A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.

Growth retardation and altered autonomic control in mice lacking brain serotonin.

Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2(-/-)) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2(-/-) mice. Moreover, Tph2(-/-) females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.

Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes.

The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.

Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.

Identification and quantitation of the N-acetyl-L-cysteine S-conjugates of bendamustine and its sulfoxides in human bile after administration of bendamustine hydrochloride.

We recently reported the detection of mercapturic acid pathway metabolites of bendamustine, namely, cysteine S-conjugates in human bile, which are supposed to subsequently undergo further metabolism. In this study, we describe the identification and quantitation of consecutive bendamustine metabolites occurring in human bile using authentic reference standards and the synthesis and structural confirmation of these compounds. Mass spectrometry data along with high-performance liquid chromatography retention data (fluorescence detection) of the synthetic reference standards were consistent with those of the metabolites found in human bile after administration of bendamustine hydrochloride to cancer patients. Analysis of the purified synthetic reference compounds showed a purity of at least 95%. Structural confirmation was achieved by one- and two-dimensional proton as well as carbon-13 NMR spectroscopy and mass spectrometry. A total of 16 bendamustine-related compounds were detected in the bile of patients, 11 of them were recovered as conjugates. Eight conjugates have been structurally confirmed as novel mercapturic acids and sulfoxides. Biliary excretion of the sulfoxides was twice that of the mercapturate precursors. Glutathione S-conjugates of bendamustine have not been detected in bile samples, indicating rapid enzymatic cleavage in humans. Both the lack of glutathione (GSH) conjugates and occurrence of diastereomeric sulfoxides emphasize species-related differences in the GSH conjugation of bendamustine between humans and rats. The total amount recovered in the bile as the sum of all conjugates over the period of 24 h after dosing averaged 5.2% of the administered dose. The question of whether the novel metabolites contribute to urinary excretion should be a target of future investigations.

Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia.

Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood, which may be critically involved in the precipitation of adult behavioural and pharmacological abnormalities after prenatal immune challenge.

The role of the subthalamic nucleus in 'compulsive' behavior in rats.

Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.

Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala.

Pathological anxiety is paralleled by deficits in serotonergic and GABAergic neurotransmission in the amygdala. Conversely, anxiety disorders and depression may be reversed by brain-derived neurotrophic factor (BDNF). BDNF signaling involves Phosphatidylinositol 3-Kinase / 3-phosphoinositide-dependent protein kinase 1 (PI3K/PDK1). We thus hypothesized that impaired function of PDK1 might be associated with increased anxiety and concomitant neurotransmitter changes. Here we used the hypomorphic PDK1(hm) mouse to investigate anxiety behavior in different settings: PDK1(hm) mice differed from Wt littermates PDK1(WT) in several behavioral measures related to anxiety and exploration, namely in the open field, dark-light box, O-maze and startle response. Further we analyzed the brain substrate underlying this phenotype and found significantly decreased GABA, taurine and serotonin concentrations in the amygdala and olfactory bulb of PDK1(hm) mice, while BDNF and nerve growth factor (NGF) concentrations were not significantly different between PDK1(hm) and PDK1(WT) mice. These results suggest that impaired PI3K signaling in the PDK1(hm) mouse reduces concentrations of GABA and serotonin in anxiety related brain regions and can serve as a molecular substrate for behavior indicative for anxious and depressive-like mood states.

Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders.

Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.

Dopamine and serotonin levels following prenatal viral infection in mouse--implications for psychiatric disorders such as schizophrenia and autism.

Prenatal viral infection has been associated with neurodevelopmental disorders such as schizophrenia and autism. It has previously been demonstrated that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and middle-late second trimester (E18) administration of influenza virus. Neurochemical analysis following infection on E18 using this model has revealed significantly altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not dopamine. In order to monitor these different patterns of monoamine expression in exposed offspring in more detail and to see if there are changes in the dopamine system at another time point, pregnant C57BL6J mice were infected with a sublethal dose of human influenza virus or sham-infected using vehicle solution on E16. Male offspring of the infected mice were collected at P0, P14, and P56, their brains removed and cerebellum dissected and flash frozen. Dopamine and serotonin levels were then measured using HPLC-ED technique. When compared to controls, there was a significant decrease in serotonin levels in the cerebella of offspring of virally exposed mice at P14. No differences in levels of dopamine were observed in exposed and control mice, although there was a significant decrease in dopamine at P14 and P56 when compared to P0. The present study shows that the serotonergic system is disrupted following prenatal viral infection, potentially modelling disruptions that occur in patients with schizophrenia and autism.

High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat.

