Neurobehavioral evidence for changes in dopamine system activity during adolescence

“Risk-taking increases during this time (Steinberg, 2008), as does vulnerability to psychiatric disorders (Kessler et al., 2005; Paus et al., 2008).”

“Based on the observed diffusion patterns, inferences are made regarding the structural properties of the white matter within which the water molecules are located, given that water cannot diffuse in an unobstructed manner in the presence of barriers to diffusion (Basser et al., 1994).”

“The remainder of the cortex develops in a parietal to frontal direction with the superior temporal cortex maturing last (Gogtay et al., 2004).”

“As this elimination is occurring, there are concomitant increases in white matter volume and density (Bartzokis et al., 2008; Giedd et al., 1999; Paus et al., 2001; Pfefferbaum et al., 1994).”

“Furthermore, a number of recent studies have received considerable interest because they demonstrate that early life experiences modify the risk for future psychopathology conferred by genetic polymorphisms (Arseneault et al., 2002; Caspi et al., 2002).”

“D1-like receptors can be differentiated from D2-like receptors because of their ability to stimulate adenylyl cyclase activity and increase cyclic adenosine monophosphate (cAMP), which results in an overall excitatory effect within the cell (Kebabian and Calne, 1979).”

“Risk-taking increases during this time (Steinberg, 2008), as does vulnerability to psychiatric disorders (Kessler et al.”

“Risk-taking increases during this time (Steinberg, 2008), as does vulnerability to psychiatric disorders (Kessler et al., 2005; Paus et al., 2008).”

“This effect has been demonstrated and replicated in healthy volunteers and schizophrenic patients (Bilder et al., 2002; Egan et al., 2001; Mattay et al., 2003; though for a recent meta-analysis that suggests the effect of COMT holds in healthy control samples only, see Barnett et al., 2007a,b).”

“For instance, human neuroimaging studies indicate decreases in cortical gray matter during adolescence (Giedd et al., 1999; Giedd, 2004; Gogtay et al., 2004; Gogtay and Thompson, 2010; Jernigan et al., 1991; Luders et al., 2005; Thompson et al., 2005; Sowell et al., 2003).”

“Theories abound to explain these patterns, most of which suggest that adolescent behavior patterns are attributable to changes in brain maturation during this period of the lifespan (Casey et al., 2008; Fareri et al., 2008; Steinberg, 2008).”

“The density of catecholaminergic appositions on individual pyramidal cells in the PFC of rhesus monkeys increases gradually until 2 years and plateaus thereafter (Lambe et al., 2000).”

“Several major cell groups have been identified (Bjorklund and Dunnett, 2007), which are located mainly in mesence-”

“Consistent with DA’s role in modulating excitatory cortical circuits, DA release is thought to aid cognitive performance by increasing neural signal-to-noise ratios (Chambers et al., 2003; Sawaguchi et al., 1990; Thurley et al., 2008).”

“decreases in cortical gray matter during adolescence (Giedd et al., 1999; Giedd, 2004; Gogtay et al., 2004; Gogtay and Thompson, 2010; Jernigan et al., 1991; Luders et al., 2005; Thompson et al., 2005; Sowell et al., 2003).”

“That is, there is an optimal level of dopamine availability in relation to cognitive function (Williams and Goldman-Rakic, 1995).”

“…that increases in white matter integrity are associated with better performance on measures of general intelligence (Schmithorst et al., 2005; Shaw et al., 2006), delay discounting (Olson et al., 2008), interhemispheric transfer (Muetzel et al., 2008), working memory (Nagy et al., 2004;…”

“Furthermore, a number of recent studies have received considerable interest because they demonstrate that early life experiences modify the risk for future psychopathology conferred by genetic polymorphisms (Arseneault et al., 2002; Caspi et al., 2002).”

“…BarneaGoraly et al., 2005; Ben Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et…”

“On the one hand, more focal activation in brain regions in response to task demands have been interpreted to reflect more efficient neural processing (see Mattay et al., 2003), whereas other data suggest that activation increases as a function of learning and practice (Karni et al., 1998).”

“As this elimination is occurring, there are concomitant increases in white matter volume and density (Bartzokis et al., 2008; Giedd et al., 1999; Paus et al., 2001; Pfefferbaum et al., 1994).”

“…(Asato et al., 2006; Luciana et al., 2009), concept formation (Chelune and Baer, 1986), working memory (Conklin et al., 2007; De Luca et al., 2003; Luna et al., 2004; Luciana et al., 2005), inhibitory control (Hooper et al., 2004; Luna et al., in press), delay discounting (Olson et al., 2008;…”

“…are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004; Levin et al., 1991; Ridderinkhof and van der Molen, 1997; Welsh et al., 1991).”

“The mesocortical DA system includes the transitional entorhinal, cingulate, and orbitofrontal cortices as well as dorsolateral PFC (Goldman-Rakic, 1987; Beckstead et al., 1979).”

“For example, despite activating a similar network of neural structures, adolescents generate larger BOLD activation in the nAcc compared to adults and young children when presented with rewarding stimuli (Ernst et al., 2005; Galvan et al., 2006; May et al., 2004).”

“When the age of maturation is reached varies by task demand (Luciana et al., 2005; Steinberg et al., 2009a,b) and may depend on the amount or complexity of information that has to be processed within a given context (Luciana et al., 2005).”

