Age modulates the effect of COMT genotype on delay discounting behavior

RATIONALE AND OBJECTIVE: A form of impulsivity, the tendency to choose immediate over delayed rewards (delay-discounting) has been associated with a single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (COMTval(158)met; rs4680). However, existing data regarding the nature of this association conflicts. We have previously reported that adults homozygous for valine (val) at the COMTval(158)met SNP demonstrate greater delay-discounting than do methionine (met) allele carriers (Boettiger et al. 2007). In contrast, a recent study of adolescent males found that those with the met/met genotype demonstrate greater delay-discounting than do val-allele carriers (Paloyelis et al. 2010). Based on reported age-related changes in frontal dopamine function and COMT expression, we hypothesized that the association of COMT genotype with delay-discounting behavior is modulated by age from late adolescence to young adulthood. METHODS: To test this hypothesis, we genotyped late adolescents (18–21 years; n=72) and adults (22–40 years; n=70) for the COMTval(158)met polymorphism, measured their delay-discounting behavior, and tested for an interaction between age group and COMT genotype. RESULTS: This cross-sectional study found that age modulates COMTval(158)met genotype effects on delay-discounting behavior. Among met-carriers, delay-discounting was negatively correlated with age from late adolescence to adulthood, while among val/val individuals delay-discounting was positively correlated with age across this range. CONCLUSIONS: These results confirm our previous finding of enhanced delay-discounting among val/val adults relative to met-allele carriers, and help reconcile existing literature. We propose a single U-shaped model of the relationship between frontal DA levels and impulsive choice that accounts for both adolescent and adult data

Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments.

Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders