Publications by authors named "Daniel Rial"

33 Publications

Mammalian Target of Rapamycin-RhoA Signaling Impairments in Direct Striatal Projection Neurons Induce Altered Behaviors and Striatal Physiology in Mice.

Biol Psychiatry 2020 12 3;88(12):945-954. Epub 2020 Jun 3.

Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium. Electronic address:

Background: As an integrator of molecular pathways, mTOR (mammalian target of rapamycin) has been associated with diseases including neurodevelopmental, psychiatric, and neurodegenerative disorders such as autism spectrum disorder, schizophrenia, and Huntington's disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified.

Methods: Using Drd1-Cre mTOR-conditional knockout male mice, we combined behavioral, biochemical, electrophysiological, and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons and how this would impact on striatal physiology.

Results: Our results indicate deep behavioral changes in absence of mTOR in Drd1-expressing neurons such as decreased spontaneous locomotion, impaired social interaction, and decreased marble-burying behavior. These alterations were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and coincident decreased distal spine density in striatal direct pathway striatal projection neurons. The physiological changes were mechanistically independent of protein synthesis but sensitive to pharmacological blockade of transforming protein RhoA activity.

Conclusions: These results identify mTOR signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related monogenic disorders associated with the mTOR signaling pathway.
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http://dx.doi.org/10.1016/j.biopsych.2020.05.029DOI Listing
December 2020

Animal models of olfactory dysfunction in neurodegenerative diseases.

Handb Clin Neurol 2019 ;164:431-452

Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.

Olfactory dysfunction seems to occur earlier than classic motor and cognitive symptoms in many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Thus, the use of the olfactory system as a clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and, potentially, prediction of treatment success. The use of genetic and neurotoxin animal models has contributed to the understanding of the mechanisms underlying olfactory dysfunction in a number of neurodegenerative diseases. In this chapter, we provide an overview of behavioral and neurochemical alterations observed in animal models of different neurodegenerative diseases (such as genetic and Aβ infusion models for AD and neurotoxins and genetic models of PD), in which olfactory dysfunction has been described.
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http://dx.doi.org/10.1016/B978-0-444-63855-7.00024-1DOI Listing
March 2020

Ablation of striatal somatostatin interneurons affects MSN morphology and electrophysiological properties, and increases cocaine-induced hyperlocomotion in mice.

Eur J Neurosci 2020 03 14;51(6):1388-1402. Epub 2019 Oct 14.

Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium.

The striatum is mainly composed by medium spiny neurons (95 %) (MSNs). Although outnumbered, in other brain regions such as the hippocampus and the cortex, somatostatin interneurons (SSTi) are known to control and fine-tune the activity of principal cells. This information is still fragmented for the striatum. Here, we questioned the striatal functional consequences of the selective ablation of SSTi in the striatum at the behavioural and cellular levels. We identified increased excitability coupled with decreased distal spine density in MSNs from SSTi-ablated mice. Although the ethological behavioural analysis did not reveal differences between the groups, SSTi-ablated mice were significantly more sensitive to the locomotor effects of cocaine without changes in motivation. This was accompanied by increased expression of the dopamine transporter (DAT) in the ventral striatum. Altogether, we show that SSTi are important players in the maintenance of MSN excitability and spine density impacting on mechanisms towards hyperdopaminergic states.
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http://dx.doi.org/10.1111/ejn.14581DOI Listing
March 2020

Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine.

Neurobiol Dis 2019 12 5;132:104570. Epub 2019 Aug 5.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; FMUC-Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. Electronic address:

Adenosine A receptors (AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5'-nucleotidase (CD73)-mediated formation of adenosine selectively activating AR. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the AR antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global AR knockout (KO) and in forebrain neuron-selective AR-KO mice, but inhibited LTP amplitude in astrocyte-selective AR-KO mice; this shows that CD73-derived adenosine solely acts on neuronal AR. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ administration, together with CD73 and AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ to impair synaptic plasticity and memory since Aβ-induced synaptic and memory deficits were eliminated in CD73-KO mice. These observations establish a key regulatory role of CD73 activity over neuronal AR and imply CD73 as a novel target for modulation of early AD.
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http://dx.doi.org/10.1016/j.nbd.2019.104570DOI Listing
December 2019

GPRIN3 Controls Neuronal Excitability, Morphology, and Striatal-Dependent Behaviors in the Indirect Pathway of the Striatum.

J Neurosci 2019 09 30;39(38):7513-7528. Epub 2019 Jul 30.