“Heterozygotes may exhibit intermediate levels of DA, as the alleles are codominant (Lotta et al., 1995; Weinshilboum and Raymond, 1977).”

“In the context of healthy aging, several cognitive processes are known to decline, notably processing speed, working and episodic memory, and fluid reasoning skills (Verhaegen and Salthouse, 1997).”

“relatively the same size in females (Giedd et al., 1996).”

“However, there are clear differences in adult level prefrontal structure and function between primates and rodents, with the former exhibiting both increased cerebral differentiation and more complex cognitive functioning (Preuss and Kaas, 1999; Uylings et al., 2003).”

“Conversely, COMT catalyzes catecholamines and appears to be most important in the PFC (Gogos et al., 1998), since COMT knockout mice exhibit increases in PFC DA despite unchanged striatal levels.”

“As this elimination is occurring, there are concomitant increases in white matter volume and density (Bartzokis et al., 2008; Giedd et al., 1999; Paus et al., 2001; Pfefferbaum et al., 1994).”

“…first step in the catabolism of excess synaptic DA with some specificity to the PFC due to a lack of DA transporter activity in this region (Giros et al., 1996; Gogos et al., 1998; Huotari et al., 2002; Lewis et al., 2001; Napolitano et al., 1995; Sesack et al., 1998; Weinshilboum et al., 1999).”

“These studies, along with findings from human autopsy studies, indicate age-related declines in D1 and D2 receptor numbers, the DA transporter, and DA cells in the midbrain and striatum (Volkow et al., 1998).”

“Specifically, the Met allele may be related to higher tonic levels of subcortical DA, and, by association, decreased subcortical phasic amplitude in response to neuronal firing and increased cortical D1 transmission (Bilder et al., 2004).”

“These patterns indicate that the DA system is patterning itself in a manner during adolescence that could support functional changes in behaviors that are DA-modulated.”

“Autoradiographic techniques in rats have demonstrated D1 and D2 binding in the forebrain, striatum, nucleus accumbens (nAcc), olfactory tubercles, and substantia nigra (SN), with D1 density higher in all areas assessed (Boyson et al., 1986).”

“…have been observed (Ashtari et al., 2007; BarneaGoraly et al., 2005; Ben Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and…”

“Depending on the task, performance improves into the late teens and perhaps early twenties (De Luca et al., 2003; Luciana et al., 2009; Steinberg et al., 2009a,b).”

“Some of the most prominent within the literature include the COMT108/158Val-Met single nucleotide polymorphism (SNP) (Grossman et al., 1992), dopamine transporter (DAT1) variable number of tandem repeats (VNTR) (Vandenbergh et al., 1992), the Taq1A SNP, which appears to impact the D2 receptor system (Neville et al., 2…”

“as well as psychiatric disorders such as ADHD, schizophrenia, and alcoholism (Brookes et al., 2006; Shifman et al., 2002).”

“For example, despite activating a similar network of neural structures, adolescents generate larger BOLD activation in the nAcc compared to adults and young children when presented with rewarding stimuli (Ernst et al., 2005; Galvan et al., 2006; May et al., 2004).”

“1992), the Taq1A SNP, which appears to impact the D2 receptor system (Neville et al., 2004; Noble, 2003), D3 receptor Ser9Gly SNP (Crocq et al.”

“It should also be mentioned at the outset that not all models adhere to the formulation that motivational circuits are in a state of over-drive; some propose that the opposite is true (Comings and Blum, 2000; Volkow et al., 2007).”

“, 1996), and all have been linked to DAmediated behaviors (Malhotra et al., 2002; Bellgrove et al., 2005),”

“Initially, DA projections from the midbrain to the striatum are undifferentiated, but nigrostriatal and mesolimbic specificity is established sometime between E15 and birth (Hu et al., 2004), as are projections to the PFC and ACC (Berger et al., 1991).”

“DA transporters are abundant in subcortical regions but virtually absent in the PFC (Sesack et al., 1998).”

“…are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004; Levin et al., 1991; Ridderinkhof and van der Molen, 1997; Welsh et al., 1991).”

“A wealth of evidence suggests that COMT is associated with performance on working memory (Goldberg et al., 2003) and executive set-shifting tasks such as the Wisconsin Card Sort (Malhotra et al., 2002), with the Met allele typically conferring relatively better performance.”

“When the age of maturation is reached varies by task demand (Luciana et al., 2005; Steinberg et al., 2009a,b) and may depend on the amount or complexity of information that has to be processed within a given context (Luciana et al., 2005).”

“Gray matter volumes may peak earlier in males versus females in most cortical regions (Lenroot and Giedd, 2010).”

“…first step in the catabolism of excess synaptic DA with some specificity to the PFC due to a lack of DA transporter activity in this region (Giros et al., 1996; Gogos et al., 1998; Huotari et al., 2002; Lewis et al., 2001; Napolitano et al., 1995; Sesack et al., 1998; Weinshilboum et al., 1999).”

“…functions that have been linked to prefrontal substrates are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004; Levin et al., 1991;…”

“as well as psychiatric disorders such as ADHD, schizophrenia, and alcoholism (Brookes et al., 2006; Shifman et al., 2002).”

