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  1. Article: Combined Antagonism of 5-HT

    Frau, Roberto / Pardu, Alessandra / Godar, Sean / Bini, Valentina / Bortolato, Marco

    Pharmaceuticals (Basel, Switzerland)

    2022  Volume 15, Issue 2

    Abstract: The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We ... ...

    Abstract The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT
    Language English
    Publishing date 2022-02-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph15020213
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Corrigendum to "Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease" [Experimental neurology 2023 May;363:114370].

    Corsi, Sara / Scheggi, Simona / Pardu, Alessandra / Braccagni, Giulia / Caruso, Donatella / Cioffi, Lucia / Diviccaro, Silvia / Gentile, Mauro / Fanni, Silvia / Stancampiano, Roberto / Gambarana, Carla / Melcangi, Roberto Cosimo / Frau, Roberto / Carta, Manolo

    Experimental neurology

    2023  Volume 373, Page(s) 114640

    Language English
    Publishing date 2023-12-15
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 207148-4
    ISSN 1090-2430 ; 0014-4886
    ISSN (online) 1090-2430
    ISSN 0014-4886
    DOI 10.1016/j.expneurol.2023.114640
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    Zs.A 184: Show issues Location:
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  3. Article ; Online: Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.

    Corsi, Sara / Scheggi, Simona / Pardu, Alessandra / Braccagni, Giulia / Caruso, Donatella / Cioffi, Lucia / Diviccaro, Silvia / Gentile, Mauro / Fanni, Silvia / Stancampiano, Roberto / Gambarana, Carla / Melcangi, Roberto Cosimo / Frau, Roberto / Carta, Manolo

    Experimental neurology

    2023  Volume 363, Page(s) 114370

    Abstract: Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; ... ...

    Abstract Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model. Moreover, this neurosteroid rescued psychotic-like phenotypes by exerting marked antidopaminergic activity. In light of this evidence, we investigated whether pregnenolone might dampen the appearance of LIDs in parkinsonian drug-naïve rats. We tested 3 escalating doses of pregnenolone (6, 18, 36 mg/kg) in 6-OHDA-lesioned male rats and compared the behavioral, neurochemical, and molecular outcomes with those induced by the 5AR inhibitor dutasteride, as positive control. The results showed that pregnenolone dose-dependently countered LIDs without affecting L-DOPA-induced motor improvements. Post-mortem analyses revealed that pregnenolone significantly prevented the increase of validated striatal markers of dyskinesias, such as phospho-Thr-34 DARPP-32 and phospho-ERK
    MeSH term(s) Male ; Rats ; Animals ; Levodopa/adverse effects ; Parkinson Disease/pathology ; Dutasteride/metabolism ; Dutasteride/pharmacology ; Dutasteride/therapeutic use ; Oxidopamine/toxicity ; Neurosteroids/metabolism ; Neurosteroids/pharmacology ; Neurosteroids/therapeutic use ; Rats, Sprague-Dawley ; Dyskinesia, Drug-Induced/metabolism ; Corpus Striatum/metabolism ; Antiparkinson Agents/adverse effects ; Disease Models, Animal
    Chemical Substances Levodopa (46627O600J) ; Dutasteride (O0J6XJN02I) ; Oxidopamine (8HW4YBZ748) ; Neurosteroids ; Antiparkinson Agents
    Language English
    Publishing date 2023-03-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207148-4
    ISSN 1090-2430 ; 0014-4886
    ISSN (online) 1090-2430
    ISSN 0014-4886
    DOI 10.1016/j.expneurol.2023.114370
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  4. Article ; Online: Selective activation of D1 dopamine receptors impairs sensorimotor gating in Long-Evans rats.

    Mosher, Laura J / Frau, Roberto / Pardu, Alessandra / Pes, Romina / Devoto, Paola / Bortolato, Marco

    British journal of pharmacology

    2015  Volume 173, Issue 13, Page(s) 2122–2134

    Abstract: Background and purpose: Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle ... ...