Laboratory of Neurophysiology, ULB-Neuroscience Institute, Université Libre de Bruxelles,

The regulation of the striatum by the GPCR signaling through neuromodulators is essential for its physiology and physiopathology, so it is necessary to know all the compounds of these pathways. In this study, we identified a new important partner of the dopaminergic pathway: GPRIN3 (a member of the GPRIN family). GPRIN3 is highly expressed in the striatum but with undefined function. Cell sorting of medium spiny neurons (MSNs) in indirect MSNs and direct MSNs indicated the presence of the GPRIN3 gene in both populations with a preferential expression in indirect MSNs. This led us to generate GPRIN3 KO mice by CRISPR/Cas9 and test male animals to access possible alterations in morphological, electrophysiological, and behavioral parameters following its absence. 3D reconstruction analysis of MSNs revealed increased neuronal arborization in GPRIN3 KO and modified passive and active electrophysiological properties. These cellular alterations were coupled with increased motivation and cocaine-induced hyperlocomotion. Additionally, using a specific indirect MSN knockdown, we showed a preferential role for GPRIN3 in indirect MSNs related to the DR signaling. Together, these results show that GPRIN3 is a mediator of DR function in the striatum playing a major role in striatal physiology. The striatum is the main input of the basal ganglia processing information from different brain regions through the combined actions of direct pathway neurons and indirect pathway neurons. Both neuronal populations are defined by the expression of dopamine DR or DR GPCRs, respectively. How these neurons signal to the respective G-protein is still debatable. Here we identified GPRIN3 as a putative selective controller of DR function in the striatum playing a critical role in striatal-associated behaviors and cellular functions. This study represents the identification of a new target to tackle striatal dysfunction associated with the DR, such as schizophrenia, Parkinson's disease, and drug addiction.
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http://dx.doi.org/10.1523/JNEUROSCI.2454-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750934PMC
September 2019

Adenosine A receptors modulate the dopamine D receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

Eur J Neurosci 2018 05 2;47(9):1127-1134. Epub 2018 Apr 2.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Polo I, Rua Larga, 3004-504, Coimbra, Portugal.

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D - and D -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A receptors (A R) also control PFC-related responses and A R antagonists are potential anti-psychotic drugs. As tight antagonistic A R-D R and synergistic A R-D R interactions occur in other brain regions, we now investigated the crosstalk between A R and D /D R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D R-like antagonist sulpiride but not by the D R antagonist SCH23390 and was mimicked by the D R agonist sumanirole, but not by the agonists of either D R (A-412997) or D R (PD128907). Dopamine inhibition was prevented by the A R antagonist, SCH58261, and attenuated in A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A R and D R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A R-D R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A R antagonists.
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http://dx.doi.org/10.1111/ejn.13912DOI Listing
May 2018

The effects of physical exercise on nonmotor symptoms and on neuroimmune RAGE network in experimental parkinsonism.

J Appl Physiol (1985) 2017 Jul 6;123(1):161-171. Epub 2017 Apr 6.

Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal;

Parkinson's disease (PD) prodromal stages comprise neuropsychiatric perturbations that critically compromise a patient's quality of life. These nonmotor symptoms (NMS) are associated with exacerbated innate immunity, a hallmark of overt PD. Physical exercise (PE) has the potential to improve neuropsychiatric deficits and to modulate immune network including receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE ) alleviates PD NMS and ) modulates neuroimmune RAGE network in experimental PD. Adult Wistar rats subjected to long-term mild treadmill were administered intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probed for PD NMS before the onset of motor abnormalities. Twelve days after MPTP, neuroimmune RAGE network transcriptomics (real-time quantitative PCR) was analyzed in frontal cortex, hippocampus, and striatum. Untrained MPTP animals displayed habit-learning and motivational deficits without gross motor impairments (cued version of water-maze, splash, and open-field tests, respectively). A suppression of RAGE and neuroimmune-related genes was observed in frontal cortex on chemical and physical stressors (untrained MPTP: RAGE, TLR5 and -7, and p22 NADPH oxidase; saline-trained animals: RAGE, TLR1 and -5 to -11, TNF-α, IL-1β, and p22 NADPH oxidase), suggesting the recruitment of compensatory mechanisms to restrain innate inflammation. Notably, trained MPTP animals displayed normal cognitive/motivational performances. Additionally, these animals showed normal RAGE expression and neuroprotective PD-related gene upregulation in frontal cortex when compared with untrained MPTP animals. These findings corroborate PE efficacy in improving PD NMS and newly identify RAGE network as a neural substrate for exercise intervention. Additional research is warranted to unveil functional consequences of PE-induced modulation of RAGE/DJ-1 transcriptomics in PD premotor stages. This study newly shows that physical exercise (PE) corrects nonmotor symptoms of the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental parkinsonism. Additionally, we show that suppression of neuroimmune receptor for advanced glycation end products (RAGE) network occurs in frontal cortex on chemical (MPTP) and physical (PE) interventions. Finally, PE normalizes frontal cortical RAGE transcriptomics and upregulates the neuroprotective gene in the intranasal MPTP model of experimental parkinsonism.
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http://dx.doi.org/10.1152/japplphysiol.01120.2016DOI Listing
July 2017

Moderate traumatic brain injury increases the vulnerability to neurotoxicity induced by systemic administration of 6-hydroxydopamine in mice.

