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Article ; Online: Selective orexin 1 receptor antagonism does not affect effort-based responding for sucrose reward in rats.

Bergamini, Giorgio / Durkin, Sean / Steiner, Michel Alexander

Journal of psychopharmacology (Oxford, England)

2024 Volume 38, Issue 3, Page(s) 305–308

Abstract: In rodents, orexin neuropeptides regulate motivation and reward-seeking via orexin 1 receptor (OX1R) signaling in the mesolimbic dopaminergic system. This role is clearly established for rewards inherent to drugs of abuse but less so for natural rewards. ...

Abstract	In rodents, orexin neuropeptides regulate motivation and reward-seeking via orexin 1 receptor (OX1R) signaling in the mesolimbic dopaminergic system. This role is clearly established for rewards inherent to drugs of abuse but less so for natural rewards. Reported effects of the selective OX1R antagonist (SO1RA) SB-334867 on motivation for palatable food are ambiguous. In our experimental conditions neither SB-334867, nor two additional, structurally different SO1RAs, ACT-335827 and the clinical development candidate nivasorexant, affected effort-based responding for sucrose in rats. The positive control lisdexamfetamine, approved for psychiatric disorders associated with altered reward sensitivity such as binge eating disorder, increased effort-based responding.
MeSH term(s)	Humans ; Rats ; Animals ; Orexins/pharmacology ; Orexin Receptors ; Sucrose/pharmacology ; Reward ; Conditioning, Operant ; Benzoxazoles ; Naphthyridines ; Urea/analogs & derivatives
Chemical Substances	Orexins ; 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea ; Orexin Receptors ; Sucrose (57-50-1) ; Benzoxazoles ; Naphthyridines ; Urea (8W8T17847W)
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639313-5
ISSN	1461-7285 ; 0269-8811
ISSN (online)	1461-7285
ISSN	0269-8811
DOI	10.1177/02698811241229523
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Article: Probing the relevance of the accelerated aging mouse line SAMP8 as a model for certain types of neuropsychiatric symptoms in dementia.

Bergamini, Giorgio / Massinet, Helene / Hart, Aaron / Durkin, Sean / Pierlot, Gabin / Steiner, Michel Alexander

Frontiers in psychiatry

2023 Volume 14, Page(s) 1054163

Abstract: Introduction: People with dementia (PwD) often present with neuropsychiatric symptoms (NPS). NPS are of substantial burden to the patients, and current treatment options are unsatisfactory. Investigators searching for novel medications need animal ... ...

Abstract	Introduction: People with dementia (PwD) often present with neuropsychiatric symptoms (NPS). NPS are of substantial burden to the patients, and current treatment options are unsatisfactory. Investigators searching for novel medications need animal models that present disease-relevant phenotypes and can be used for drug screening. The Senescence Accelerated Mouse-Prone 8 (SAMP8) strain shows an accelerated aging phenotype associated with neurodegeneration and cognitive decline. Its behavioural phenotype in relation to NPS has not yet been thoroughly investigated. Physical and verbal aggression in reaction to the external environment (e.g., interaction with the caregiver) is one of the most prevalent and debilitating NPS occurring in PwD. Reactive aggression can be studied in male mice using the Resident-Intruder (R-I) test. SAMP8 mice are known to be more aggressive than the Senescence Accelerated Mouse-Resistant 1 (SAMR1) control strain at specific ages, but the development of the aggressive phenotype over time, is still unknown. Methods: In our study, we performed a longitudinal, within-subject, assessment of aggressive behaviour of male SAMP8 and SAMR1 mice at 4, 5, 6 and 7 months of age. Aggressive behaviour from video recordings of the R-I sessions was analysed using an in-house developed behaviour recognition software. Results: SAMP8 mice were more aggressive relative to SAMR1 mice starting at 5 months of age, and the phenotype was still present at 7 months of age. Treatment with risperidone (an antipsychotic frequently used to treat agitation in clinical practice) reduced aggression in both strains. In a three-chamber social interaction test, SAMP8 mice also interacted more fervently with male mice than SAMR1, possibly because of their aggression-seeking phenotype. They did not show any social withdrawal. Discussion: Our data support the notion that SAMP8 mice might be a useful preclinical tool to identify novel treatment options for CNS disorders associated with raised levels of reactive aggression such as dementia.
Language	English
Publishing date	2023-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2023.1054163
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Article ; Online: Longitudinal assessment of aggression and circadian rhythms in the APPswe mouse model of Alzheimer`s disease.

Bergamini, Giorgio / Massinet, Helene / Durkin, Sean / Steiner, Michel Alexander

Physiology & behavior

2022 Volume 250, Page(s) 113787

Abstract: Agitation, which comprises verbal or physical aggression and hyperactivity, is one of the most frequent neuropsychiatric symptoms observed in patients with Alzheimer's disease (AD). It often co-occurs with dysregulated circadian rhythms. Current ... ...