Despite the benefit high frequency stimulation (HFS) of the subthalamic nucleus (STN) has on motor symptoms of Parkinson's Disease (PD), accumulating data also suggest effects of STN-HFS on non-motor behavior. This may be related to the involvement of the STN in the limbic basal ganglia-thalamocortical loops. In the present study we investigated the effect of acute STN-HFS on neurotransmission in associated structures of these pathways, i.e. the nucleus accumbens (NAc) core and shell as well as the ventral tegmental area (VTA) using in vivo microdialysis. Experiments were performed in anaesthetized naive rats and rats selectively lesioned in the substantia nigra pars compacta (SNc) or VTA. We demonstrate that: 1. STN-HFS leads to an increase in DA in the NAc, 2., these effects are more pronounced in the NAc shell than in the NAc core, 3. STN-HFS leads to a decrease in GABA in the VTA, 4. preceding lesion of the SNc does not seem to affect the effect of STN-HFS on accumbal DA transmission whereas 5. preceding lesion of the VTA seems to prohibit further detection of DA in the NAc. We conclude that STN-HFS significantly affects neurotransmission in the limbic system, which might contribute to explain the non-motor effects of STN-HFS.

Altered serotonergic and GABAergic neurotransmission in a mice model of obsessive-compulsive disorder.

There is ample evidence that obsessive-compulsive disorder (OCD) is based on reduced serotonergic function. Replicated bidirectional selection for thermoregulatory nest-building behavior in the laboratory house mouse (Mus musculus) resulted in compulsive-like, non-compulsive-like and randomly bred control mice that represent a non-induced animal model of OCD. The present study aimed at investigating the neurochemical patterns in specific brain regions of compulsive-like (HA) versus non-compulsive-like (LA) and normal (CA) mice. The neurochemical investigation of several brain regions of the corticostriato-thalamocortical circuity, i.e., nucleus caudatus (CPU), nucleus accumbens (NAc), globus pallidus (GP), hippocampus (HPC), amygdala (AM), ventral tegmental area (VTA) and substantia nigra (SN) was performed by electrochemical (serotonin and dopamine) and fluorescence (glutamate and GABA) HPLC detection. HA mice displayed significantly decreased 5-HT concentrations in the mPFC and LA mice displayed a significant increase in GABA concentrations in the mPFC. This supports the pathophysiological relevance of serotonin in the manifestation of OCD and adding to the construct validity of the non-induced mouse model of OCD.

Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression.

Deep brain stimulation (DBS) of several targets induces beneficial responses in approximately 60% of patients suffering from treatment-resistant depression (TRD). The remaining 40% indicate that these stimulation sites do not bear therapeutic relevance for all TRD patients and consequently DBS-targets should be selected according to individual symptom profiles. We here used two animal models of depression known to have different genetic backgrounds and behavioral responses: the therapy-responsive Flinders sensitive line (FSL) and the therapy-refractory congenitally learned helpless rats (cLH) to study symptom-specific DBS effects i) of different brain sites ii) at different stimulation parameters, and iii) at different expressions of the disease. Sham-stimulation/DBS was applied chronic-intermittently or chronic-continuously to either the ventromedial prefrontal cortex (vmPFC, rodent equivalent to subgenual cingulate), nucleus accumbens (Nacc) or subthalamic nucleus (STN), and effects were studied on different depression-associated behaviors, i.e. anhedonia, immobility/behavioral despair and learned helplessness. Biochemical substrates of behaviorally effective versus ineffective DBS were analyzed using in-vivo microdialysis and post-mortem high-performance liquid chromatography (HPLC). We found that i) vmPFC-DBS outperforms Nacc-DBS, ii) STN-DBS increases depressive states, iii) chronic-continuous DBS does not add benefits compared to chronic-intermittent DBS, iv) DBS-efficacy depends on the disease expression modeled and iv) antidepressant DBS is associated with an increase in serotonin turnover alongside site-specific reductions in serotonin contents. The reported limited effectiveness of vmPFC DBS suggests that future research may consider the specific disease expression, investigation of different DBS-targets and alternative parameter settings.

Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders.

The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.

Anxious and hyperactive phenotype following brief ischemic episodes in mice.

BACKGROUND: Poststroke emotional and behavioral abnormalities have an impact on outcome but have scarcely been characterized in animal models. We tested whether brief ischemic episodes induce behavioral changes in mice. METHODS: 129/Sv mice were subjected to 30-min occlusion of left or right middle cerebral artery (MCAo) followed by reperfusion or sham operation (n = 9 or 10 per group). Eight to ten weeks later, mice were tested for spontaneous locomotor activity, anxiety in the elevated plus maze, and depressive behavior in the modified Porsolt forced swim test. Outcome was correlated to monoamine and amino acid levels and compared with histologic damage at 10 weeks. RESULTS: Ischemia was associated with increased activity (right MCAo) and anxiety (left MCAo), but not poststroke depression. Noradrenaline increased by 30%-45% in the ischemic striatum and correlated with locomotor activity (r = .48); dopamine and homovanillinic acid were decreased compared with sham. The lesion was confined to the striatum, and scattered neuronal death was observed in a number of remote brain regions. CONCLUSION: Brief ischemic episodes in the mouse induce an anxious, hyperactive but not depressive phenotype that may relate to left versus right hemispheric lesion location, alterations in brain monoamine levels, and selective neurodegeneration.