Brain Res 2017 05 11;1663:78-86. Epub 2017 Mar 11.

Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis 88049-900, Brazil; Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, Florianópolis 88049-900, Brazil. Electronic address:

Moderate traumatic brain injury (TBI) might increase the vulnerability to neuronal neurodegeneration, but the basis of such selective neuronal susceptibility has remained elusive. In keeping with the disruption of the blood-brain barrier (BBB) caused by TBI, changes in BBB permeability following brain injury could facilitate the access of xenobiotics into the brain. To test this hypothesis, here we evaluated whether TBI would increase the susceptibility of nigrostriatal dopaminergic fibers to the systemic administration of 6-hydroxydopamine (6-OHDA), a classic neurotoxin used to trigger a PD-like phenotype in mice, but that in normal conditions is unable to cross the BBB. Adult Swiss mice were submitted to a moderate TBI using a free weight-drop device and, 5h later, they were injected intraperitoneally with a single dose of 6-OHDA (100mg/kg). Afterwards, during a period of 4weeks, the mice were submitted to a battery of behavioral tests, including the neurological severity score (NSS), the open field and the rotarod. Animals from the TBI plus 6-OHDA group displayed significant motor and neurological impairments that were improved by acute l-DOPA administration (25mg/kg, i.p.). Moreover, the observation of the motor deficits correlates with (i) a significant decrease in the tyrosine hydroxylase levels mainly in the rostral striatum and (ii) a significant increase in the levels of striatal glial fibrillary acidic protein (GFAP) levels. On the whole, the present findings demonstrate that a previous moderate TBI event increases the susceptibility to motor, neurological and neurochemical alterations induced by systemic administration of the dopaminergic neurotoxin 6-OHDA in mice.
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http://dx.doi.org/10.1016/j.brainres.2017.03.002DOI Listing
May 2017

Parkinson's disease-associated GPR37 receptor regulates cocaine-mediated synaptic depression in corticostriatal synapses.

Neurosci Lett 2017 01 19;638:162-166. Epub 2016 Dec 19.

Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Institut de Neurosciències, Universitat de Barcelona, Barcelona, Spain. Electronic address:

GPR37 is an orphan G protein-coupled receptor highly expressed in the brain. The precise function of GPR37 is still unknown, but a number of evidences indicate it modulates the dopaminergic system. Here, we aimed to determine the role of GPR37 on the control of cocaine-mediated electrophysiological effects (synaptic transmission and short-term plasticity) in corticostriatal synapses. Accordingly, we evaluated basal synaptic transmission and paired-pulse stimulation (PPS) in wild-type and GPR37KO mice slices. Regardless of the genotype, a low concentration of cocaine (2μM) did not modify basal synaptic transmission. Conversely, a higher dose of cocaine (30μM) decreased synaptic transmission in both genotypes, although with different intensities: approximately 30% in slices from wild-type mice and 45% in slices from GPR37-KO mice. On the other hand, no differences in PPS ratio were observed between wild-type and GPR37-KO cocaine-treated mice. Overall, our data suggest that GPR37 is involved in cocaine-induced modification of basal synaptic transmission without modifying cocaine effects in short-term plasticity.
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http://dx.doi.org/10.1016/j.neulet.2016.12.040DOI Listing
January 2017

Adenosine A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

Neuropsychopharmacology 2016 11 17;41(12):2862-2871. Epub 2016 Jun 17.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A receptors (ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if ARs in the amygdala regulate synaptic plasticity and fear memory. We report that ARs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting AR (shAR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of ARs in the amygdala after fear acquisition. The importance of ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; AR antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; AR antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in ARs to manage fear-related pathologies.
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http://dx.doi.org/10.1038/npp.2016.98DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061896PMC
November 2016

Caffeine Mitigates the Locomotor Hyperactivity in Middle-aged Low-density Lipoprotein Receptor (LDLr)-Knockout Mice.

CNS Neurosci Ther 2016 May 25;22(5):420-2. Epub 2016 Mar 25.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.

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http://dx.doi.org/10.1111/cns.12544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492875PMC
May 2016

Depression as a Glial-Based Synaptic Dysfunction.

Front Cell Neurosci 2015 22;9:521. Epub 2016 Jan 22.

CNC - Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Faculty of Medicine, University of CoimbraCoimbra, Portugal.

Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processes occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the "quad-partite" synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increased microglia "activation" in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, brain-derived neurotrophic factor, BDNF) affect glia functioning, whereas antidepressant treatments (serotonin-selective reuptake inhibitors, SSRIs, electroshocks, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication-such as the purinergic neuromodulation system operated by adenosine 5'-triphosphate (ATP) and adenosine-emerge as promising candidates to "re-normalize" synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.
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http://dx.doi.org/10.3389/fncel.2015.00521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722129PMC
February 2016

Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

Behav Brain Res 2016 Mar 18;301:43-54. Epub 2015 Dec 18.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88049-900, SC, Brazil; Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário (HU), Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address:

Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.
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http://dx.doi.org/10.1016/j.bbr.2015.12.011DOI Listing
March 2016

Exercise Improves Cognitive Impairment and Dopamine Metabolism in MPTP-Treated Mice.

Neurotox Res 2016 Jan;29(1):118-25

The classical motor symptoms of Parkinson’s disease (PD) are preceded by non-motor symptoms in preclinical stages, including cognition impairment. The current drug treatment for PD is palliative and does not meet the clinical challenges of the disease, such as levodopa-induced dyskinesia, non-motor symptoms, and neuroprotection. We investigated the neuroprotective and disease-modifying potential of physical exercise in a preclinical animal model of PD. C57BL/6 mice (adult males) ran on a horizontal treadmill for 6 weeks (moderate intensity, 5 times/week) and were treated intranasally with 65 mg/kg of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Exercise did not protect against MPTP-induced nigrostriatal neurodegeneration or frontostriatal dopamine depletion but decreased striatal dopamine turnover. Exercise also attenuated procedural and working memory impairment and D2 receptor hypersensitivity in MPTP-treated mice. In summary, exercise improved dopaminergic neurotransmission and enhanced cognition in a preclinical animal model of PD.
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http://dx.doi.org/10.1007/s12640-015-9566-4DOI Listing
January 2016

Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain.

Purinergic Signal 2015 Dec 7;11(4):561-9. Epub 2015 Oct 7.

CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.

ATP consumption during intense neuronal activity leads to peaks of both extracellular adenosine levels and increased glucose uptake in the brain. Here, we investigated the hypothesis that the activation of the low-affinity adenosine receptor, the A2B receptor (A(2B)R), promotes glucose uptake in neurons and astrocytes, thereby linking brain activity with energy metabolism. To this end, we mapped the spatiotemporal accumulation of the fluorescent-labelled deoxyglucose, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), in superfused acute hippocampal slices of C57Bl/6j mice. Bath application of the A(2B)R agonist BAY606583 (300 nM) triggered an immediate and stable (>10 min) increase of the velocity of 2-NBDG accumulation throughout hippocampal slices. This was abolished with the pretreatment with the selective A(2B)R antagonist, MRS1754 (200 nM), and was also absent in A(2B)R null-mutant mice. In mouse primary astrocytic or neuronal cultures, BAY606583 similarly increased (3)H-deoxyglucose uptake in the following 20 min incubation period, which was again abolished by a pretreatment with MRS1754. Finally, incubation of hippocampal, frontocortical, or striatal slices of C57Bl/6j mice at 37 °C, with either MRS1754 (200 nM) or adenosine deaminase (3 U/mL) significantly reduced glucose uptake. Furthermore, A(2B)R blockade diminished newly synthesized glycogen content and at least in the striatum, increased lactate release. In conclusion, we report here that A(2B)R activation is associated with an instant and tonic increase of glucose transport into neurons and astrocytes in the mouse brain. These prompt further investigations to evaluate the clinical potential of this novel glucoregulator mechanism.
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http://dx.doi.org/10.1007/s11302-015-9474-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648789PMC
December 2015

Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats.

Mol Neurobiol 2016 08 12;53(6):3891-3899. Epub 2015 Jul 12.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, 88049-900, Brazil.

The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10 μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7 days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21 days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD.
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http://dx.doi.org/10.1007/s12035-015-9330-zDOI Listing
August 2016

Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models.

Neurobiol Dis 2015 Jul 16;79:70-80. Epub 2015 Apr 16.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA. Electronic address:

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A2(A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation.
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http://dx.doi.org/10.1016/j.nbd.2015.03.030DOI Listing
July 2015

Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus.

Eur J Neurosci 2015 Apr 19;41(7):878-88. Epub 2015 Feb 19.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal.