Abstract	Agitation, which comprises verbal or physical aggression and hyperactivity, is one of the most frequent neuropsychiatric symptoms observed in patients with Alzheimer's disease (AD). It often co-occurs with dysregulated circadian rhythms. Current medications are associated with serious adverse effects, and novel therapeutics are therefore needed. Rodent models can be instrumental to provide a first signal for potential efficacy of novel drug candidates. Longitudinal data assessing the face validity of such models for AD-related agitation are largely missing. We employed telemeterized APPswe mice, a frequently used AD transgenic mouse line overexpressing the human beta-amyloid precursor protein (APP) with the Swedish KM670/671NL mutation, to study the occurrence and progression of changes in reactive aggressive behavior as well as the circadian profile of locomotor activity and body temperature. Analysis was conducted between 5 and 11 months of age, at regular 2-months intervals. The aggressivity of all mice was highest at 5 months and waned with increasing age. APPswe mice were more aggressive than WT at 5 and 7 months of age. The locomotor activity and body temperature of WT mice declined with increasing age, while that of APPswe mice remained rather constant. This genotype difference was solely evident during the active, dark phase. APPswe mice did not display a phase shift of their circadian rhythms. We conclude that the APPswe mouse line can recapitulate some of the behavioral disturbances observed in AD, including an agitation-relevant phenotype characterized by active phase hyperactivity and aggressivity. It does not recapitulate the nighttime disturbances (also characterized by hyperactivity) and the shift of circadian rhythms observed in AD patients. Therefore, the APPswe strain could be used at specific ages to model a subset of agitation-relevant behavioral problems and to test the modulatory effects of drugs.
MeSH term(s)	Aggression ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Circadian Rhythm/genetics ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic
Chemical Substances	Amyloid beta-Protein Precursor
Language	English
Publishing date	2022-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2022.113787
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Article: Longitudinal assessment of aggression and circadian rhythms in the APPswe mouse model of Alzheimer`s disease

Bergamini, Giorgio / Massinet, Helene / Durkin, Sean / Steiner, Michel Alexander

Physiology & behavior. 2022 Mar. 23,

2022

Abstract	Agitation, which comprises verbal or physical aggression and hyperactivity, is one of the most frequent neuropsychiatric symptoms observed in patients with Alzheimer's disease (AD). It often co-occurs with dysregulated circadian rhythms. Current medications are associated with serious adverse effects, and novel therapeutics are therefore needed. Rodent models can be instrumental to provide a first signal for potential efficacy of novel drug candidates. Longitudinal data assessing the face validity of such models for AD-related agitation are largely missing. We employed telemeterized APPswe mice, a frequently used AD transgenic mouse line overexpressing the human beta-amyloid precursor protein (APP) with the Swedish KM670/671NL mutation, to study the occurrence and progression of changes in reactive aggressive behavior as well as the circadian profile of locomotor activity and body temperature. Analysis was conducted between 5 and 11 months of age, at regular 2-months intervals. The aggressivity of all mice was highest at 5 months and waned with increasing age. APPswe mice were more aggressive than WT at 5 and 7 months of age. The locomotor activity and body temperature of WT mice declined with increasing age, while that of APPswe mice remained rather constant. This genotype difference was solely evident during the active, dark phase. APPswe mice did not display a phase shift of their circadian rhythms. We conclude that the APPswe mouse line can recapitulate some of the behavioral disturbances observed in AD, including an agitation-relevant phenotype characterized by active phase hyperactivity and aggressivity. It does not recapitulate the night-time disturbances (also characterized by hyperactivity) and the shift of circadian rhythms observed in AD patients. Therefore, the APPswe strain could be used at specific ages to model a subset of agitation-relevant behavioral problems and to test the modulatory effects of drugs.
Keywords	Alzheimer disease ; aggression ; agitation ; body temperature ; drugs ; genotype ; humans ; locomotion ; mice ; mutation ; phenotype ; therapeutics ; validity
Language	English
Dates of publication	2022-0323
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2022.113787
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Article ; Online: The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils.

Nordquist, Rebecca E / Durkin, Sean / Jacquet, Aurélie / Spooren, Will

European journal of pharmacology

2008 Volume 600, Issue 1-3, Page(s) 87–92

Abstract: The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK(3) receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK(3) receptor between rats, mice and ... ...

