d -Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice

Huotari, Marko; Garcı́a-Horsman, J. Arturo; Karayiorgou, Maria; Gogos, Joseph A.; Männistö, Pekka T.

doi:10.1007/s00213-003-1627-3

Cited by 55 publications

(42 citation statements)

References 36 publications

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“…Although local effects of COMT in the ventral striatum have been hypothesized (13), current evidence (17) favors an explanation based on prefrontal regulation of striatal DA metabolism via top-down projections (16).…”

Section: Discussionmentioning

confidence: 87%

“…COMT is known to regulate extrasynaptical DA breakdown, which is mainly true for the prefrontal cortex (PFC), where COMT is relatively more abundant than in the striatum (16). COMT might also have a small, local effect in DA metabolism in the striatum (17). More importantly, an interaction between prefrontal COMT and subcortical function has been suggested (12), probably mediated by excitatory glutamatergic efferents from the PFC to the striatum, which are thought to translate a high prefrontal into a high striatal dopaminergic tone (13).…”

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confidence: 99%

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Gene–gene interaction associated with neural reward sensitivity

Yacubian

Sommer

Schröeder

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

216

182

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Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/ Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.is critical to motivational and reward-related functions of the brain, including adaptation through reinforcement learning (1, 2) and decision making (3). Considerable interindividual differences with respect to decision making have been observed (4), and it has been speculated that genetic variability in the dopaminergic system could be related to these differences (5, 6). In addition, interindividual variation in dopaminergic function has been hypothesized as a major factor contributing to inheritable personality traits (7) and addiction (8). However, little is known about how variation in DA-related genes modulates the described physiological properties of the dopaminergic reward system (1-3, 9, 10) and how such physiological variation affects reward processing. To bridge this gap between genetics and behavior, we combined genetics and personality assessment with fMRI measures of brain activation as an intermediate (endo)phenotype (11,12), an approach based on the assumption that brain activation is causally more directly linked to genotype than is behavior (12).In the study of individual differences in DA system physiology, a useful conceptual distinction is often made between tonic and phasic dopaminergic neurotransmission (13,14). In the striatum, a basal level of extracellular DA results from tonic, slow, and irregular ''background'' firing of dopaminergic neurons originating in the ventral tegmental area. By contrast, burst firing of ventral tegmental area neurons induces phasic DA release, a me...

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

Gene–gene interaction associated with neural reward sensitivity

Yacubian

Sommer

Schröeder

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

216

182

View full text Add to dashboard Cite

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“…Further studies in the COMT knockout mice, using cocaine, GBR 12909 (a dopamine transporter inhibitor), levodopa, or amphetamine, showed that some but not all neurochemical and behavioral responses to these pharmacological challenges are sex specific (Huotari et al, 2002a(Huotari et al, , b, 2004see also O'Tuathaigh et al, 2007). For example, d-amphetamine administration affected dopamine metabolism equally in male and female knockout mice (Huotari et al, 2004), whereas hyperactivity in response to GBR 12909 was attenuated only in male mice (Huotari et al, 2002b).…”

Section: Comt and Sexual Dimorphismsmentioning

confidence: 99%

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Harrison

Tunbridge

2007

Neuropsychopharmacol

273

217

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Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val 158 Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

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“…The quantitative contribution of COMT to dopamine degradation is under debate, with several studies suggesting that its role is secondary to that of dopamine reuptake and oxidation by monoamine oxidase A and B (Budygin et al, 1999;Huotari et al, 2002Huotari et al, , 2004. These studies have focused on dopamine metabolism in the striatum in which DAT1 expression is abundant.…”

Section: Effects Of Comt Val108/158met Genotype On Memoryrelated Braimentioning

confidence: 99%

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

et al. 2006

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Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.

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d -Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice

Cited by 55 publications

References 36 publications

Gene–gene interaction associated with neural reward sensitivity

Gene–gene interaction associated with neural reward sensitivity

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

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