Adenosine is a neuromodulator mostly acting through A1 (inhibitory) and A2A (excitatory) receptors in the brain. A2B receptors (A(2B)R) are G(s/q)--protein-coupled receptors with low expression in the brain. As A(2B)R function is largely unknown, we have now explored their role in the mouse hippocampus. We performed electrophysiological extracellular recordings in mouse hippocampal slices, and immunological analysis of nerve terminals and glutamate release in hippocampal slices and synaptosomes. Additionally, A(2B)R-knockout (A(2B)R-KO) and C57/BL6 mice were submitted to a behavioural test battery (open field, elevated plus-maze, Y-maze). The A(2B)R agonist BAY60-6583 (300 nM) decreased the paired-pulse stimulation ratio, an effect prevented by the A(2B)R antagonist MRS 1754 (200 nM) and abrogated in A(2B)R-KO mice. Accordingly, A(2B)R immunoreactivity was present in 73 ± 5% of glutamatergic nerve terminals, i.e. those immunopositive for vesicular glutamate transporters. Furthermore, BAY 60-6583 attenuated the A(1)R control of synaptic transmission, both the A(1)R inhibition caused by 2-chloroadenosine (0.1-1 μM) and the disinhibition caused by the A(1)R antagonist DPCPX (100 nM), both effects prevented by MRS 1754 and abrogated in A(2B)R-KO mice. BAY 60-6583 decreased glutamate release in slices and also attenuated the A(1)R inhibition (CPA 100 nM). A(2B)R-KO mice displayed a modified exploratory behaviour with an increased time in the central areas of the open field, elevated plus-maze and the Y-maze and no alteration of locomotion, anxiety or working memory. We conclude that A(2B)R are present in hippocampal glutamatergic terminals where they counteract the predominant A(1)R-mediated inhibition of synaptic transmission, impacting on exploratory behaviour.
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http://dx.doi.org/10.1111/ejn.12851DOI Listing
April 2015

Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease.

PLoS One 2014 8;9(12):e114216. Epub 2014 Dec 8.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, 88049-900, SC, Brazil.

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/-) to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination), anxiety (elevated plus-maze), depressive-like behavior (forced swimming and tail suspension) and motor function (rotarod, grasping strength and pole). However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP). These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259468PMC
August 2015

The adenosine neuromodulation system in schizophrenia.

Int Rev Neurobiol 2014 ;119:395-449

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

The management of schizophrenia endophenotypes, namely positive, negative, and cognitive symptoms is still an open goal, justifying the search of novel therapeutic avenues. We now review the evidence supporting the interest in targeting the adenosine modulation system to counteract the core features of schizophrenia. This interest is forwarded by the combined ability of strategies aimed at bolstering adenosine levels together with the increasingly recognized impact of adenosine A2A receptors to control dopaminergic signaling, working memory, and behavioral sensitization; this is further heralded by the suggested clinical effectiveness of therapies increasing extracellular adenosine such as dipyridamole and allopurinol and the emergent recognition of a role for adenosine in neurodevelopment. Finally, the combined role of A1 and A2A receptors in assisting the implementation of adaptive changes and encoding of information salience in neuronal circuits together with the adaptive alterations of A1 and A2A receptor density upon brain dysfunction prompts the novel working hypothesis that the parallel imbalance of adenosine formation and of A1 and A2A receptors blurs the adequate encoding of information salience in neuronal circuits, which we propose to be a core pathogenic feature in the development of schizophrenia endophenotypes. This proposal should also provide a rationale to assist the design of future therapeutic intervention targeting the adenosine modulation system to manage schizophrenia endophenotypes: these should not be based only on an attempt to target adenosine kinase-A1 receptors or only A2A receptors, but should instead simultaneously target these two arms of the adenosine modulation system.
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http://dx.doi.org/10.1016/B978-0-12-801022-8.00016-7DOI Listing
May 2015

Cellular prion protein (PrP(C)) modulates ethanol-induced behavioral adaptive changes in mice.

Behav Brain Res 2014 Sep 26;271:325-32. Epub 2014 Jun 26.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil; Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.

Chronic consumption of drugs with addictive potential induces profound synaptic changes in the dopaminergic mesocorticolimbic pathway that underlie the long-term behavioral alterations seen in addicted subjects. Thus, exploring modulation systems of dopaminergic function may reveal novel targets to interfere with drug addiction. We recently showed that cellular prion protein (PrP(C)) affects the homeostasis of the dopaminergic system by interfering with dopamine synthesis, content, receptor density and signaling pathways in different brain areas. Here we report that the genetic deletion of PrP(C) modulates ethanol (EtOH)-induced behavioral alterations including the maintenance of drug seeking, voluntary consumption and the development of EtOH tolerance, all pivotal steps in drug addiction. Notably, these behavioral changes were accompanied by a significant depletion of dopamine levels in the prefrontal cortex and reduced dopamine D1 receptors in PrP(C) knockout mice. Furthermore, the pharmacological blockade of dopamine D1 receptors, but not D2 receptors, attenuated the abnormal EtOH consumption in PrP(C) knockout mice. Altogether, these findings provide new evidence that the PrP(C)/dopamine interaction plays a pivotal role in EtOH addictive properties in mice.
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http://dx.doi.org/10.1016/j.bbr.2014.05.067DOI Listing
September 2014

Cellular prion protein is present in dopaminergic neurons and modulates the dopaminergic system.

