We thank M.E. Hasselmo, E. Kropff, T. Solstad, and E.A. Zilli for helpful discussions. This work was supported by a Marie Curie Fellowship, the Kavli Foundation, and a Centre of Excellence grant from the Research Council of Norway. “
“Comparative and pathological studies suggest the mammalian cerebral cortex to be the anatomical substrate of higher cognitive functions including language, episodic memory, and voluntary movement (Jones and Rakic, 2010, Kaas, 2008 and Rakic, 2009). The cerebral cortex has a uniform laminar structure that historically has been divided into six layers (Brodmann, 1909). The upper layers (1 to 4) form localized

Selleckchem INCB024360 intracortical connections (Gilbert and Wiesel, 1979 and Toyama et al., 1974) and are thought to process information locally. The deep layers of the cortex, 5 and 6, LGK-974 research buy form longer-distance projections to subcortical targets (including the thalamus, striatum, basal pons, tectum, and spinal cord) and to the opposite hemisphere. Some layer 5 neurons are among the largest cells of the brain and exhibit the longest connections. Layer 6b in mouse neocortex is a distinct sublamina with characteristic connections, gene expression patterns, and physiological

properties (Hoerder-Suabedissen et al., 2009 and Kanold and Luhmann, 2010). Understanding how neurons and glia are organized into layers to assemble into functional microcircuits (Douglas and Martin, 2004) is one of the first steps that will be required to relate anatomical structures to cellular functions. Subclasses of pyramidal neurons

and interneurons populate specific layers, each characterized by a different depth in the cortex with a specific pattern of dendritic and axonal connectivity (Jones, 2000, Lorente de No, 1949 and Peters and Yilmaz, 1993). However, Non-specific serine/threonine protein kinase analyzing these laminar differences is difficult and often suffers from subjectivity (Zilles and Amunts, 2010). The currently available repertoire of markers that allow the distinction of cortical layers and of many neuronal and glial subtypes is rapidly improving because of developments in cell sorting and gene expression analysis (Doyle et al., 2008, Heintz, 2004, Miller et al., 2010, Molyneaux et al., 2007, Monyer and Markram, 2004, Nelson et al., 2006, Thomson and Bannister, 2003 and Winden et al., 2009). These molecular tags allow highly specific classes of neurons and glia to be monitored, modulated, or eliminated, thereby providing greater insights into cortical neurogenesis and the classification of lamina specific subclasses of cells. Laminar molecular markers were first identified by studying single protein-coding genes (Hevner et al., 2006, Molyneaux et al., 2007 and Yoneshima et al., 2006) but more recently, high-throughput in situ hybridization (Hawrylycz et al., 2010, Lein et al., 2007 and Ng et al., 2010) and microarrays (Oeschger et al., 2011, Arlotta et al.

These findings show that TSPAN7 and PICK1 interact in neurons. Because the C-terminal tail of TSPAN7

also pulls down GluA2/3 and β1 integrin, it is likely that TSPAN7, PICK1, AMPAR, and β1 integrins associate to form macromolecular complexes in neurons. Osimertinib ic50 Because PICK1 is a ligand of AMPAR GluA2/3 subunits and is involved in internalizing and recycling AMPARs (Hanley, 2008b and Perez et al., 2001), we next investigated PICK1/AMPAR interaction in neurons in presence and absence of TSPAN7. From primary neuron extracts expressing siRNA14 or scrambled siRNA14, we immunopurified AMPAR complexes using GluA2/3 C-terminal antibodies, assessing the results by western blot. In TSPAN7-knockdown neurons, PICK1 and GluA2/3 associated together more strongly than in neurons expressing scrambled siRNA14 (Figure 6E, right; 1.22 ± 0.05 versus 1.01 ± 0.01, ∗∗p = 0.004, PICK1/GluA2/3

ratio in siRNA14-expressing neurons normalized to the ratio in scrambled siRNA14 neurons). Furthermore β1 integrin associated with AMPARs only in the presence of TSPAN7 (Figure 6E, middle). These findings indicate that, in rat hippocampal neurons, TSPAN7 regulates the extent of interaction between GluA2/3 subunits, PICK1 and β1 integrin, possibly by acting as a macromolecular organizer. Because selleck chemicals llc TSPAN7 is important for the morphological and functional maturation of excitatory synapses (Figures 1, 2, 3, 4, and 5), and because it interacts dynamically with other synaptic proteins (Figure 6), we next investigated whether TSPAN7 interactions are required for regulating excitatory synaptic function. In view of the well-established role of PICK1 in AMPAR turnover (Hanley, 2008a) and the direct

