A systematic review of preclinical studies exploring the role of insulin signalling in executive function and memory.

Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer's disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia - as a proxy of insulin-related metabolic dysfunctions - and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.

Embryonic and adult synaptic proteome perturbations after maternal immune activation: Identification of persistent changes relevant for early intervention.

Maternal infections during pregnancy pose an increased risk for neurodevelopmental psychiatric disorders (NPDs) in the offspring. Here, we examined age- and sex-dependent dynamic changes of the hippocampal synaptic proteome after maternal immune activation (MIA) in embryonic and adult mice. Adult male and female MIA offspring exhibited social deficits and sex-specific depression-like behaviours, among others, validating the model. Furthermore, we observed dose-, age-, and sex-dependent synaptic proteome differences. Analysis of the embryonic synaptic proteome implicates sphingolipid and ketoacid metabolism pathway disruptions during neurodevelopment for NPD-pertinent sequelae. In the embryonic hippocampus, prenatal immune activation also led to changes in neuronal guidance, glycosphingolipid metabolism important for signalling and myelination, and post-translational modification of proteins that regulate intercellular interaction and developmental timing. In adulthood, the observed changes in synaptoneurosomes revealed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, and hormone-mediated metabolism. Importantly, 68 of the proteins with differential abundance in the embryonic brains of MIA offspring were also altered in adulthood, 75% of which retained their directionality. These proteins are involved in synaptic organisation, neurotransmitter receptor regulation, and the vesicle cycle. A cluster of persistently upregulated proteins, including AKT3, PAK1/3, PPP3CA, formed a functional network enriched in the embryonic brain that is involved in cellular responses to environmental stimuli. To infer a link between the overlapping protein alterations and cognitive and psychiatric traits, we probed human phenome-wise association study data for cognitive and psychiatric phenotypes and all, but PORCN were significantly associated with the investigated domains. Our data provide insights into the dynamic effects of an early prenatal immune activation on developing and mature hippocampi and highlights targets for early intervention in individuals exposed to such immune challenges.

Insulin and disorders of behavioural flexibility.

Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.

The translational genetics of ADHD and related phenotypes in model organisms.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder resulting from the interaction between genetic and environmental risk factors. It is well known that ADHD co-occurs frequently with other psychiatric disorders due, in part, to shared genetics factors. Although many studies have contributed to delineate the genetic landscape of psychiatric disorders, their specific molecular underpinnings are still not fully understood. The use of animal models can help us to understand the role of specific genes and environmental stimuli-induced epigenetic modifications in the pathogenesis of ADHD and its comorbidities. The aim of this review is to provide an overview on the functional work performed in rodents, zebrafish and fruit fly and highlight the generated insights into the biology of ADHD, with a special focus on genetics and epigenetics. We also describe the behavioral tests that are available to study ADHD-relevant phenotypes and comorbid traits in these models. Furthermore, we have searched for new models to study ADHD and its comorbidities, which can be useful to test potential pharmacological treatments.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network.

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30-40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.

Psycho-social factors associated with mental resilience in the Corona lockdown.

The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p < 0.0001). The resilience factor PAS also partly mediated the positive association between perceived social support and resilience, and its association with resilience was in turn partly mediated by the ability to easily recover from stress (both p < 0.0001). In comparison with other resilience factors, good stress response recovery and positive appraisal specifically of the consequences of the Corona crisis were the strongest factors. Preregistered exploratory subgroup analyses (osf.io/thka9) showed that all tested resilience factors generalize across major socio-demographic categories. This research identifies modifiable protective factors that can be targeted by public mental health efforts in this and in future pandemics.

Comparison of psychotropic medication use in the Baltic countries.

Purpose: While the pivotal role of pharmacotherapy in psychiatry is universal, significant regional differences exist in drug use patterns. Herewith we compare the use of ATC psychotropic drugs (N05, psycholeptics and N06A, antidepressants) in 2010-2015 in the three Baltic Countries with reference to the Nordic Countries.Methods: Data were obtained from the national authorities on medicines as expressed in DDD per 1000 inhabitants per day. A semi-structured questionnaire was used for expert statements on the rationale of current use of medicines.Results: During the observation period the use of antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants steadily increased, while the growth in use of anxiolytics stagnated in the more recent years. Antipsychotic use was the largest in Lithuania and the lowest in Estonia. The use on anxiolytics in Lithuania was more than twice of that in Estonia and Latvia. Conversely, the use of hypnotics and sedatives was about three times higher in Estonia than in Latvia or Lithuania. Antidepressant use was dominated by the selective serotonin reuptake inhibitors in all three countries, but overall was much lower in Latvia as compared to Lithuania and Estonia. As compared to the Nordic Countries in 2015, antidepressants are used at much lower level throughout Baltics, probably reflecting underdiagnostics of depression and anxiety disorders.Conclusion: While the health-care expenditures in Estonia, Latvia and Lithuania are largely similar, as is the cultural and recent political background of these EU member countries, the extent and the pattern of psychotropic drug use is remarkably variable.