“Part of DA’s role in these developmental processes might relate to nerve growth given that DA cells contain neuro-trophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (Seroogy et al., 1994; Tucker et al., 2001).”

“This finding is most reliably demonstrated in the caudate and putamen (Gelbard et al., 1989; Giorgi et al., 1987; Tarazi et al., 1999; Teicher et al., 1995), although other studies suggest that D1 binding in the dorsal striatum increases to adult levels in periadolescence and then stabilizes, as…”

“1992), the Taq1A SNP, which appears to impact the D2 receptor system (Neville et al., 2004; Noble, 2003), D3 receptor Ser9Gly SNP (Crocq et al.”

“It should also be mentioned at the outset that not all models adhere to the formulation that motivational circuits are in a state of over-drive; some propose that the opposite is true (Comings and Blum, 2000; Volkow et al., 2007).”

“2 deletion syndrome, which is caused by a hemizygous deletion in a small region of chromosome 22 that contains the COMT gene and results in debilitating cognitive impairments and a significant increase in the risk for schizophrenia (Bassett and Chow, 1999; Scambler, 2000).”

“degree of burst activity of DA neurons, the amount of DA turnover, the sensitivity to DA agonists and antagonists, the absence of impulse-and nerve-terminal autoreceptors, and the development of tolerance following chronic neuroleptic administration (Bannon and Roth, 1983; Bjorklund and Dunnett, 2007; Tam and Roth, 19…”

“, 2003), inhibitory control (Liston et al., 2006), and reading ability (Qiu et al.”

“D1 density appears to be higher compared to D2 density in limbic and cortical regions (Hall et al., 1994), although the densities of both receptor types are greater in striatal and limbic regions as compared to the cortex (Meador-Woodruff et al., 1991).”

“Additionally, adolescents exhibit unique patterns of amygdala activation when emotional facial expressions are viewed (Baird et al., 1999; Thomas et al., 2001).”

“, 2009), concept formation (Chelune and Baer, 1986), working memory (Conklin”

“decreases in cortical gray matter during adolescence (Giedd et al., 1999; Giedd, 2004; Gogtay et al., 2004; Gogtay and Thompson, 2010; Jernigan et al., 1991; Luders et al., 2005; Thompson et al., 2005; Sowell et al., 2003).”

“D1 density appears to be higher compared to D2 density in limbic and cortical regions (Hall et al., 1994), although the densities of both receptor types are greater in striatal and limbic regions as compared to the cortex (Meador-Woodruff et al.”

“…transporter genes are also likely candidates for analysis, because individual differences in SNPs associated with these genes have been linked to variations in personality traits, externalizing behaviors, and higher-order cognition (DeYoung et al., 2006; Durston et al., 2008; Munafo et al., 2008).”

“A majority of DA terminals in layer III form synapses with pyramidal neurons, which have been implicated in the maintenance of working memory (Goldman-Rakic, 1998) and are the primary source of afferent projections to other cortical regions (Goldman-Rakic et al., 1989; Jones, 1984).”

“These decreases have been attributed to increases in myelination or axonal caliber (Paus, 2010), support-”

“…(Chelune and Baer, 1986), working memory (Conklin et al., 2007; De Luca et al., 2003; Luna et al., 2004; Luciana et al., 2005), inhibitory control (Hooper et al., 2004; Luna et al., in press), delay discounting (Olson et al., 2008; Steinberg et al., 2009b) and motivated decision-making as…”

“The effect sizes of individual polymorphisms on behavior are often small (Barnett et al., 2007a,b), and meta-analyses attempting to link COMT to cognition or psychopathology have sometimes resulted in null findings (Barnett et al., 2008; Munafó et al., 2005).”

“…are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004; Levin et al., 1991; Ridderinkhof and van der Molen, 1997; Welsh et al., 1991).”

“Adolescence is a transitional period between childhood and adulthood characterized by behavioral, hormonal, and neurochemical changes designed to prepare organisms for independent survival (Casey et al., 2008; Doremus-Fitzwater et al., 2010; Spear, 2003).”

“, 2008), working memory (Nagy et al., 2004; Olesen et al., 2003), inhibitory control (Liston et al.”

“A majority of DA terminals in layer III form synapses with pyramidal neurons, which have been implicated in the maintenance of working memory (Goldman-Rakic, 1998) and are the primary source of afferent projections to other cortical regions (Goldman-Rakic et al., 1989; Jones, 1984).”

“…of adolescents have suggested that increases in white matter integrity are associated with better performance on measures of general intelligence (Schmithorst et al., 2005; Shaw et al., 2006), delay discounting (Olson et al., 2008), interhemispheric transfer (Muetzel et al., 2008), working…”

“In a sample of 8–14 year-old children (mean age = 9), Diamond et al. (2004) demonstrated that the Met allele was associated with a test of inhibition previously shown to depend on prefrontal DA.”

“…functions that have been linked to prefrontal substrates are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004; Levin et al., 1991;…”

“These projections have been labeled collectively as the ‘‘mesolimbic’’ DA pathway (Moore and Bloom, 1978; Oades and Halliday, 1987; Simon et al., 1980).”

