, 1998) and human males with alcohol dependence (Heinz et al, 2002), in which low serotonin transporter availability in the brainstem was associated with elevated 5-HIAA concentrations. On the other hand, a recent study reported no difference in the 5-HTT binding potential by genotypes in healthy volunteers and in MDDs (Parsey et al, 2006).…”

Section: Discussionsupporting

confidence: 80%

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Kishida

Aklillu

Kawanishi

et al. 2007

Neuropsychopharmacol

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The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p ¼ 0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p ¼ 0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p ¼ 0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p ¼ 0.0001) and L/S (p ¼ 0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p ¼ 0.002) and L/S subjects (p ¼ 0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.

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Section: Discussionsupporting

confidence: 80%

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Kishida

Aklillu

Kawanishi

et al. 2007

Neuropsychopharmacol

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“…18 In a previous study with a small sample 19 (n = 11), we found no significant contribution of the rh5-HTTLPR genotype to availability of brainstem 5-HTT measured by ␤-CIT binding. The primary purpose of the study reported here was to provide a direct test of the association between the rh5-HTTLPR and CNS serotonin (5-HT) functioning, as measured by cerebrospinal fluid concentrations (CSF) of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), using a large sample of rhesus monkeys.…”

mentioning

confidence: 52%

Early experience and serotonin transporter gene variation interact to influence primate CNS function

et al. 2002

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Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

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“…Heinz et al, 1998 PR (n ϭ 10) vs. humans, heritability accounts for about 35% of this variance, and environmental factors play a very important role in the regulation of the serotonin turnover rate (Beck et al, 1984;Oxenstierna et al, 1986). Environmental factors are of special interest if they have long-lasting effects on serotonergic neurotransmission, as has been shown following early social separation stress (Clarke et al, 1996;Higley et al, 1991;G.…”

Section: Infant Rhesus Macaquesmentioning

confidence: 99%

Serotonergic dysfunction: Brain imaging and behavioral correlates

Wrase

Reimold

Puls

et al. 2006

Cognitive, Affective, & Behavioral Neuroscience

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In Vivo Association Between Alcohol Intoxication, Aggression, and Serotonin Transporter Availability in Nonhuman Primates

Abstract: In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.

Cited by 165 publications

References 37 publications

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Early experience and serotonin transporter gene variation interact to influence primate CNS function

Serotonergic dysfunction: Brain imaging and behavioral correlates

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