    Abstract Background and purpose: Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D1 and D2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain-dependent. Conversely, the role of D1 receptors in the regulation of PPI across different rat strains remains unclear.
    Experimental approach: We tested the effects of selective D1 and D2 receptor agonists and antagonists on the startle reflex and PPI of Sprague-Dawley, Wistar and Long-Evans rats.
    Key results: In contrast with Sprague-Dawley and Wistar rats, the full D1 receptor agonist SKF82958 elicited significant PPI deficits in Long-Evans rats, an effect sensitive to the selective D1 antagonist SCH23390.
    Conclusions and implications: Our results suggest that, in Long-Evans rats, D1 receptor activation may be sufficient to significantly impair PPI. These data emphasize the role of D1 receptors in the pathophysiology of neuropsychiatric disorders featuring alterations in sensorimotor gating, and uphold the importance of the genetic background in shaping the role of dopamine receptors in the regulation of this key information-processing function.
    Linked articles: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
    MeSH term(s) Animals ; Benzazepines/administration & dosage ; Benzazepines/pharmacology ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Dopamine D1/agonists ; Receptors, Dopamine D1/metabolism ; Sensory Gating/drug effects
    Chemical Substances Benzazepines ; Receptors, Dopamine D1 ; SK&F 82958 (80751-65-1)
    Language English
    Publishing date 2015-07-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.13232
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  5. Article ; Online: Juvenile cannabinoid treatment induces frontostriatal gliogenesis in Lewis rats.

    Bortolato, Marco / Bini, Valentina / Frau, Roberto / Devoto, Paola / Pardu, Alessandra / Fan, Yijun / Solbrig, Marylou V

    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

    2014  Volume 24, Issue 6, Page(s) 974–985

    Abstract: Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely ... ...

    Abstract Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely depends on the key influence of diverse genetic vulnerability factors. Inbred rodent strains afford a highly informative tool to study the contribution of genetic determinants to the long-term effects of juvenile cannabinoid exposure. In this study, we analyzed the phenotypical impact of the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 2mg/kg/day from postnatal day 35-48) in adolescent Lewis rats, an inbred strain exhibiting resistance to psychotomimetic effects of environmental manipulations. At the end of this treatment, WIN-injected animals displayed increased survival of new cells (mainly oligodendroglia precursors) in the striatum and prefrontal cortex (PFC), two key terminal fields of DAergic pathways. To test whether these changes may be associated with enduring behavioral alterations, we examined the consequences of adolescent WIN treatment in adulthood (postnatal days 60-70), with respect to DA levels and metabolism as well as multiple behavioral paradigms. Rats injected with WIN exhibited increased turnover, but not levels, of striatal DA. In addition, cannabinoid-treated animals displayed increases in acoustic startle latency and novel-object exploration; however, WIN treatment failed to induce overt deficits of sensorimotor gating and social interaction. These results indicate that, in Lewis rats, juvenile cannabinoid exposure leads to alterations in frontostriatal gliogenesis, as well as select behavioral alterations time-locked to high DAergic metabolism, but not overt schizophrenia-related deficits.
    MeSH term(s) Animals ; Benzoxazines/pharmacology ; Cannabinoids/adverse effects ; Cell Survival/drug effects ; Corpus Striatum/drug effects ; Corpus Striatum/growth & development ; Corpus Striatum/pathology ; Corpus Striatum/physiopathology ; Dopamine/metabolism ; Exploratory Behavior/drug effects ; Exploratory Behavior/physiology ; Male ; Maze Learning/drug effects ; Maze Learning/physiology ; Morpholines/pharmacology ; Naphthalenes/pharmacology ; Neurogenesis/drug effects ; Neurogenesis/physiology ; Neuroglia/drug effects ; Neuroglia/pathology ; Neuroglia/physiology ; Phenotype ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/growth & development ; Prefrontal Cortex/pathology ; Prefrontal Cortex/physiopathology ; Prepulse Inhibition/drug effects ; Prepulse Inhibition/physiology ; Rats, Inbred Lew ; Sensory Gating/drug effects ; Sensory Gating/physiology ; Social Behavior
    Chemical Substances Benzoxazines ; Cannabinoids ; Morpholines ; Naphthalenes ; (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone (5H31GI9502) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2014-01-18
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1082947-7
    ISSN 1873-7862 ; 0924-977X
    ISSN (online) 1873-7862
    ISSN 0924-977X
    DOI 10.1016/j.euroneuro.2013.12.011
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    Zs.A 3288: Show issues Location:
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    Zs.MO 630: Show issues

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  6. Article ; Online: Positive allosteric modulation of GABAB receptors ameliorates sensorimotor gating in rodent models.

    Frau, Roberto / Bini, Valentina / Pillolla, Giuliano / Malherbe, Pari / Pardu, Alessandra / Thomas, Andrew W / Devoto, Paola / Bortolato, Marco

    CNS neuroscience & therapeutics

    2014  Volume 20, Issue 7, Page(s) 679–684

    Abstract: Background: Converging evidence points to the involvement of γ-amino-butyric acid B receptors (GABABRs) in the regulation of information processing. We previously showed that GABABR agonists exhibit antipsychotic-like properties in rodent models of ... ...