“In addition, either smaller (Esher et al., 2007) or less focally distributed (Galvan et al., 2006) activations in response to reward presentation have been demonstrated in the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), indicating that increased subcortical activity might be…”

“…in nigrostriatal regions due to the relative ease through which biomarkers of DA availability can be measured in the striatum during Positron Emission Tomography (PET) scans and SPECT imaging (Bäckman et al., 2006; Kaasinen et al., 2000; Suhara et al., 1991; Volkow et al., 1994, 2000, 2004).”

“…first step in the catabolism of excess synaptic DA with some specificity to the PFC due to a lack of DA transporter activity in this region (Giros et al., 1996; Gogos et al., 1998; Huotari et al., 2002; Lewis et al., 2001; Napolitano et al., 1995; Sesack et al., 1998; Weinshilboum et al., 1999).”

“…Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et al., 2005, 2007; Zhang et al., 2005).”

“decreases in cortical gray matter during adolescence (Giedd et al., 1999; Giedd, 2004; Gogtay et al., 2004; Gogtay and Thompson, 2010; Jernigan et al., 1991; Luders et al., 2005; Thompson et al., 2005; Sowell et al., 2003).”

“…approaches, executive functions that have been linked to prefrontal substrates are evident late in infancy, coincident with independent locomotion (Bell and Fox, 1992; Diamond, 1990a,b) and show a steady course of improvement through childhood (Luciana and Nelson, 2002; Kerr and Zelazo, 2004;…”

“…of PFC-mediated behaviors including planning (Asato et al., 2006; Luciana et al., 2009), concept formation (Chelune and Baer, 1986), working memory (Conklin et al., 2007; De Luca et al., 2003; Luna et al., 2004; Luciana et al., 2005), inhibitory control (Hooper et al., 2004; Luna et al., in…”

“Similar to innervation patterns, receptor densities in the cortex increase throughout adolescence (Tarazi and Baldessarini, 2000).”

“This effect has been demonstrated and replicated in healthy volunteers and schizophrenic patients (Bilder et al., 2002; Egan et al., 2001; Mattay et al., 2003; though for a recent meta-analysis that suggests the effect of COMT holds in healthy control samples only, see Barnett et al., 2007a,b).”

“Conversely, area 4 is characterized by an adolescent peak in axonal length in layers I/II and III, while the number of varicosities peak during adolescence in all three cortical layers (Rosenberg and Lewis, 1995).”

“These cells migrate to the striatum by E15 (Voorn et al., 1986) and reach”

“Specifically, Gothelf et al. (2005) demonstrated that the Met allele predicts higher IQ in young adolescents (mean age 13 years) with 22q11.”

“2 deletion syndrome, which is caused by a hemizygous deletion in a small region of chromosome 22 that contains the COMT gene and results in debilitating cognitive impairments and a significant increase in the risk for schizophrenia (Bassett and Chow, 1999; Scambler, 2000).”

“When the age of maturation is reached varies by task demand (Luciana et al., 2005; Steinberg et al., 2009a,b) and may depend on the amount or complexity of information that has to be processed within a given context (Luciana et al., 2005).”

“However, others suggest that the available synaptic storage pool is increased in adolescence relative to both childhood and adulthood (Andersen et al., 1997; Stamford, 1989).”

“…this model predicts individual differences in neuroplasticity on the basis of genotype, and indeed, we observe that adolescents who carry the Met-Met genotype have a more protracted rate of working memory development than individuals with the Val-Met and Val-Val genotypes (Wahlstrom et al., 2010).”

“For example, DA may influence neuronal migration and differentiation given its modulation of growth cone activity and axonal outgrowth (Lankford et al., 1988).”

“Some of the most prominent within the literature include the COMT108/158Val-Met single nucleotide polymorphism (SNP) (Grossman et al., 1992), dopamine transporter (DAT1) variable number of tandem repeats (VNTR) (Vandenbergh et al., 1992), the Taq1A SNP, which appears to impact the D2 receptor system (Neville et al., 2…”

“Part of DA’s role in these developmental processes might relate to nerve growth given that DA cells contain neuro-trophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (Seroogy et al., 1994; Tucker et al., 2001).”

“Transgenic mice who over-express the Val polymorphism exhibit disrupted attentional set-shifting and show impairments in multiple forms of memory, including both working and recognition memory, as compared to mice with a null COMT mutation (Papaleo et al., 2008).”

“atomical perspective of assuming greater regulation over subcortical, primary sensory, and motor processing (Eluvathingal et al., 2007).”

“…in nigrostriatal regions due to the relative ease through which biomarkers of DA availability can be measured in the striatum during Positron Emission Tomography (PET) scans and SPECT imaging (Bäckman et al., 2006; Kaasinen et al., 2000; Suhara et al., 1991; Volkow et al., 1994, 2000, 2004).”

“They can be divided into ascending, descending, and local neuron systems (Fuxe et al., 1974).”

“age 2–3 years in the macaque); conversely, DA concentrations peak in the parietal cortex at age 5 months and do not exhibit any change after birth in the occipital cortex (Brown and Goldman, 1977; Goldman-Rakic and Brown, 1982).”

“, 2004; Noble, 2003), D3 receptor Ser9Gly SNP (Crocq et al., 1992), and the MAO-A tandem repeat (Zhu et al.”