interaction between PICK1 and TSPAN7 (Figure 6), we first addressed whether TSPAN7 and PICK1 cooperate in regulating GluA2 trafficking. Neurons expressing siRNA14 or scrambled siRNA14 were first incubated for 10 min with antibody against an extracellular epitope of GluA2. The time course of GluA2 internalization was estimated from the ratio of intracellular to total fluorescence (internalization index) (Passafaro et al., 2001) in neurons fixed 0, 5, and 10 min after antibody incubation. The GluA2 internalization index was significantly higher in TSPAN7 knockdown than scrambled siRNA14 neurons at all times (Figures 7A and 7B; 0 min: 1.26 ± PD184352 (CI-1040) 0.05 versus 1.00 ± 0.09, ∗p = 0.04; 5 min: 1.74 ± 0.04 versus 1.46 ± 0.04, ∗∗∗p < 0.001; 10 min: 1.27 ± 0.07 versus 1.08 ± 0.05, ∗p = 0.04; values normalized to the levels in scrambled siRNA14 neurons at time 0). To ascertain whether these effects were due to increased GluA2 internalization, we repeated the experiments in the presence of the dynamin inhibitor dynasore (80 μM for 30 min before internalization assay). As expected, dynasore abolished all differences in the internalization index between TSPAN7-knockdown and scrambled siRNA14 neurons at the three times (Figures 7A and 7B; 0 min: 1.00 ± 0.

We first performed microtransplantation assays in slices, as described before ( López-Bendito et al., 2008) ( Figure 8A). We previously showed that E13.5

wild-type MGE-derived interneurons isochronically transplanted into the cortex disperse tangentially and avoid entering the CP, as they normally do in vivo, whereas Cxcr4 mutant interneurons prematurely invade the CP ( López-Bendito et al., 2008). Unexpectedly, the migration of Cxcr7 mutant interneurons transplanted into wild-type cortices was indistinguishable from that of wild-type Adriamycin cells ( Figures 8B, 8D, and 8E). Furthermore, we observed that most Cxcr7 mutant interneurons contained detectable levels of Cxcr4 while migrating into wild-type slices ( Figures 8C and 8F), which demonstrated that the function of Cxcr7 in nearby interneurons is enough

to sustain the levels of Cxcr4 receptors in Cxcr7 mutant interneurons. To confirm these selleck compound library observations, we next carried out similar transplantation experiments in vivo (Figure 8G). We previously showed that E15.5 wild-type interneurons transplanted isochronically and homotypically in utero end up primarily in superficial layers of the cortex (López-Bendito et al., 2008 and Pla et al., 2006), as they normally do in vivo. In contrast, many E15.5 Cxcr4 mutant interneurons end up in deep cortical layers, probably because they prematurely invade the CP ( López-Bendito et al., 2008). As predicted by our organotypic cultures, E15.5 MGE-derived Cxcr7 mutant interneurons transplanted into wild-type embryos adopt a laminar pattern that is indistinguishable

from control interneurons born isochronically ( Figures 8H and 8I). Altogether, our experiments demonstrated that Cxcr7 is not essential within each individual interneuron for their migration. Instead, these results revealed that Cxcr7 functions at the population level to regulate the migration of cortical interneurons. In this study, we have used cortical interneurons as a model system to investigate the function of the mafosfamide atypical chemokine receptor Cxcr7 in neuronal migration. We have found that Cxcr7 is required in migrating interneurons to regulate the levels of Cxcr4 receptors expressed by these cells, through a process that requires the interaction of migrating cells with the chemokine Cxcl12. Interestingly, this function emerges as a property of the entire population of migrating interneurons, because the loss of Cxcr7 in an individual cell can be rescued by the function of Cxcr7 in other migrating interneurons. These results provide a clear demonstration that an atypical chemokine receptor can modulate the highly specialized function of a classical chemokine receptor by controlling the amount of receptor that is made available for signaling at the cell surface.

