Dopamine, empathy and the neurobiology of leadership

Objectives: Organisational Psychologists have long sought after methods by which to train individuals to become more effective leaders. Indeed considerable sums of money are spent on the design of such training programs. Yet it is not clear whether or not leadership skills can be taught or whether they are innate. Social leadership is a varied construct consisting of many diverse aspects, yet the ability to empathise with subordinates is a core skill that underpins effective transformational leadership. This type of leadership consists of four characteristics which are labelled ‘idealized influence’, ‘inspirational motivation’, ‘intellectual stimulation’ and ‘individualized consideration’. This is distinct from the transactional style of leadership, which is based on offering contingent rewards for completion of specific tasks. By identifying a specific gene that mediates distinct leadership traits, more effective training regimes can be designed. Design: There are two likely candidate genes that may mediate empathic leadership. The first is catechol-O-methyltransferase (COMT) which is involved with dopamine synthesis, and the second is the serotonin transporter promoter gene (5-HTTLPR). Both these genes mostly appear in the general population in their heterozygotic form. Thus by comparing phenotypes in leadership traits a measure of base line differences can be examined. Methods: 115 volunteers completed the Multifactor Leadership questionnaire (MLQ), which is a standard 12-item leadership psychometric scale and also underwent buccal swab for subsequent genotyping. Results: Of the 115 subjects 37 were heterozygotic for the COMT gene and 47 heterozygotic for 5-HTTLPR. Of the 12 MLQ subscales, the scores for two of the subscales only differed between the two participant groups. Individuals who were heterozygotic for the COMT gene scored higher on the ‘Inspirational motivation’ t(84)=1.99, p=0.05 and ‘Intellectual stimulation’ t(82)=1.94, p=0.05 scales compared to the carriers for the heterozygotic 5HTPP gene. Conclusions: Given that the behaviours described by these two MLQ subscales require leaders to empathise with subordinates, the current results suggest that dopamine may play a role in this important social task. The fact that both heterozygotic carriers for COMT and 5HTPP were compared allows a comparison to be made between the genotypes most prevalent in the general population.

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Genetic modulation of the response bias towards facial displays of anger and happiness

Background: Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol- O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals. Methods: Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped. Results: Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found. Conclusions: These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders. © 2013 Elsevier Masson SAS.

Bridging the link between trauma, brain development and depression: epigenetic mechanisms

Despite its large impact on the individual and society, we currently have only a rudimentary understanding of the biological basis of Major Depressive Disorder, even less so in adolescent populations. This thesis focuses on two research questions. First, how do adolescents with depression differ from adolescents who have never been depressed on (1a) brain morphology and (1b) DNA methylation? We studied differences in the fronto-limbic system (a collection of areas responsible for emotion regulation) and methylation at the serotonin transporter (SLC6A4) and FK506 binding protein gene (FKBP5) genes (two genes strongly linked to stress regulation and depression). Second, how does childhood trauma, which is known to increase risk for depression, affect (2a) brain development and (2b) SLC6A4 and FKBP5 methylation? Further, (2c) how might DNA methylation explain how trauma affects brain development in depression? We studied these questions in 24 adolescent depressed patients and 21 controls. We found that (1a) depressed adolescents had decreased left precuneus volume and greater volume of the left precentral gyrus compared to controls; however, no differences in fronto-limbic morphology were identified. Moreover, (1b) individuals with depression had lower levels of FKBP5 methylation than controls. In line with our second hypothesis (2a) greater levels of trauma were associated with decreased volume of a number of fronto-limbic regions. Further, we found that (2b) greater trauma was associated with decreased SLC6A4, but not FKBP5, methylation. Finally, (2c) greater FKBP5, but not SLC6A4, methylation was associated with decreased volume of a number of fronto-limbic regions. The results of this study suggest an association among trauma, DNA methylation and brain development in youth, but the direction of these relationships appears to be inconsistent. Future studies using a longitudinal design will be necessary to clarify these results and help us understand how the brain and epigenome change over time in depressed youth.