“This effect has been demonstrated and replicated in healthy volunteers and schizophrenic patients (Bilder et al., 2002; Egan et al., 2001; Mattay et al., 2003; though for a recent meta-analysis that suggests the effect of COMT holds in healthy control samples only, see Barnett et al., 2007a,b).”

“As this elimination is occurring, there are concomitant increases in white matter volume and density (Bartzokis et al., 2008; Giedd et al., 1999; Paus et al., 2001; Pfefferbaum et al., 1994).”

“…that occur prenatally in non-human primates are protracted as compared to rodents, presumably to meet the needs of a more complicated neurochemical infrastructure as evidenced by the more widespread innervation and laminar-specific differences in density described above (Berger et al., 1988, 1991).”

“…as assessed through diffusion tensor imaging (DTI), have been observed (Ashtari et al., 2007; BarneaGoraly et al., 2005; Ben Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et…”

“…Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et al., 2005, 2007; Zhang et al., 2005).”

“…Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et al., 2005, 2007; Zhang et al., 2005).”

“…Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et al., 2005, 2007; Zhang et al., 2005).”

“COMT activity is lower in females compared to males (Boudikova et al., 1990); thus, females presumably exhibit higher DA levels in the PFC and would show no benefit from the Met allele, which pushes them into the excess range of the inverted-U and impairs their performance.”

“…patterns observed in adolescence, we and others have suggested that the dopamine system is of interest given its known role in modulationg reward responding, reinforcement learning, and high-level cognition (Frank and Hutchison, 2009; Schultz et al., 2008; Spear, 2003; Wahlstrom et al., 2010).”

“In rats, which have a total gestation of approximately 21 days, the neurogenesis of TH-containing cells in the mesencephalon begins on embryonic day (E) 12 (Altman and Bayer, 1981).”

“Both D1 and D2 receptors peak between 2 and 4 postnatal months in the developing rhesus monkey, with concurrent development occurring across prefrontal, motor, somatosensory, and visual cortices (Lidow et al., 1991; Lidow and Rakic, 1992).”

“Additionally, adolescents exhibit unique patterns of amygdala activation when emotional facial expressions are viewed (Baird et al., 1999; Thomas et al., 2001).”

“…Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 2007; Klingberg et al., 2000; Hasan et al., 2007; Lebel et al., 2008; Li and Noseworthy, 2002; Muetzel et al., 2008; Qiu et al., 2008; Schmithorst and Yuan, 2010; Schneider et al., 2004; Snook et al., 2005, 2007; Zhang et al., 2005).”

“…et al., 2005), inhibitory control (Hooper et al., 2004; Luna et al., in press), delay discounting (Olson et al., 2008; Steinberg et al., 2009b) and motivated decision-making as measured by gambling tasks (Crone and van der Molen, 2004; Hooper et al., 2004; Overman, 2004; Cauffman et al., in press).”

“…in nigrostriatal regions due to the relative ease through which biomarkers of DA availability can be measured in the striatum during Positron Emission Tomography (PET) scans and SPECT imaging (Bäckman et al., 2006; Kaasinen et al., 2000; Suhara et al., 1991; Volkow et al., 1994, 2000, 2004).”

“…in nigrostriatal regions due to the relative ease through which biomarkers of DA availability can be measured in the striatum during Positron Emission Tomography (PET) scans and SPECT imaging (Bäckman et al., 2006; Kaasinen et al., 2000; Suhara et al., 1991; Volkow et al., 1994, 2000, 2004).”

“neurons remain unchanged between childhood and adulthood (Lambe et al., 2000).”

“Consistent with DA’s role in modulating excitatory cortical circuits, DA release is thought to aid cognitive performance by increasing neural signal-to-noise ratios (Chambers et al., 2003; Sawaguchi et al., 1990; Thurley et al., 2008).”

“COMT, on the other hand, is unique in that its activity has been shown to increase in both human PFC (Tunbridge et al., 2007a,b) and porcine striatum (Brust et al., 2004) during adolescence.”

“Similar inconsistencies have been found with respect to AADC, where data demonstrate both decreases in the striatum after the age of 2 in humans (Haycock et al., 2003) and increases throughout the brain in pigs (Brust et al., 2004).”

“TH has been identified as early as E11 in the rat brain (Teitelman et al., 1979) and gestational week 5 in humans (Pearson et al.”

“…first step in the catabolism of excess synaptic DA with some specificity to the PFC due to a lack of DA transporter activity in this region (Giros et al., 1996; Gogos et al., 1998; Huotari et al., 2002; Lewis et al., 2001; Napolitano et al., 1995; Sesack et al., 1998; Weinshilboum et al., 1999).”

“D4 density within the striatum increases until periadolescence and decreases thereafter; conversely, the forebrain undergoes steady increases in density until periadolescence that then plateau into adulthood (Tarazi et al., 1998b).”

“Other conditions of interest, such as PKU, have been used as models to illustrate developmental aspects of PFC DA availability (Diamond, 1996; Luciana et al., 2004), but this work is indirect.”

“…true because metabolite levels are confounded by DA usage, which decreases with age (Leslie et al., 1991; Teicher et al., 1993), and regional innervation patterns (McGeer et al., 1967), which vary widely across developmental periods and species (Kalsbeek et al., 1988; Rosenberg and Lewis, 1994).”