We can only conjecture that either GABAergic VTA cells, or glutamate corelease from DA cell synapses, may convey the oscillatory input to PFC. Nonetheless, the study by Fujisawa and Buzsáki (2011) paves the way for future experiments centered on these themes. “
“More than 2,000 years ago the Chinese advanced the concept of Yin and Yang to help explain the progressive and regressive forces that operate during life. As depicted in the Taiji diagram, Yin and Yang are interdependent, interconnected, and transformable. Today, this ancient theory still provides a useful conceptual framework for viewing the

dynamic relationship between progressive and regressive events during neural development and maintenance. see more Here we describe how this principle applies to multiple organizational levels of the nervous system: from circuits, to cells, to molecules (Figure 1A). Neural circuit formation involves many progressive events including neural stem cell proliferation, axon and dendrite outgrowth, and synapse formation. Later in development, however, regressive events such as cell death, axon pruning, and synapse elimination further refine the precise pattern of connectivity needed for proper function of the mature circuitry. Neuron death and synapse loss also occur under pathophysiological conditions such as amyotrophic lateral sclerosis and Alzheimer’s disease, for example (Vanderhaeghen ABT-737 molecular weight and Cheng, 2010). Unfortunately,

the counterforces that might offset the degeneration of neural circuits seem to be far less robust in the adult than the embryonic nervous system of higher vertebrates, creating a major clinical challenge (Giger et al., 2010). Progressive and regressive events also apply to the attractive and repulsive forces that guide growing axons (O’Donnell et al., 2009). Some cellular targets express attractive cues, which promote the assembly of cytoskeletal networks within growth cones, leading to axonal turning and extension, whereas other others targets express repulsive cues that cause cytoskeleton

disassembly. Interestingly, the signaling pathways that cause axon attraction and repulsion are transformable when levels of cyclic nucleotides and Ca2+ are altered (Hong et al., 2000, Höpker et al., 1999 and Nishiyama et al., 2003). In fact, the responsiveness of axons to guidance signals often changes over their course of growth. Long axons typically navigate using a series of intermediate targets. For each intermediate target, the axon is first attracted then switches its response upon arrival and becomes repelled, allowing it to move on to the next leg of its journey (Tessier-Lavigne and Goodman, 1996 and Yu and Bargmann, 2001). At a molecular level, the synthesis and degradation of proteins can likewise be viewed as progressive and regressive processes. Accordingly, it is easy to understand how the synthesis of new proteins is critical for cell proliferation, the specification of neuronal identity, and axonal extension.

In the early 1970s Eriksson

et al.22, 23, 24, 25 and 26 carried out a series of innovative muscle biopsy studies on small samples of 11–16 years old boys which have influenced the understanding of paediatric exercise metabolism for almost 40 years. Muscle biopsies from the lateral part of the CP-673451 datasheet quadriceps femoris revealed resting adenosine triphosphate (ATP) stores which were invariant over the age range 11.6–15.5 years. The PCr stores of the 15-year-old boys were 63% higher than those of the 11-year-old boys. The ATP stores at all ages and the PCr stores of the 15-year-old boys were not dissimilar to values others had reported in adults. Glycogen stores at rest were reported to increase by 61% from 11 years to 15 years. The concentration of ATP remained virtually unchanged following several bouts of submaximal exercise but minor reductions were reported following maximal exercise. The PCr stores gradually depleted following exercise sessions of increasing intensity. Muscle glycogen stores decreased following exercise in all age groups but the depletion was three times greater in the older boys suggesting enhanced glycolysis

selleck chemical with age.26 Eriksson et al.26 reported succinic dehydrogenase and phosphofructokinase (PFK) activity at rest in 11-year-old boys to be 20% and 50% respectively lower than they had previously reported for adults.27 Haralambie28 determined the activity of 22 enzymes involved in energy metabolism in 13–15-year-old boys and girls and in adult men Edoxaban and women and, in conflict with Eriksson’s observations, he found no significant difference in the activity of glycolytic enzymes between adolescents

and adults. He did, however, confirm his earlier observation29 of greater activity of oxidative enzymes in adolescents than in adults. Subsequently, Berg et al.30 and 31 reported glycolytic enzymes activity to be positively correlated with age and oxidative enzymes activity to be negatively correlated with age over the age range 6–17 years, in both males and females. All muscle biopsies were taken at rest. Haralambie28 and 29 reported a comparison of the resting activity of potential rate limiting enzymes of glycolysis and the tricarboxylic acid cycle, namely, PFK and isocitric dehydrogenase (ICDH). The ratio PFK/ICDH was reported to be 93% higher in adults than in adolescents at 1.633 and 0.844, respectively. A re-calculation of Berg’s data indicated a similar relationship of glycolytic and oxidative enzymes with the ratio of pyruvate kinase to fumarase varying from 3.585 in adults, 3.201 in adolescents to 2.257 in children.30 and 31 Eriksson et al.25 and 26 reported muscle lactate accumulation following exercise to increase with age and, on the basis of an ‘almost significant’ relationship between lactate accumulation in the muscles and testicular volume, they hypothesised a maturational effect on lactate production.