Adversity in early adolescence alters female rats' anxiety-related behaviours and serotonergic innervation profiles in adulthood

Stress during early development produces lasting effects on psychopathological outcomes. The impact of prior intermittent, physical stress (IPS) during early-adolescence (PD 22-33) on anxiety-related behaviour of female rats was analyzed in adulthood. After behavioural testing, serotonergic innervation was evaluated using immunohistochemistry for the serotonin transporter (SERT) in the medial prefrontal cortex (mPFC) and ventral hippocampus. Administration of IPS (i.e., water immersion, elevated platform, foot shock) in early adolescence increased rats’ anxiety-like behaviour in the elevated plus-maze but had no effects in the shock-probe burying test. In the social interaction test, IPS decreased social interaction, and this effect was driven by selective decreases in the duration of playfighting with no evident changes in contact or investigative behaviour. Selective stress-induced increases in SERT-immunoreactive axon density were found in the infralimbic (IL) subregion of the mPFC, but not in the cingulate or prelimbic (PL) subregions. IPS in early adolescence did not affect serotonergic innervation profiles in any sub-fields of the ventral hippocampus. The findings confirm and extend on earlier evidence that stress during early adolescence promotes the emergence of an anxious phenotype, and provide novel evidence that these effects may be mediated, at least in part, by increased serotonergic innervation of the IL mPFC.

ENVIRONMENTAL INFLUENCES AND EPIGENETIC MECHANISMS IN RISK FOR DEPRESSION

Genetic and environmental factors interact to influence vulnerability for internalizing psychopathology, including Major Depressive Disorder (MDD). The mechanisms that account for how environmental stress can alter biological systems are not yet well understood yet are critical to develop more accurate models of vulnerability and targeted interventions. Epigenetic influences, and more specifically, DNA methylation, may provide a mechanism by which stress could program gene expression, thereby altering key systems implicated in depression, such as frontal-limbic circuitry and its critical role in emotion regulation. This thesis investigated the role of environmental factors from infancy and throughout the lifespan affecting the serotonergic (5-HT) system in the vulnerability to and treatment of depression and anxiety and potential underlying DNA methylation processes. First, we investigated the contributions of additive genetic vs. environmental factors on an early trait phenotype for depression (negative emotionality) in infants and their stability over time in the first 2 years of life. We provided evidence of the substantial contributions of both genetic and shared environmental factors to this trait, as well as genetically- and environmentally- mediated stability and innovation. Second, we studied how childhood environmental stress is associated with peripheral DNA methylation of the serotonin transporter gene, SLC6A4, as well as long-term trajectories of internalizing behaviours. There was a relationship between childhood psychosocial adversity and SLC6A4 methylation in males, as well as between SLC6A4 methylation and internalizing trajectory in both sexes. Third, we investigated changes in emotion processing and epigenetic modification of the SLC6A4 gene in depressed adolescents before and after Mindfulness-Based Cognitive Therapy (MBCT). The alterations from pre- to post-treatment in connectivity between the ACC and other network regions and SLC6A4 methylation suggested that MBCT may work to optimize the connectivity of brain networks involved in cognitive control of emotion as well as also normalize the relationship between SLC6A4 methylation and activation patterns in frontal-limbic circuitry. Our results from these three studies strengthen the theory that environmental influences are critical in establishing early vulnerability factors for MDD, driving epigenetic processes, and altering brain processes as an individual undergoes treatment, or experiences relapse.

Maternal history of early adversity and child emotional development : investigating intervening factors