“This finding is most reliably demonstrated in the caudate and putamen (Gelbard et al., 1989; Giorgi et al., 1987; Tarazi et al., 1999; Teicher et al., 1995), although other studies suggest that D1 binding in the dorsal striatum increases to adult levels in periadolescence and then stabilizes, as…”

“…is mediated by a second polymorphism (i.e., the effect of the first is evident in only in the presence of a certain allele in the second) are also emerging in the cognitive literature (Gosso et al., 2008; Reuter et al., 2006; Roffman et al., 2008; Stelzel et al., 2009; Tan et al., 2007).”

“…in nigrostriatal regions due to the relative ease through which biomarkers of DA availability can be measured in the striatum during Positron Emission Tomography (PET) scans and SPECT imaging (Bäckman et al., 2006; Kaasinen et al., 2000; Suhara et al., 1991; Volkow et al., 1994, 2000, 2004).”

“DA modulates the excitability of pyramidal cells by lowering the voltage threshold required for cell firing (Henze et al., 2000); thus, it is possible that adolescence is characterized by increased excitability of the neural substrates responsible for cognitive functioning and corticocortical…”

“…have found steady increases in D1 density into adolescence (Leslie et al., 1991), others have reported a periadolescent-limited peak in density (Tarazi et al., 1999), and yet others suggest a periadolescent-limited peak followed by decline and then another peak at PD 80 (Andersen et al., 1997;…”

“In our view and based on success in using pharmacological probes to index neurochemical reactivity in young adults (Luciana and Collins, 1997; Luciana et al., 2004; Vrshek-Schallhorn et al., 2006), this is a technology that could be applied safely to adolescent samples.”

“…is mediated by a second polymorphism (i.e., the effect of the first is evident in only in the presence of a certain allele in the second) are also emerging in the cognitive literature (Gosso et al., 2008; Reuter et al., 2006; Roffman et al., 2008; Stelzel et al., 2009; Tan et al., 2007).”

“…al., 1989; Giorgi et al., 1987; Tarazi et al., 1999; Teicher et al., 1995), although other studies suggest that D1 binding in the dorsal striatum increases to adult levels in periadolescence and then stabilizes, as opposed to peaking on approximately PD 35 (Leslie et al., 1991; Rao et al., 1991).”

“Monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) are the primary enzymes responsible for this inactivation, with MAO accounting for approximately 90% of DA catabolism and COMT accounting for the other 10% (Westerink, 1985).”

“In addition to the assessment of white matter volumes, age-related increases in the directional organization of white matter, as assessed through diffusion tensor imaging (DTI), have been observed (Ashtari et al., 2007; BarneaGoraly et al., 2005; Ben Bashat et al., 2005; Bonekamp et al., 2007; Eluvathingal et al., 200…”

“Interestingly, sex differences in receptor overproduction do not appear to be related to adolescent surges in gonadal hormones, as neither castration nor ovariectomy changed the developmental trajectory of D1 or D2 receptor density (Andersen et al., 2002).”

“…trajectory in humans is largely similar to that of non-human primates, where DA-containing cells reach the subplate by 13 weeks gestation and are distributed throughout the cerebral wall at 24 weeks (Verney et al., 1993; Zecevic and Verney, 1995), corresponding to the end of neuronal migration.”

“first third of gestation in primates (Berger et al., 1993; Levitt and Rakic, 1982).”

“D4 density within the striatum increases until periadolescence and decreases thereafter; conversely, the forebrain undergoes steady increases in density until periadolescence that then plateau into adulthood (Tarazi et al., 1998b).”

“Although changes in D1 and D2 densities occur simultaneously across cortical areas in non-human primates, the motor and visual cortices appear to be unique in that they display differential receptor changes across cortical layers that result in the reorganization of the laminar distributions of D1 and D2 densities (Li…”

“Theories abound to explain these patterns, most of which suggest that adolescent behavior patterns are attributable to changes in brain maturation during this period of the lifespan (Casey et al., 2008; Fareri et al., 2008; Steinberg, 2008).”

“For instance, the Taq1 A allele, associated with D2 dopamine receptor mechanisms (Neville et al., 2004), has been associated with novelty seeking as well as with reinforcement learning (Berman et al., 2002; Frank and Hutchison, 2009).”

“This finding is most reliably demonstrated in the caudate and putamen (Gelbard et al., 1989; Giorgi et al., 1987; Tarazi et al., 1999; Teicher et al., 1995), although other studies suggest that D1 binding in the dorsal striatum increases to adult levels in periadolescence and then stabilizes, as…”

“…1992), dopamine transporter (DAT1) variable number of tandem repeats (VNTR) (Vandenbergh et al., 1992), the Taq1A SNP, which appears to impact the D2 receptor system (Neville et al., 2004; Noble, 2003), D3 receptor Ser9Gly SNP (Crocq et al., 1992), and the MAO-A tandem repeat (Zhu et al., 1992).”

“MAO-A is primarily responsible for the inactivation of DA in rats (Butcher et al., 1990), though similar findings have not been documented in humans.”

“This effect has been demonstrated and replicated in healthy volunteers and schizophrenic patients (Bilder et al., 2002; Egan et al., 2001; Mattay et al., 2003; though for a recent meta-analysis that suggests the effect of COMT holds in healthy control samples only, see Barnett et al., 2007a,b).”