, 1987; reviewed in Sanes and Lichtman, 2001) and by the Drosophila glypican Dally-like, a GPI-anchored HSPG ( Johnson et al., 2006). In the CNS, overexpression of the transmembrane HSPG syndecan-2 accelerates dendritic spine morphogenesis ( Ethell and Yamaguchi, 1999). Secreted forms of glypican

Selleck MK-1775 4 and 6 promote glutamate receptor clustering and excitatory synapse formation in retinal ganglion cells ( Allen et al., 2012), suggesting that glypican may have synaptic organizing activity. However, the molecular interactions that mediate the effects of glypican have not been identified. Here we used a mass spectrometric approach to compare LRRTM2 and LRRTM4 binding partners and find that these proteins have distinct receptor preferences: whereas LRRTM2 primarily binds to neurexins, the preferential binding partners for LRRTM4 are glypicans. We find that the glypican-LRRTM4 interaction requires HS and can occur in trans. LRRTM4 regulates excitatory synapse development in cultured neurons and in vivo, and the synaptogenic activity of LRRTM4, but not of LRRTM2, requires HS. Our data identify glypican as a receptor for LRRTM4 and indicate that a trans-synaptic glypican-LRRTM4 interaction regulates excitatory synapse development. The LRRTM genes are expressed in specific and partially

nonoverlapping expression patterns during synaptogenesis and in the adult brain ( de Wit et al., 2009 and Laurén et al., 2003). During the synaptogenic period from postnatal day (P) 7 to P14, Imatinib LRRTM2 and LRRTM4 show complementary expression patterns in cortex, with LRRTM2 expression restricted to layer 6 and LRRTM4 mainly expressed in layer 2/3 and layer 5 ( Figures 1A and 1B). In the hippocampus, LRRTM2 and LRRTM4 are coexpressed in dentate gyrus (DG) granule cells ( Figures 1A and 1B, arrowheads). Whether different LRRTM family members expressed in the same neuron signal through the same new presynaptic receptor, or whether various LRRTMs have different mechanisms of action, is unknown. Phylogenetic analysis indicates that human LRRTM2 and LRRTM4 share only 43% amino acid identity and that LRRTM4 and LRRTM3 are

more closely related to each other than to other LRRTMs ( Laurén et al., 2003). These observations raised the possibility that LRRTM4 may have a different presynaptic receptor than LRRTM2. To identify candidate LRRTM4 interactors, we took an unbiased, discovery-based approach. We purified recombinant ecto-Fc proteins for LRRTM2 and LRRTM4 (Figure 1C) and used these in a side-by-side comparison to identify interacting proteins in detergent-solubilized whole-brain homogenate from 3- to 4-week-old rats by affinity chromatography. Bound proteins were analyzed by tandem mass spectrometry. In agreement with previous results (de Wit et al., 2009 and Ko et al., 2009a), the most abundant proteins bound to LRRTM2-Fc were neurexins (Figure 1D).

, 2002), reinforcing the suppression of food intake and opposing the effects of ghrelin (see above). Interestingly, leptin stimulates

the transcription factor STAT3, which in conjunction with the transcription factor Nhlh2 regulates transcription of prohormone-converting enzymes 1 (PC1) and 2 (PC2) (Fox and Good, 2008). These enzymes are involved in the conversion of POMC to various hormones, such as ACTH, and various types of melanocyte-stimulating hormones (MSH) (reviewed in Mountjoy, 2010). Central administration of α-MSH reduces appetite this website and increases energy expenditure (Cone, 2006) via its actions on melanocortin receptors (Mc3r and Mc4r) (Cone, 2006). Lack of Mc3r in mice leads to reduced FAA under restricted feeding conditions, and the expression of the clock genes Npas2 and Per2 in the cortex is also reduced ( Sutton et al., 2008). These observations are consistent with the reported reduction or absence of FAA in mutant DAPT order mice that lack clock components Npas2 or Per2, respectively ( Dudley et al., 2003 and Feillet et al., 2006). Collectively, it appears that circadian leptin in the serum binds to its