L’objectif de cette thèse était de contribuer à l’avancement des connaissances quant aux circonstances permettant une transmission intergénérationnelle du risque émanant de l’adversité maternelle et aux mécanismes sous-tendant cette transmission, dans quatre articles empiriques. Le premier visait à explorer la relation entre un historique d’adversité maternelle, la sécurité d’attachement mère-enfant et le tempérament de l’enfant. Les mères ont complété une entrevue semi-structurée portant sur leurs représentations d’attachement avec leurs parents, à 6 mois, et ont évalué le tempérament de leur enfant à 2 ans. La sécurité d’attachement fut également évaluée à 2 ans. Les résultats ont démontré que les enfants dont les mères rapportaient des niveaux supérieurs d’adversité présentaient de moins bons niveaux d’activité comportementale, uniquement lorsqu’ils avaient un attachement sécurisant avec leur mère. Ces résultats suggèrent une transmission intergénérationnelle des effets d’un historique d’adversité maternelle sur le tempérament des enfants. Le deuxième article visait à investiguer si le transporteur de sérotonine (5-HTTLPR) module la transmission de risque intergénérationnelle de l’adversité maternelle sur le tempérament des enfants. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également évalué le tempérament de leur enfant à 18 et à 36 mois. Le génotype des enfants fut extrait à 36 mois. Les résultats ont révélé un effet d’interaction entre l’adversité maternelle et le génotype de l’enfant sur le tempérament, suggérant une transmission intergénérationnelle des effets de l’adversité maternelle sur le fonctionnement émotionnel des enfants. Le troisième article visait à explorer la relation entre les difficultés d’adaptation psychosociale des mères, la sensibilité maternelle et les symptômes intériorisés de leurs enfants. Les mères ont complété plusieurs questionnaires desquels un score composite de difficultés d’adaptation psychosociale fut extrait. La sensibilité maternelle fut observée à 12 mois. Les symptômes intériorisés des enfants furent évalués par les deux parents à 2 et à 3 ans. Les résultats ont démontré qu’une augmentation des difficultés maternelles d’adaptation psychosociale étaient associée à davantage de symptômes intériorisés chez les enfants, mais seulement chez ceux dont les mères étaient moins sensibles. Ces résultats ont été observés par les mères à 2 ans et par les deux parents à 3 ans. Ces résultats suggèrent que les enfants peuvent être différemment affectés par l’adaptation émotionnelle de leur mère tout en mettant l’emphase sur le rôle protecteur de la sensibilité maternelle. Le quatrième article visait à investiguer les rôles médiateurs de la dépression et de la sensibilité maternelle dans la relation entre un historique d’adversité maternelle et le tempérament de l’enfant. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également rapporté leurs symptômes dépressifs à 6 mois. La sensibilité maternelle fut évaluée de façon concomitante. Les mères ont évalué le tempérament de leur enfant à 36 mois. Les résultats ont révélé une transmission intergénérationnelle des effets d’un historique d’adversité maternelle à la génération suivante suivant une médiation séquentielle passant d’abord par la dépression maternelle et ensuite par la sensibilité maternelle. Finalement, les résultats des quatre articles ont été intégrés dans la conclusion générale.

Maternal history of early adversity and child emotional development : investigating intervening factors

L’objectif de cette thèse était de contribuer à l’avancement des connaissances quant aux circonstances permettant une transmission intergénérationnelle du risque émanant de l’adversité maternelle et aux mécanismes sous-tendant cette transmission, dans quatre articles empiriques. Le premier visait à explorer la relation entre un historique d’adversité maternelle, la sécurité d’attachement mère-enfant et le tempérament de l’enfant. Les mères ont complété une entrevue semi-structurée portant sur leurs représentations d’attachement avec leurs parents, à 6 mois, et ont évalué le tempérament de leur enfant à 2 ans. La sécurité d’attachement fut également évaluée à 2 ans. Les résultats ont démontré que les enfants dont les mères rapportaient des niveaux supérieurs d’adversité présentaient de moins bons niveaux d’activité comportementale, uniquement lorsqu’ils avaient un attachement sécurisant avec leur mère. Ces résultats suggèrent une transmission intergénérationnelle des effets d’un historique d’adversité maternelle sur le tempérament des enfants. Le deuxième article visait à investiguer si le transporteur de sérotonine (5-HTTLPR) module la transmission de risque intergénérationnelle de l’adversité maternelle sur le tempérament des enfants. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également évalué le tempérament de leur enfant à 18 et à 36 mois. Le génotype des enfants fut extrait à 36 mois. Les résultats ont révélé un effet d’interaction entre l’adversité maternelle et le génotype de l’enfant sur le tempérament, suggérant une transmission intergénérationnelle des effets de l’adversité maternelle sur le fonctionnement émotionnel des enfants. Le troisième article visait à explorer la relation entre les difficultés d’adaptation psychosociale des mères, la sensibilité maternelle et les symptômes intériorisés de leurs enfants. Les mères ont complété plusieurs questionnaires desquels un score composite de difficultés d’adaptation psychosociale fut extrait. La sensibilité maternelle fut observée à 12 mois. Les symptômes intériorisés des enfants furent évalués par les deux parents à 2 et à 3 ans. Les résultats ont démontré qu’une augmentation des difficultés maternelles d’adaptation psychosociale étaient associée à davantage de symptômes intériorisés chez les enfants, mais seulement chez ceux dont les mères étaient moins sensibles. Ces résultats ont été observés par les mères à 2 ans et par les deux parents à 3 ans. Ces résultats suggèrent que les enfants peuvent être différemment affectés par l’adaptation émotionnelle de leur mère tout en mettant l’emphase sur le rôle protecteur de la sensibilité maternelle. Le quatrième article visait à investiguer les rôles médiateurs de la dépression et de la sensibilité maternelle dans la relation entre un historique d’adversité maternelle et le tempérament de l’enfant. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également rapporté leurs symptômes dépressifs à 6 mois. La sensibilité maternelle fut évaluée de façon concomitante. Les mères ont évalué le tempérament de leur enfant à 36 mois. Les résultats ont révélé une transmission intergénérationnelle des effets d’un historique d’adversité maternelle à la génération suivante suivant une médiation séquentielle passant d’abord par la dépression maternelle et ensuite par la sensibilité maternelle. Finalement, les résultats des quatre articles ont été intégrés dans la conclusion générale.