    Abstract Background: Converging evidence points to the involvement of γ-amino-butyric acid B receptors (GABABRs) in the regulation of information processing. We previously showed that GABABR agonists exhibit antipsychotic-like properties in rodent models of sensorimotor gating deficits, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. The therapeutic potential of these agents, however, is limited by their neuromuscular side effects; thus, in this study, we analyzed whether rac-BHFF, a potent GABABR-positive allosteric modulator (PAM), could counter spontaneous and pharmacologically induced PPI deficits across various rodent models.
    Methods: We tested the antipsychotic effects of rac-BHFF on the PPI deficits caused by the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine, in Sprague-Dawley rats and C57BL/6 mice. Furthermore, we verified whether rac-BHFF ameliorated the spontaneous PPI impairments in DBA/2J mice.
    Results: rac-BHFF dose-dependently countered the PPI deficits across all three models, in a fashion akin to the GABABR agonist baclofen and the atypical antipsychotic clozapine; in contrast with these compounds, however, rac-BHFF did not affect startle magnitude.
    Conclusions: The present data further support the implication of GABABRs in the modulation of sensorimotor gating and point to their PAMs as a novel promising tool for antipsychotic treatment, with fewer side effects than GABABR agonists.
    MeSH term(s) Allosteric Regulation/drug effects ; Allosteric Regulation/physiology ; Animals ; Benzofurans/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Models, Animal ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-B/physiology ; Sensory Gating/drug effects ; Sensory Gating/physiology
    Chemical Substances (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one ; Benzofurans ; Receptors, GABA-B
    Language English
    Publishing date 2014-04-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2423461-8
    ISSN 1755-5949 ; 1755-5930
    ISSN (online) 1755-5949
    ISSN 1755-5930
    DOI 10.1111/cns.12261
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    Zs.A 4537: Show issues Location:
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  7. Article ; Online: The Neurosteroidogenic Enzyme 5α-Reductase Mediates Psychotic-Like Complications of Sleep Deprivation.

    Frau, Roberto / Bini, Valentina / Soggiu, Alessio / Scheggi, Simona / Pardu, Alessandra / Fanni, Silvia / Roncada, Paola / Puligheddu, Monica / Marrosu, Francesco / Caruso, Donatella / Devoto, Paola / Bortolato, Marco

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2017  Volume 42, Issue 11, Page(s) 2196–2205

    Abstract: Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we ... ...

    Abstract Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone. SD selectively enhanced 5αR expression and activity, as well as AP levels, in the prefrontal cortex; furthermore, finasteride (10-100 mg/kg, IP) dose-dependently ameliorated PPI deficits, hyperactivity, and risk-taking behaviors, in a fashion akin to the antipsychotic haloperidol and the mood stabilizer lithium carbonate. Finally, PPI deficits were exacerbated by allopregnanolone (10 mg/kg, IP) and attenuated by progesterone (30 mg/kg, IP) in SD-subjected, but not control rats. Collectively, these results provide the first-ever evidence that 5αR mediates a number of psychosis- and mania-like complications of SD through imbalances in cortical levels of neuroactive steroids.
    MeSH term(s) 5-alpha Reductase Inhibitors/pharmacology ; 5-alpha Reductase Inhibitors/therapeutic use ; Acoustic Stimulation/adverse effects ; Animals ; Antipsychotic Agents/pharmacology ; Brain/drug effects ; Brain/metabolism ; Cholestenone 5 alpha-Reductase/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Finasteride/pharmacology ; Finasteride/therapeutic use ; Gene Expression Regulation, Enzymologic/drug effects ; Male ; Pregnanolone/pharmacology ; Psychotic Disorders/drug therapy ; Psychotic Disorders/etiology ; Psychotic Disorders/pathology ; Rats ; Rats, Sprague-Dawley ; Reflex, Startle/drug effects ; Sleep Deprivation/complications ; Steroids/metabolism
    Chemical Substances 5-alpha Reductase Inhibitors ; Antipsychotic Agents ; Steroids ; Finasteride (57GNO57U7G) ; Pregnanolone (BXO86P3XXW) ; Cholestenone 5 alpha-Reductase (EC 1.3.1.22)
    Language English
    Publishing date 2017-02-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/npp.2017.13
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    Zs.A 2379: Show issues Location:
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