receptors in a time-dependent fashion, thereby activating neurons in the ARC and modulating transcription of target genes in a 24 hr cycle. However, the details of how this is achieved are still a matter of investigation. There is surmounting evidence to support the theory that the consumption of both food and drugs of abuse converge on a shared pathway within the limbic system that mediates motivated behaviors (reviewed in Simerly, 2006). Much of the research has focused on the mesolimbic dopamine pathway because common drugs of abuse increase dopamine signaling from nerves that originate in the ventral Urease tegmental area (VTA) and project to the nucleus accumbens (NAc), which is part of the striatum (Figure 5) (Nestler and Carlezon, 2006). An increase in dopaminergic transmission is thought to occur either by direct action of drugs on dopaminergic neurons (cocaine, nicotine) or indirectly by inhibition of GABAergic interneurons in the VTA (alcohol, opiates). In addition, the peptide neurotransmitter

orexin, which is expressed in a subset of neurons in the lateral hypothalamus (LH) that have projections to the VTA, is also implicated in mediating drug-induced activation of dopaminergic neurons in the VTA (Borgland et al., 2006). Interestingly, the activation of orexin neurons appears to be under circadian control (Marston et al., 2008), linking arousal and drug-induced behavior by the circadian clock mechanism. Natural rewards such as food induce similar responses in the mesolimbic dopamine pathway (Kelley and Berridge, 2002). Presentation of palatable food induces the release of dopamine into the NAc, which in turn promotes the animal’s behavioral attempts to obtain food rewards via increased arousal and psychomotor activation.

All ROIs were taken from

t maps corrected at FDR < 0.05, with a cluster threshold of 10 mm3 (10 contiguous voxels). In some cases, the FDR threshold was made more conservative, e.g., when the Small-OTS and Small-LO regions, which each MLN8237 research buy have distinct peaks, were connected by voxels with lower t values. If any of the targeted ROIs were not present at FDR < 0.05, the threshold was lowered to FDR < 0.1. If no clear ROI was present at that threshold, then that ROI was not defined for that participant. ROIs were defined as the set of contiguous voxels that were significantly activated around the peak voxel identified from within a restricted part of cortex based on the anatomical position. For all ROI analyses, all ROIs were defined from the Big versus Small object experiment (independent dataset), and the response of these regions to different experimental conditions was assessed in subsequent experiments. For each subject and each ROI, GLMs were run on the average time series of the voxels in the ROI to obtain regression coefficients (betas) for the experimental conditions. For the subsequent experiments with 2 × 2 designs (Experiment 2: retinal size manipulation; Experiment 3: mental imagery), to evaluate the effects of www.selleckchem.com/products/gsk1120212-jtp-74057.html each factor across observers, repeated-measures ANOVAs were run on the betas across observers for each ROI. This work was funded

by a National Science Foundation Graduate Fellowship (to Talia Konkle), Dipeptidyl peptidase and a National Eye Institute grant EY020484 (to Aude Oliva), and was conducted at the Athinoula A. Martinos Imaging Center at McGovern

Institute for Brain Research, MIT. We thank George Alvarez, Timothy Brady, Mark Williams, Daniel Dilks, and the reviewers for thoughtful comments on the manuscript. “
“A fundamental human ability in social environments is the simulation of another person’s mental states, or hidden internal variables, to predict their actions and outcomes. Indeed, the ability to simulate another is considered a basic component of mentalizing or theory of mind (Fehr and Camerer, 2007, Frith and Frith, 1999, Gallagher and Frith, 2003 and Sanfey, 2007). However, despite its importance for social cognition, little is known about simulation learning and its cognitive and neural mechanisms. A commonly assumed account of simulation is the direct recruitment of one’s own decision-making process to model the other’s process ( Amodio and Frith, 2006, Buckner and Carroll, 2007 and Mitchell, 2009). The direct recruitment hypothesis predicts that one makes and simulates a model of how the other will act, including the other’s internal variables, as if it is one’s own process, and assumes that this simulated internal valuation process employs the same neural circuitry that one uses for one’s own process.