Eur J Neurosci 2014 Aug 26;40(3):2479-86. Epub 2014 Apr 26.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, Brazil; Center for Neuroscience and Cell Biology, Faculty of Medicine, Rua Larga University of Coimbra, 3004-504 Coimbra, Portugal.

Cellular prion protein (PrP(C) ) is widely expressed in the brain. Although the precise role of PrP(C) remains uncertain, it has been proposed to be a pivotal modulator of neuroplasticity events by regulating the glutamatergic and serotonergic systems. Here we report the existence of neurochemical and functional interactions between PrP(C) and the dopaminergic system. PrP(C) was found to co-localize with dopaminergic neurons and in dopaminergic synapses in the striatum. Furthermore, the genetic deletion of PrP(C) down-regulated dopamine D1 receptors and DARPP-32 density in the striatum and decreased dopamine levels in the prefrontal cortex of mice. This indicates that PrP(C) affects the homeostasis of the dopaminergic system by interfering differently in different brain areas with dopamine synthesis, content, receptor density and signaling pathways. This interaction between PrP(C) and the dopaminergic system prompts the hypotheses that the dopaminergic system may be implicated in some pathological features of prion-related diseases and, conversely, that PrP(C) may play a role in dopamine-associated brain disorders.
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http://dx.doi.org/10.1111/ejn.12600DOI Listing
August 2014

Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice.

J Ethnopharmacol 2012 Aug 18;143(1):158-69. Epub 2012 Jun 18.

Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.

Ethnopharmacological Relevance: Rosemary, Rosmarinus officinalis L., has several therapeutic applications in folk medicine for the treatment of a wide range of diseases, including depression.

Aim Of The Study: To evaluate the ability of Rosmarinus officinalis hydroalcoholic extract (ROHE), as compared to the positive control fluoxetine, to reverse behavioral (hyperactivity, anhedonic behavior and learning deficit in water maze) and biochemical alterations (serum glucose level and acetylcholinesterase, AChE, activity) induced by an animal model of depression, the olfactory bulbectomy (OB) in mice.

Materials And Methods: Locomotor and exploratory behavior was assessed in the open-field, novel object and novel cage tests, anhedonic behavior was assessed in the splash test; cognitive deficits were evaluated in the water maze task. For the first set of experiments, ROHE (10-300 mg/kg) or fluoxetine (10mg/kg) was administered once daily (p.o.) for 14 days after OB and the behavioral tests were performed. For the second set of experiments, serum glucose and hippocampal and cerebrocortical AChE activity were determined in OB and SHAM-operated mice treated orally with ROHE (10mg/kg), fluoxetine (10mg/kg) or vehicle.

Results: ROHE (10-300 mg/kg), similar to fluoxetine, reversed OB-induced hyperactivity, increased exploratory and anhedonic behavior. OB needed significantly more trials in the training session to acquire the spatial information, but they displayed a similar profile to that of SHAM mice in the test session (24h later), demonstrating a selective deficit in spatial learning, which was not reversed by ROHE or fluoxetine. A reduced serum glucose level and an increased hippocampal AChE activity were observed in bulbectomized mice; only the latter effect was reversed by fluoxetine, while both effects were reversed by ROHE.

Conclusions: ROHE exerted an antidepressant-like effect in bulbectomized mice and was able to abolish AchE alterations and hypoglycemia, but not spatial learning deficit induced by OB. Overall, results suggest the potential of Rosmarinus officinalis for the treatment of depression, validating the traditional use of this plant.
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http://dx.doi.org/10.1016/j.jep.2012.06.017DOI Listing
August 2012

Proanthocyanidin-rich fraction from Croton celtidifolius Baill confers neuroprotection in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rat model of Parkinson's disease.

J Neural Transm (Vienna) 2010 Dec 8;117(12):1337-51. Epub 2010 Oct 8.

Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC 88049-900, Brazil.

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, the proanthocyanidin-rich fraction (PRF) obtained from the bark of Croton celtidifolius Baill (Euphorbiaceae), a tree frequently found in the Atlantic forest in south Brazil, has been described to have several neurobiological activities including antioxidant and anti-inflammatory properties, which may be of interest in the treatment of PD. The present data indicated that the pretreatment with PRF (10 mg/kg, i.p.) during five consecutive days was able to prevent mitochondrial complex-I inhibition in the striatum and olfactory bulb, as well as a decrease of the enzyme tyrosine hydroxylase expression in the olfactory bulb and substantia nigra of rats infused with a single intranasal administration of MPTP (1 mg/nostril). Moreover, pretreatment with PRF was found to attenuate the short-term social memory deficits, depressive-like behavior and reduction of locomotor activity observed at different periods after intranasal MPTP administration in rats. Altogether, the present findings provide strong evidence that PRF from C. celtidifolius may represent a promising therapeutic tool in PD, thus being able to prevent both motor and non-motor early symptoms of PD, together with its neuroprotective potential.
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http://dx.doi.org/10.1007/s00702-010-0464-xDOI Listing
December 2010

Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β(1-40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage.