Altered local field potential activity and serotonergic neurotransmission are further characteristics of the Flinders sensitive line rat model of depression.

A significant portion of patients suffering from major depression remains refractory to available antidepressant treatment strategies. This highlights the need for a better understanding of the underlying neuropathology in order to develop rationale-based treatments. Here we aimed to further characterize neurobiological abnormalities of the Flinders Sensitive Line (FSL) rat model of depression. Biochemically, in FSL rats we mainly found increased levels of serotonin in most cortical and subcortical brain regions when compared to controls. Using electrophysiological measurements, in FSL rats we found decreased alpha, beta and low gamma oscillatory activity in the medial prefrontal cortex and nucleus accumbens and decreased alpha and beta as well as increased low gamma oscillatory activity in the subthalamicus nucleus when compared to controls. In summary, we show distinct neurochemical properties in combination with particular oscillatory activity patterns for brain areas thought to be pathophysiologically relevant for depression. Our data contribute to the further understanding of neurobiological alterations in the FSL rat model of depression that could provide a basis for research into future therapeutic strategies.

Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course.

A growing body of evidence sheds light on the neurodevelopmental nature of schizophrenia with symptoms typically emerging during late adolescence or young adulthood. We compared the pre-symptomatic adolescence period with the full symptomatic period of adulthood at the behavioral and neurobiological level in the poly I:C maternal immune stimulation (MIS) rat model of schizophrenia. We found that in MIS-rats impaired sensorimotor gating, as reflected in disrupted prepusle inhibition (PPI), emerged post-pubertally, with behavioral deficits being only recorded in adulthood but not during adolescence. Using post mortem HPLC we found that MIS-rats show distinct dopamine and serotonin changes in the medial prefrontal cortex (mPFC), nucleus accumbens (Nacc), caudate putamen, globus pallidus, and hippocampus. Further, FDG-PET has shown that these animals had lower glucose uptake in the ventral hippocampus and PFC and a higher metabolism in the amygdala and Nacc when compared to controls. Changes in neurotransmission and metabolic activity varied across brain structures with respect to first appearance and further development. In the mPFC and Hipp, MIS-rats showed abnormal neurochemical and metabolic activity prior to and with the development of behavioral deficits in both adolescent and adult states, reflecting an early impairment of these regions. In contrast, biochemical alteration in the Nacc and globus pallidus developed as a matter of age. Our findings suggest that MIS-induced neurochemical and metabolic changes are neurodevelopmental in nature and either progressive or non-progressive and that the behavioral deficits manifest as these abnormalities increase.

Partial bilateral mesencephalic lesions affect D1 but not D2 binding in both the striatum and cortex.

The substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) are the two major mesencephalic dopaminergic systems. Mesencephalic dopamine denervation is followed by long-term modifications in striatum and cortex that preserve dopamine functions. Here, we have studied the impact of isolated bilateral 6-hydroxydopamine lesioning of the SNc or the VTA on D(1) and D(2) dopamine receptor binding in striatal and cortical areas of rat. Neither SNc nor VTA bilateral partial lesioning changed D(2) binding at the striatal or cortical level. Intriguingly, only VTA lesioning increased D(1) binding in the cortex, whereas both bilateral partial lesioning of the SNc or the VTA increased striatal D(1) binding. This suggests that increased cortical D(1) binding could be an indicator of VTA lesioning. Further behavioural experiments may explain the pathophysiological meaning of increased cortical D(1) binding, and determine whether this observation is involved in compensatory mechanisms.

Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates Parkinson's disease (PD) symptoms. Although widely used, the mechanisms of action are still unknown. In an attempt to elucidate those mechanisms, we have previously demonstrated that STN-DBS increases striatal extracellular dopamine (DA) metabolites in anaesthetized rats. PD being a movement disorder, it remains to be determined whether these findings are related to any relevant motor or behavioural changes. Thus, this study investigates concomitant behavioural changes during STN-DBS and extracellular striatal DA metabolites measured using microdialysis in freely moving 6-hydroxydopamine-lesioned rats. STN-DBS induced an increase of striatal DA metabolites in awake, freely moving animals. Furthermore, we observed concomitant contralateral circling behaviour. Taken together, these results suggest that STN-DBS could disinhibit (consequently activate) substantia nigra compacta neurons via inhibition of gamma-aminobutyric acid-ergic substantia nigra reticulata neurons.