“Recently, some supportive evidence has emerged indicating that sex also modulates the effect of COMT on cognition, as elderly females appear to benefit from the Val allele when performing the Wisconsin Card Sort, whereas aging males show benefit from possessing the Met allele (Diamond, 2007).”

“shown to decrease with age in human PFC (Weickert et al., 2006) and striatum (McGeer and McGeer, 1976), though others have”

“…al., 1989; Giorgi et al., 1987; Tarazi et al., 1999; Teicher et al., 1995), although other studies suggest that D1 binding in the dorsal striatum increases to adult levels in periadolescence and then stabilizes, as opposed to peaking on approximately PD 35 (Leslie et al., 1991; Rao et al., 1991).”

“HVA levels have been shown to decrease in the rat striatum (Ungethüm et al., 1996) and human cerebrospinal fluid (Seifert et al., 1980), though others have indicated that it does not change with age in the human striatum (Haycock et al., 2003).”

“D2 receptors are more densely concentrated in the striatum compared to D1 receptors in the prenatal brain (Jung and Bennett, 1996), and the density and affinity of both appears to increase with age (Jung and Bennett, 1996; Sales et al., 1989).”

“We reported that the COMT Val158/Met genotype was significantly related to measures of working memory/attention, and motor coordination, all of which depend on prefrontal DA (Glickstein et al., 2005; Luciana and Collins, 1997; Yang et al., 2003).”

“Depending on the task, performance improves into the late teens and perhaps early twenties (De Luca et al., 2003; Luciana et al., 2009; Steinberg et al., 2009a,b).”

“Several reports indicate slight age-dependent increases in DA tissue concentrations in the cortex (Giorgi et al., 1987; Nomura et al., 1976) and striatum and midbrain (Ungethüm et al.”

“age 2–3 years in the macaque); conversely, DA concentrations peak in the parietal cortex at age 5 months and do not exhibit any change after birth in the occipital cortex (Brown and Goldman, 1977; Goldman-Rakic and Brown, 1982).”

“…that COMT is unrelated to performance on tests of executive functions such as working memory, setshifting, planning, and response inhibition (Mills et al., 2004; Taerk et al., 2004), whereas others have found that being homozygous for the Met allele impairs sustained attention performance…”

“decreases in cortical gray matter during adolescence (Giedd et al., 1999; Giedd, 2004; Gogtay et al., 2004; Gogtay and Thompson, 2010; Jernigan et al., 1991; Luders et al., 2005; Thompson et al., 2005; Sowell et al., 2003).”

“The protracted postadolescent period of synaptic elimination and increase in dopaminergic innervation of the prefrontal cortex (61) may be linked to human-specific cognitive functions and circuitry specializations (58) that are a product of cooperation between genetic endowment and environment, as postulated by the se…”

“Wehypothesize that these structures will represent nodes of the ascending mesocorticolimbic dopamine system (Berridge and Robinson, 1998; Goto and Grace, 2005; Wahlstrom et al., 2010b).”

“It may be mentioned here that recent studies have indicated changes in dopaminergic innervation to have more in fl uence on circuitry development during adolescence (Rosenberg and Lewis 1995; Weickert et al. 2007; Wahlstrom et al. 2010) .”

“Healthy brain development, therefore, is fostered by appropriate interactions between maturing brain systems, sex hormones, and stress hormones during adolescence and results in acquisition of cognitive processes such as inhibitory control, long-term planning, and abstract problem solving, Duncan…”

“Given these links, adolescent changes in striatal structure and function are the focus of a burgeoning literature, and several excellent reviews have been written focusing on adolescent changes in reward responsiveness [26–30].”

“An interesting parallel may be drawn with research on aging, also indicating that during adolescence, changes in dopaminergic projections are associated with profound changes in the development of one’s beliefs and preferences [182].”

“This perspective can be quite informative given the known changes in neurotransmitter function with age, particularly within the dopamine system (Ernst et al., 2009; Ernst and Spear, 2009; Spear, 2000; Wahlstrom et al., 2010).”

“It has previously been argued that adolescence is a time of stronger dopamine release, which may also contribute to the greater reward sensitivity in the NAcc in mid-adolescence (Wahlstrom et al., 2010).”

“Table 1, reprinted from Wahlstrom et al. (2010b), summarizes evidence of adolescentspecific changes in dopamine function.”

“These changes are accompanied by dramatic changes in those behaviours that the dopamine system is thought to subserve, namely, reward-seeking and incentive-driven action, which also peak during adolescence (Wahlstrom et al., 2010).”

“There is also evidence in rodents for adolescent peaks in cortical dopamine synthesis and subcortical synaptic availability (e.g., Andersen et al., 1997; Wahlstrom et al., 2010).”

“Codominant effects for COMT Val/Met have been reported for neurobehavioral functioning (Gosso et al., 2008; Wahlstrom et al., 2010) and schizophrenia (for a meta-analysis, see Costas et al.”

“Conversely, the worsening of TS until periadolescence may conceivably result from increased activation of the striatal DA system: studies in rodents show that DA neuron firing, striatal D1 and D2 receptors, and striatal DAT binding all peak during periadolescence (116,117).”