Exp Neurol 2010 Dec 15;226(2):274-84. Epub 2010 Sep 15.

Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil.

The accumulation of amyloid-beta (Aβ) peptides in the brain of human and rodents has been associated with the activation of glial cells, neuroinflammatory and oxidative responses, and cognitive deficits. These oxidative changes leave glutamate transporters more vulnerable and may result in reduction of their functions, resulting in excitotoxic damage. Herein, we evaluated the effects of atorvastatin, a HMG-CoA reductase inhibitor, in molecular and behavioral alterations induced by a single intracerebroventricular injection of aggregated Aβ(1-40) (400 pmol) in mice. An increased glial fibrillar acidic protein (GFAP) expression and cyclooxygenase-2 (COX-2) levels, as well as increased lipid peroxidation and impairment in the glutathione antioxidant system and cell degeneration was found in the hippocampus of Aβ(1-40)-treated mice. Aβ(1-40) also induced a marked decrease in glutamatergic transporters (GLAST and GLT-1) expression and in l-[³H] glutamate uptake in mice hippocampus, in addition to spatial learning and memory deficits. Atorvastatin (10 mg/kg/day v.o.) was administered after Aβ(1-40) injection and through seven consecutive days. Atorvastatin treatment was neuroprotective against cell degeneration induced by Aβ(1-40), reducing inflammatory and oxidative responses and increasing the expression of glutamatergic transporters. On the other hand, atorvastatin did not reverse the cognitive impairments and failed to alter the hippocampal glutamate uptake in Aβ(1-40)-treated mice. These results reinforce and extend the notion of the potential neuroprotective action of atorvastatin against the neuronal toxicity induced by Aβ(1-40). In addition, the present findings suggest that the spatial learning and memory deficits induced by Aβ peptides in rodents may not be entirely related to neuronal damage.
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http://dx.doi.org/10.1016/j.expneurol.2010.08.030DOI Listing
December 2010

Central nervous system activity of the proanthocyanidin-rich fraction obtained from Croton celtidifolius in rats.

J Pharm Pharmacol 2010 Aug;62(8):1061-8

Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil.

Objectives: The aim of the present study was to evaluate the possible neurobehavioural effects in rats of the proanthocyanidin-rich fraction (PRF) isolated from the bark of Croton celtidifolius (Euphorbiaceae).

Methods: Adult Wistar rats were treated with the PRF (0.3-30 mg/kg) and evaluated in different behavioural paradigms classically used for the screening of drugs with psychoactive effects.

Key Findings: Acute intraperitoneal (i.p.) administration of PRF decreased spontaneous locomotor activity (open field arena and activity cage), enhanced the duration of ethyl ether-induced hypnosis, increased the latency to the first convulsion induced by pentylenetetrazole (60 mg/kg, i.p.) and attenuated apomorphine-induced (0.5 mg/kg, i.p.) stereotyped behaviour. In lower doses, PRF (0.3 or 3 mg/kg, i.p.) increased the frequency of open arm entries in the elevated plus-maze test.

Conclusions: The present findings suggest that the systemic administration of PRF induces a wide spectrum of behavioural alterations in rats, consistent with the putative existence of hypnosedative, anticonvulsant and anxiolytic compounds.
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http://dx.doi.org/10.1111/j.2042-7158.2010.01124.xDOI Listing
August 2010

Effects of traumatic brain injury of different severities on emotional, cognitive, and oxidative stress-related parameters in mice.

J Neurotrauma 2010 Oct;27(10):1883-93

Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, Brazil.

Cognitive deficits and psychiatric disorders are significant sequelae of traumatic brain injury (TBI). Animal models have been widely employed in TBI research, but few studies have addressed the effects of experimental TBI of different severities on emotional and cognitive parameters. In this study, mice were subjected to weight-drop TBI to induce mild, intermediate, or severe TBI. After neurological assessment, the mice recovered for 10 days, and were then subjected to a battery of behavioral tests, which included open-field, elevated plus-maze, forced swimming, tail suspension, and step-down inhibitory avoidance tests. Oxidative stress-related parameters (nonprotein thiols [NPSH], glutathione peroxidase [GPx], glutathione reductase [GR], and thiobarbituric acid reactive species [TBARS]) were quantified in the cortex and hippocampus at 2 and 24 h and 14 days after TBI, and histopathological analysis was performed 15 days after TBI. Mice subjected to mild TBI showed increased anxiety and depressive-like behaviors, while intermediate and severe TBI induced robust memory deficits. The severe TBI group also displayed increased locomotor activity. Intermediate and severe TBI caused extensive macroscopic and microscopic brain damage, while mild TBI typically had no histological abnormalities. Moreover, a significant increase in TBARS in the ipsilateral cortex and GPx in the ipsilateral hippocampus was observed at 24 h and 14 days, respectively, following intermediate TBI. The current experimental TBI model induced emotional and cognitive changes comparable to sequelae seen in human TBI, and it might therefore represent a useful approach to the study of mechanisms of and new treatments for TBI and related disorders.
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http://dx.doi.org/10.1089/neu.2010.1318DOI Listing
October 2010

Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) rat model of Parkinson's disease.