Nitric oxide synthase genotype interacts with stressful life events to increase aggression in male subjects in a population-representative sample.

Nitric oxide signalling has been implicated in impulsive and aggressive traits and behaviours in both animals and humans. In the present study, we investigated the effects of a functional variable number of tandem repeats (VNTR) polymorphism in exon 1f (ex1f) of the nitric oxide synthase 1 (NOS1) gene (NOS1 ex1f-VNTR) and stressful life events on aggressive behaviour in population representative sample of adolescents followed up from third grade to 25 years of age. We studied the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study (subjects in the last study wave n = 437, males n = 193; mean age 24.8 ± 0.5 years). Aggressive behaviour was rated at age 25 with the Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Life history of aggression was evaluated in a structured interview. Stressful life events and family relationships were self-reported at age 15. The hypothesized risk genotype (homozygosity for the short allele) was associated with higher levels of aggression in males (statistical significance withstanding the multiple correction procedure). Exposure to stressful life events or adverse family relationships was associated with increased aggressive behaviour in subjects homozygous for either of the alleles, and these associations were mostly observed in males. However, these associations in these stratified analyses did not survive correction for multiple testing. Aggressiveness was relatively unaffected by the NOS1 ex1f-VNTR genotype in the female subjects even when taking exposure to childhood adversity into account. Our findings support the hypothesized involvement of a functional NOS1 polymorphism on aggression in a population representative sample of young adults.

Nitric oxide interacts with monoamine oxidase to modulate aggression and anxiety-like behaviour.

Nitric oxide (NO) is a gaseous neurotransmitter that has important behavioural functions in the vertebrate brain. In this study we compare the impact of decreased nitric NO signalling upon behaviour and neurobiology using both zebrafish and mouse. nitric oxide synthase mutant (nos1-/-) zebrafish show significantly reduced aggression and an increase in anxiety-like behaviour without altered production of the stress hormone cortisol. Nos1-/- mice also exhibit decreased aggression and are hyperactive in an open field test. Upon reduction of NO signalling, monoamine neurotransmitter metabolism is reduced as a consequence of decreased Monoamine oxidase activity. Treatment of nos1-/- zebrafish with the 5-HT receptor 1A agonist 8-OH-DPAT rescues aggression and some aspects of anxiety-like behaviour. Taken together, the interplay between NO and 5-HT appears to be critical to control behaviour. Our cross-species approach challenges the previous notion that reduced neuronal NOS leads to increased aggression. Rather, Nos1 knock-out can also lead to decreased aggression in some situations, a finding that may have implications for future translational research.

Limited effects of early life manipulations on sex-specific gene expression and behavior in adulthood.

Exposure to childhood adversity is associated with increased vulnerability to stress-related disorders in adulthood which has been replicated in rodent stress models, whereas environmental enrichment has been suggested to have beneficial effects. However, the exact neurobiological mechanisms underlying these environment influences on adult brain and behavior are not well understood. Therefore, we investigated the long-term effects of maternal separation (MS) or environmental enrichment (EE) in male and female CD1 mice. We found clear sex-specific effects, but limited influence of environmental manipulations, on adult behavior, fecal corticosterone metabolite (FCM) levels and stress- and plasticity related gene expression in discrete brain regions. In detail, adult females displayed higher locomotor activity and FCM levels compared to males and EE resulted in attenuation in both measures, but only in females. There were no sex- or postnatal manipulation-dependent differences in anxiety-related behaviors in either sex. Gene expression analyses revealed that adult males showed higher Fkbp5 mRNA levels in hippocampus, hypothalamus and raphe nuclei, and higher hippocampal Nos1 levels. Interestingly, MS elevated Nos1 levels in hippocampus but reduced Fkbp5 expression in hypothalamus of males. Finally, we also found higher Maoa expression in the hypothalamus of adult females, however no differences were observed in the expression levels of Bdnf, Crhr1, Nr3c1 and Htr1a. Our findings further contribute to sex-dependent differences in behavior, corticosterone and gene expression and reveal that the effects of postnatal manipulations on these parameters in outbred CD1 mice are limited.

Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation.

Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum. Adgrl3-/- mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3+/- mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain.

To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.

Expression of the ADHD candidate gene Diras2 in the brain.