, 2007, Su et al., 2009a, Su et al., 2009b and Truong et al.,

2006). Other studies using an independently derived p63 null allele suggested an additional requirement for p63 in the differentiation of epithelial stem cells into more mature progeny ( Mills et al., 1999), a conclusion that has gained support from a number of follow-up reports ( Candi et al., 2006a, Candi et al., 2006b, Koster et al., 2004, Koster et al., 2007 and Truong et al., 2006). The basis of this discrepancy has remained unresolved for over a decade, in spite of intensive investigations using gain- and loss-of-function approaches in both in vivo and in vitro models of a variety of different epithelial systems. A somewhat different view posits that

p63 functions to suppress, rather than promote, the differentiation of epithelial stem cells. Galunisertib In support of this model, ectopic expression of p63 in cultured keratinocytes blocks their differentiation into more mature epithelial INK1197 molecular weight cell types (Ellisen et al., 2002, King et al., 2003 and King et al., 2006). Such gain-of-function overexpression studies should be interpreted with some caution, however, because the effects may be due to nonphysiological levels of ectopically expressed protein. Indeed, in one case TAp63, but not ΔNp63, was found to block differentiation of human keratinocytes (Ellisen et al., 2002), whereas other studies found that ΔNp63, but not TAp63, had such

differentiation inhibiting activity in mouse keratinocytes (King et al., 2003 and King et al., 2006). Nonetheless, investigations on the role of microRNAs in regulating epidermal stem cells indirectly implicate p63 in repressing differentiation (Lena Linifanib (ABT-869) et al., 2008 and Yi et al., 2008). In these studies, miR203, a microRNA that targets p63 mRNA, was found to be required for the differentiation of mouse epidermal stem cells in vivo and in culture: loss of miRNA expression in suprabasal cells caused defects in differentiation (Yi et al., 2008), whereas overexpression of miR203 in stem cells resulted in their premature differentiation and a reduction in proliferative capacity (Lena et al., 2008 and Yi et al., 2008). Together these observations suggest that stem cell differentiation is facilitated by miRNA-mediated suppression of mRNAs that promote self-renewal or “stemness” in these proliferating progenitor cells. However, because p63 is just one among a number of genes subject to posttranscriptional suppression by miR203, these observations are consistent with, but certainly do not prove, the notion that p63 alone is sufficient to suppress epithelial differentiation. Our analysis of the conditional p63 knockout in olfactory HBCs provides clarity of the role of p63 in regulating epithelial stem cell differentiation.

A significant group × drug challenge interaction was found in the left putamen for the anticipation of reward vs. anticipation of a neutral condition contrast (Fig. 2, panel C). The mean percentage signal change as shown for the striatum in Fig. 3 during reward anticipation

confirms the different effects induced by reward anticipation in both groups, and the effect of MPH there upon: under activation in the dAMPH users at baseline (without MPH) and reduced brain activation after the MPH challenge in the controls. Moreover, in the dAMPH RAD001 in vitro users, the left putamen became more strongly activated during anticipation of reward after the MPH challenge. No interaction effects for the other contrasts (loss versus neutral, reward versus loss, large reward versus small reward) were observed. We observed a different striatal response following MK0683 a monetary incentive delay task in recreational dAMPH users compared to healthy controls. This task has been found to robustly activate the nucleus accumbens and the caudate when anticipating reward, where receiving the actual reward mainly elicits a response

in the medial PFC (Knutson et al., 2001 and Haber and Knutson, 2010). When anticipating reward, dAMPH users showed diminished striatal activation in comparison to control subjects. We also observed a statistically different effect of a DA challenge in which MPH induced a decrease in striatal activation during reward anticipation in healthy controls, whereas no effect in dAMPH users was found. No effects of group or challenge were observed on anticipation of loss and size of the reward. One of the explanations for the lower reward anticipation found in recreational dAMPH users may be an innate hypofunction of the

DAergic system, which, in turn, may reflect increased sensitivity toward dAMPH (ab)use and or addiction. A leading theory about addiction states that reduced sensitivity for natural reinforcers underlies the development of addiction (also referred to as the reward deficiency hypothesis; Comings and Blum, 2000). According to this theory, the dAMPH group may have an innate DAergic hypofunction, which, in turn, old has predisposed them to developing a penchant for stimulant use. Indeed, even after prolonged abstinence, lower D2 receptor availability in a wide variety of addicted individuals has been reported (for review see Volkow et al., 2009). In addition, lower D2 receptor availability has been linked to increased impulsivity measures (Buckholtz et al., 2010), which in itself has been put forward as a component cause for the development of addiction (for review see Hommer et al., 2011). Thus, it is possible that our findings may not relate to dAMPH use, but rather increased impulsivity due to low D2 receptor availability.