Ann N Y Acad Sci 2009 Jul;1170:629-36

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.

The presence of smell loss and the early pathological involvement of the olfactory pathways in the early stages of some neurodegenerative disorders are in accord with the tenants of the olfactory vector hypothesis. This hypothesis postulates that some such diseases may be caused or catalyzed by agents that enter the brain via the olfactory mucosa. In this study, rats infused intranasally (i.n.) with a low concentration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subsequently suffered olfactory, cognitive, and motor function impairments conceivably analogous to those observed during different stages of the development of Parkinson's disease (PD). Such infusion decreased the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra by means of apoptotic mechanisms, reducing dopamine levels in different brain structures, such as the olfactory bulb, striatum, and prefrontal cortex. These findings reinforce the suggestion that the olfactory system may be a particularly sensitive route for the penetration of xenobiotic agents into the central nervous system and that the i.n. MPTP rat model may provide insight into the underlying mechanisms of PD pathogenesis, potentially leading to the development of new therapeutic strategies for this devastating disease.
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http://dx.doi.org/10.1111/j.1749-6632.2009.03885.xDOI Listing
July 2009

Differential gender-related susceptibility to learning and memory deficits in mice submitted to neonatal freezing microgyria model.

Brain Res Bull 2009 May 21;79(3-4):177-81. Epub 2009 Feb 21.

Departamento de Farmacologia, UFSC, Florianópolis, SC, Brazil.

Sexual dimorphism during mammalian neural development seems to contribute to differential gender-related incidence in malformations of cortical development in both humans and rodents. Here we investigated the existence of differential gender-related susceptibility to learning and memory deficits and brain injury severity in mice submitted to a microgyria model. Newborn male and female C57BL/6 mice (P0) were submitted to a unilateral freezing lesion (FL) using a cooled steel probe, placed over the right midline anteroposterior plane. Mice were allowed to survive for 12-14 weeks and then were submitted to behavioral tasks and brain morphological analyses. Injured mice from both genders did not present gross locomotor alterations, and the freezing lesion resulted in similar brain damage in male and female mice. Additionally, a selective disruption in the short-term social recognition memory was observed in injured male mice while the long-term inhibitory avoidance memory was not affected by both the factors. These results indicate a reduced susceptibility of female to short-term social-memory deficits induced by neonatal model of microgyria in mice, suggesting that the cognitive deficits induced by freezing lesions in rodents may not be entirely related to the severity of brain injury.
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http://dx.doi.org/10.1016/j.brainresbull.2009.02.003DOI Listing
May 2009

Aniracetam and DNQX affect the acquisition of rapid tolerance to ethanol in mice.

Pharmacol Biochem Behav 2009 Mar 25;92(1):32-8. Epub 2008 Oct 25.

Dept Farmacologia, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, SC, Brazil.

Several studies have emphasized the role of learning in the development of rapid tolerance and have shown that glutamate-mediated neurotransmission plays an important role in this phenomenon. Since the AMPA/kainate receptor system is directly involved in plasticity mechanisms, the influence of this receptor system on rapid tolerance induced by ethanol was studied using the rotarod. In the first experiment, mice were pretreated with aniracetam, an agonist of AMPA/kainate receptors, 30 min before ethanol (2.75 g/kg; IP) treatment, and tested on the rotarod. After 24 h, the groups were tested on the rotarod under ethanol treatment. Aniracetam facilitated the acquisition of rapid tolerance to ethanol. In the second experiment, mice received DNQX, a competitive antagonist of the AMPA receptor, 30 min before ethanol treatment (3 g/kg) and submitted to the rotarod. This dose of ethanol produced tolerance per se. Groups were tested under ethanol treatment (1.75 g/kg) after 24 h. DNQX blocked rapid tolerance to ethanol. Using a similar protocol, the third experiment showed that DNQX blocked the aniracetam-induced facilitation of rapid tolerance to ethanol. Our results show that aniracetam facilitates whereas DNQX blocks ethanol tolerance, suggesting that the non-NMDA receptors are involved in this phenomenon.
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http://dx.doi.org/10.1016/j.pbb.2008.10.006DOI Listing
March 2009