The distinct subgroup of the Ras family member 2 (DIRAS2) gene has been found to be associated with attention-deficit/hyperactivity disorder (ADHD) in one of our previous studies. This gene is coding for a small Ras GTPase with unknown function. DIRAS2 is highly expressed in the brain. However, the exact neural expression pattern of this gene was unknown so far. Therefore, we investigated the expressional profile of DIRAS2 in the human and murine brain. In the present study, qPCR analyses in the human and in the developing mouse brain, immunocytological double staining on murine hippocampal primary cells and RNA in situ hybridization (ISH) on brain sections of C57BL/6J wild-type mice, have been used to reveal the expression pattern of DIRAS2 in the brain. We could show that DIRAS2 expression in the human brain is the highest in the hippocampus and the cerebral cortex, which is in line with the ISH results in the mouse brain. During mouse brain development, Diras2 levels strongly increase from prenatal to late postnatal stages. Co-expression studies indicate Diras2 expression in glutamatergic and catecholaminergic neurons. Our findings support the idea of DIRAS2 as a candidate gene for ADHD as the timeline of its expression as well as the brain regions and cell types that show Diras2 expression correspond to those assumed to underlie the pathomechanisms of the disease.

Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis.

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.

Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury.

Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.

Interaction of NOS1AP with the NOS-I PDZ domain: Implications for schizophrenia-related alterations in dendritic morphology.

Schizophrenia involves morphological brain changes, including changes in synaptic plasticity and altered dendritic development. Amongst the most promising candidate molecules for schizophrenia are neuronal nitric oxide (NO) synthase (NOS-I, also known as nNOS) and its adapter protein NOS1AP (previously named CAPON). However, the precise molecular mechanisms by which NOS-I and NOS1AP affect disease pathology remain to be resolved. Interestingly, overexpression of NOS1AP affects dendritic morphology, possibly through increased association with the NOS-I PDZ domain. To investigate the effect of NOS1AP on dendritic morphology we overexpressed different NOS1AP isoforms, NOS1AP deletion mutants and the aminoterminal 133 amino acids of NOS-I (NOS-IN133) containing an extended PDZ domain. We examined the interaction of the overexpressed constructs with endogenous NOS-I by co-immunoprecipitation and the consequences of increased NOS-I/NOS1AP PDZ interaction in primary cultures of hippocampal and cortical neurons from C57BL/6J mice. Neurons overexpressing NOS1AP isoforms or deletion mutants showed highly altered spine morphology and excessive growth of filopodia-like protrusions. Sholl analysis of immunostained primary cultured neurons revealed that dendritic branching was mildly affected by NOS1AP overexpression. Our results hint towards an involvement of NOS-I/NOS1AP interaction in the regulation of dendritic spine plasticity. As altered dendritic spine development and filopodial outgrowth are important neuropathological features of schizophrenia, our findings may provide insight into part of the molecular mechanisms involved in brain morphology alterations observed in schizophrenia. As the NOS-I/NOS1AP interface can be targeted by small molecules, our findings ultimately might help to develop novel treatment strategies for schizophrenia patients.

Antidepressants differentially affect striatal amphetamine-stimulated dopamine and serotonin release in rats with high and low novelty-oriented behaviour.

In the studies of depression pathogenesis and antidepressant action, the monoaminergic hypothesis of depression has mainly focused on the serotonergic and noradrenergic mechanisms. However, dopaminergic neurotransmission is also linked to both depressive symptomatology as well as antidepressant effects. We have previously shown that persistent inter-individual differences in the rat behavioural activity in novel environments is associated with differences in the striatal extracellular levels of dopamine and serotonin, depressive-like behaviour and the expression of several depression-related genes. The aim of the current study was to investigate the relative potency of the tricyclic antidepressant imipramine, the selective serotonin re-uptake inhibitor fluoxetine, and the selective noradrenaline re-uptake inhibitor reboxetine (all drugs administered in the dose of 10mg/kg, i.p.) to enhance amphetamine-stimulated dopamine and serotonin release in the striatum using in vivo microdialysis in awake, freely-moving rats, categorized into high explorers (HE) and low explorers (LE) based on their spontaneous novelty-oriented behaviour. The basal extracellular dopamine and serotonin concentration in the striatum did not differ between the LE- and HE-rats. None of the antidepressants alone were able to modify baseline striatal dopamine levels, but the amphetamine-stimulated dopamine release was significantly higher in the HE-rats after acute and chronic imipramine (but not fluoxetine or reboxetine). Acute imipramine and fluoxetine, but not reboxetine, increased both the basal and amphetamine-stimulated levels of serotonin in the striatum. Again, the HE-rats had higher amphetamine-stimulated serotonin release after fluoxetine administration. These findings suggest that rats with depressive-like phenotype are less sensitive to the neurochemical effects of antidepressants in the striatum. These results may have relevance in understanding the neurobiological bases for inter-individual differences in antidepressant treatment response in humans and development of novel medicines.