ENVIRONMENTAL INFLUENCES AND EPIGENETIC MECHANISMS IN RISK FOR DEPRESSION

Thesis (Ph.D, Psychology) -- Queen's University, 2016-10-04 17:37:07.888

Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians

We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.

Post-translational regulation of an Aplysia glutamate transporter during long-term facilitation.

Regulation of glutamate transporters accompanies plasticity of some glutamatergic synapses. The regulation of glutamate uptake at the Aplysia sensorimotor synapse during long-term facilitation (LTF) was investigated. Previously, increases in levels of ApGT1 (Aplysia glutamate transporter 1) in synaptic membranes were found to be related to long-term increases in glutamate uptake. In this study, we found that regulation of ApGT1 during LTF appears to occur post-translationally. Serotonin (5-HT) a transmitter that induces LTF did not increase synthesis of ApGT1. A pool of ApGT1 appears to exist in sensory neuron somata, which is transported to the terminals by axonal transport. Blocking the rough endoplasmic reticulum-Golgi-trans-Golgi network (TGN) pathway with Brefeldin A prevented the 5-HT-induced increase of ApGT1 in terminals. Also, 5-HT produced changes in post-translational modifications of ApGT1 as well as changes in the levels of an ApGT1-co-precipitating protein. These results suggest that regulation of trafficking of ApGT1 from the vesicular trafficking system (rough endoplasmic reticulum-Golgi-TGN) in the sensory neuron somata to the terminals by post-translational modifications and protein interactions appears to be the mechanism underlying the increase in ApGT1, and thus, glutamate uptake during memory formation.

Effects of opioids on human serotonin transporters.

The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 μM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 μM, tramadol 20 μM, pethidine 30 μM, and ketamine 100 μM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.

Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.

A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library. The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2. Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells. VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla. VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the oxyntic mucosa of the stomach. The transport characteristics and pharmacology of each VMAT isoform have been directly compared after expression in digitonin-permeabilized fibroblastic (CV-1) cells, providing information about substrate feature recognition by each transporter and the role of vesicular monoamine storage in the mechanism of action of psychopharmacologic and neurotoxic agents in human. Serotonin has a similar affinity for both transporters. Catecholamines exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher affinity, for VMAT2. Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. N-methyl-4-phenylpyridinium, phenylethylamine, amphetamine, and methylenedioxymethamphetamine are all more potent inhibitors of VMAT2 than of VMAT1, whereas fenfluramine is a more potent inhibitor of VMAT1-mediated monamine transport than of VMAT2-mediated monoamine transport. The unique distributions of hVMAT1 and hVMAT2 provide new markers for multiple neuroendocrine lineages, and examination of their transport properties provides mechanistic insights into the pharmacology and physiology of amine storage in cardiovascular, endocrine, and central nervous system function.

Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may lead to decreased 5-HT content in the nerve fibers themselves; however, this has not previously been directly demonstrated. We have studied the effects of administration of two drugs, imipramine and citalopram, on levels of 5-HT in nerve fibers in the murine brain. Quantitative analysis of the areal density of 5-HT fibers throughout the brain was performed using ImageJ software. While a high density of fibers was observed in mid- and hind-brain regions and areas such as thalamus and hypothalamus, densities were far lower in areas such as cortex, where SSRIs might be thought to exert their actions. As anticipated, imipramine and citalopram produced a decline in 5-HT levels in nerve fibers, but the result was not uniform. Areas such as inferior colliculus showed significant reduction whereas little, if any, change was observed in the adjacent superior colliculus. The reason for, and significance of, this regionality is unclear. It has been proposed that serotonin effects in the brain might be linked to changes in glutamatergic transmission. Extracellular glutamate levels are regulated primarily by glial glutamate transporters. Qualitative evaluation of glutamate transporter immunolabeling in cortex of control and drug-treated mice revealed no discernable difference in intensity of glutamate transporter immunoreactivity. These data suggest that changes in intracellular and extracellular levels of serotonin do not cause concomitant changes in astroglial glutamate transporter expression, and thus cannot represent a mechanism for the delayed efficacy of antidepressants when administered clinically. © 2005 Elsevier B.V. All rights reserved.