“This may be due, in part, to changes in dopaminergic function during this period (Wahlstrom et al., 2010).”

“Also, there are changes in the dopamine system that occur in adolescence, including changes in dopamine receptor distribution and tonic increase in the availability of dopamine (Wahlstrom et al., 2010).”

“In rodents, striatal D1 and D2 receptors follow exactly that pattern (138).”

“Furthermore, in the ventral striatum, D1 receptor density continues to increase until late adulthood, while D2 receptor density remains stable between adolescence and adulthood (Teicher et al., 1995; Wahlstrom et al., 2010).”

“The dopamine system undergoes important maturational changes in early adolescence (Wahlstrom et al., 2010).”

“The dopamine system has been strongly implicated in adolescent vulnerability to addiction as well as transition to psychosis (Spear, 2000; Wahlstrom et al, 2010; O’Donnell, 2011; Sturman and Moghaddam, 2011; Forbes and Dahl, 2012).”

“Thus, it has been hypothesized that age-related differences in brain resources might modulate genotype-phenotype relations during different life periods (Lindenberger et al., 2008; Posner et al., 2006; Wahlstrom et al., 2010).”

“The IMAGEN study has been following 2,000 youth from Europe for over eight years, and the NCANDA study will be following over 800 youth at five sites in the U.S. for at least 10 years (Brown et al., 2015; Dwyer & Leslie, 2016; Schumann et al., 2010; Wahlstrom et al., 2010).”

“In addition, it has been suggested that FC and NA have different maturation trajectories (Casey et al., 2010; Wahlstrom et al., 2010; Naneix et al., 2012).”

“From a behavioural perspective, adolescent rodents [2, 5, 6] and humans [2] show increased social activity [7], risk-taking [8] and impulsivity [6], compared to other age groups.”

“In the prefrontal cortex of normal rats, D1 and D2 binding increase rapidly from P28–40, then decline to mature values from P60 to P100 [35,36,37].”

“Dopamine signaling displays a unique maturation profile during adolescence, over and above many other neurotransmitter systems in the PFC (O’Donnell, 2010; Wahlstrom et al., 2010; Kim et al., 2016).”

“We refer the reader to recent reviews of this topic.(16,52) We focus here on shifts in DA receptor densities during adolescence as well as changes in tonic and phasic DA activity.”

“Consistent with this idea, a hyperdopaminergic state in patients with schizophrenia has been suggested to resemble the dopamine hyperactivity in the adolescent brain [17].”

“Overactivity of this system during adolescence, relative to adulthood (Wahlstrom et al. 2010), conceivably underlies the age-related effects of morphine on locomotion observed in the present study.”

“The mesolimbic dopamine system—involving connections originating in the VTA and projecting to the NAcc has been consistently implicated in the neurobiology of addictions [45, 46].”

“impaired development in control contribute to heightened rates of risk-taking (Steinberg 2008; Wahlstrom et al. 2010).”

“Adolescence is a developmental period characterized by the maturation of several brain systems that aid in the brain’s ability to perform functions such as self-control, decisionmaking, emotional processing and risk-taking (Wahlstrom et al., 2010).”

“In the NAc (Andersen et al., 1997) and other brain regions (Andersen et al., 2000 ; Brenhouse et al., 2008; Wahlstrom et al., 2010), DAergic signalling undergoes rapid, ontogenetic changes during adolescence.”

“Although few studies have assessed second-messenger selective signaling in adolescence [21], DA receptor expression is known to be agedependent, with transient overproduction and subsequent pruning of D1 and D2 binding sites in the adolescent prefrontal cortex [6,22] and striatum [23,24].”

“We included age as a covariate because previous evidence has shown that this variable is related to brain activity within the dopaminergic system [40,41].”

“As observed for other neurotransmitter systems, DA system undergoes changes during adolescence.(24) These changes take place at different time, depending on the brain area considered.”

“The hyperactivation of the core areas of reward processing (VS and VMPFC) during adolescence may be associated with the higher levels of dopamine during adolescence [Galvan, 2010; Wahlstrom et al., 2010] and the lower inhibitory top–down control might be caused by a not fully matured prefrontal cortex [Casey et al.”

“Prior animal work has shown that dopamine receptor availability as well as baseline firing rate of dopamine neurons are enhanced in adolescent rodents (Wahlstrom et al., 2010a,b), both of which are putative neurobiological mechanisms of enhanced motivation (Lisman and Grace, 2005; Luo et al., 2011).”

“Several brain regions associated with social stress (e.g., victimization and lack of social well-being) undergo maturation processes and dopamine system activity changes (Brenhouse & Andersen, 2011; Wahlstrom et al., 2010).”

“, [85]) and dopamine activity peaks in adolescence (see [86]), studies using selective behavioral measures of food palatability suggest that DA does not play a crucial role in this aspect of reward processing [34].”

“…both child development and older age such as maturation of GABAergic and glutamatergic neurons during childhood and adolescence (10); dopaminergic (11) and hormonal changes that occur during adolescence; and decreased dopaminergic, serotoninergic, and cholinergic transmission later in life…”

“This system promotes reward-seeking behavior by activating limbic, striatal, and frontal networks, enhancing an individual ’ s capacity to transfer positive motives into adaptive actions (Wahlstrom et al., 2010).”