Abstract	The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK(3) receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK(3) receptor between rats, mice and humans make rats and mice less acceptable species for testing tachykinin NK(3) receptor antagonism. This has led to testing of tachykinin NK(3) receptor activity in gerbils and guinea pigs. As these species are much less common laboratory animals than rats and mice, there is a relative paucity of in vivo testing models for tachykinin NK(3) receptor activation. In the present study, locomotor activity induced by the tachykinin NK(3) receptor agonist senktide was characterized. Injection of senktide i.c.v. was found to dose-dependently induce hyperlocomotion from a dose of 0.06 nmol to the maximal dose tested, 0.6 nmol. Locomotion induced by 0.1 nmol of senktide could be blocked by injection of the tachykinin NK(3) receptor antagonists SB222200 (10 and 30 mg/kg i.p.) and talnetant (SB223412; 10 and 30 mg/kg i.p.), as well as by osanetant (SR142801; 10 and 30 mg/kg i.p.) when administered in a vehicle containing vitamin E and glycofurol. Senktide-induced activity was also reversed by the antipsychotics haloperidol (0.3 and 1 mg/kg p.o.) and risperidone (1 mg/kg p.o.), but not by the serotonin 5HT(2a/c) receptor antagonist MDL100907 (tested at 0.1, 0.3 and 1 mg/kg p.o.). Hyperlocomotion induced by 0.03 nmol of senktide was potentiated by antagonism of the tachykinin NK(1) receptor with aprepitant (1, 3 and 10 mg/kg, p.o.). Thus, hyperlocomotion induced by senktide in gerbils is a tachykinin NK(3) receptor-mediated behavior that is appropriate for use in testing tachykinin NK(3) receptor activity of novel compounds.
MeSH term(s)	Animals ; Behavior, Animal/drug effects ; Dose-Response Relationship, Drug ; Gerbillinae ; Hyperkinesis/chemically induced ; Injections, Intraventricular ; Male ; Models, Animal ; Morpholines/administration & dosage ; Morpholines/pharmacology ; Neurokinin-1 Receptor Antagonists ; Peptide Fragments/administration & dosage ; Peptide Fragments/pharmacology ; Pharmaceutical Vehicles/chemistry ; Receptors, Neurokinin-3/agonists ; Receptors, Neurokinin-3/antagonists & inhibitors ; Species Specificity ; Substance P/administration & dosage ; Substance P/analogs & derivatives ; Substance P/pharmacology
Chemical Substances	Morpholines ; Neurokinin-1 Receptor Antagonists ; Peptide Fragments ; Pharmaceutical Vehicles ; Receptors, Neurokinin-3 ; senktide (106128-89-6) ; aprepitant (1NF15YR6UY) ; Substance P (33507-63-0)
Language	English
Publishing date	2008-12-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2008.10.011
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Article: Stress-induced hyperthermia: effects of acute and repeated dosing of MPEP.

Nordquist, Rebecca E / Durkin, Sean / Jaeschke, Georg / Spooren, Will

European journal of pharmacology

2007 Volume 568, Issue 1-3, Page(s) 199–202

Abstract: The mGlu5 receptor antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP) is highly anxiolytic in rodent models of anxiety. Recent studies showed that MPEP remains effective in some models of anxiety after repeated treatment, but tolerance may develop in ...

Abstract	The mGlu5 receptor antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP) is highly anxiolytic in rodent models of anxiety. Recent studies showed that MPEP remains effective in some models of anxiety after repeated treatment, but tolerance may develop in other models. To further evaluate anxiolytic properties of repeated MPEP, a single administration of 3, 10, or 30 mg/kg p.o. and repeated administration of 30 mg/kg p.o. was tested in the stress-induced hyperthermia model in mice. MPEP dose-dependently inhibited stress-induced hyperthermia when given acutely. MPEP remained equally active in reducing stress-induced hyperthermia after five daily treatments with 30 mg/kg, further validating MPEP as a potential anxiolytic for chronic use.
MeSH term(s)	Animals ; Anti-Anxiety Agents/administration & dosage ; Anxiety/drug therapy ; Anxiety/physiopathology ; Excitatory Amino Acid Antagonists/administration & dosage ; Fever/drug therapy ; Fever/physiopathology ; Male ; Mice ; Mice, Inbred Strains ; Pyridines/administration & dosage ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Stress, Psychological/complications
Chemical Substances	Anti-Anxiety Agents ; Excitatory Amino Acid Antagonists ; Pyridines ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate ; 6-methyl-2-(phenylethynyl)pyridine (7VC0YVI27Y)
Language	English
Publishing date	2007-07-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2007.04.034
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Article: TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

Revel, Florent G / Moreau, Jean-Luc / Gainetdinov, Raul R / Bradaia, Amyaouch / Sotnikova, Tatyana D / Mory, Roland / Durkin, Sean / Zbinden, Katrin Groebke / Norcross, Roger / Meyer, Claas A / Metzler, Veit / Chaboz, Sylvie / Ozmen, Laurence / Trube, Gerhard / Pouzet, Bruno / Bettler, Bernhard / Caron, Marc G / Wettstein, Joseph G / Hoener, Marius C

Proceedings of the National Academy of Sciences of the United States of America. 2011 May 17, v. 108, no. 20

2011

Abstract: The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and Î²-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising ... ...

Abstract	The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and Î²-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HTâA receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1â»/â» mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.
Keywords	Macaca fascicularis ; agonists ; amino acids ; antagonists ; behavior disorders ; brain stem ; dopamine ; fever ; humans ; knockout mutants ; metabolites ; mice ; neurons ; rats ; receptors
Language	English
Dates of publication	2011-0517
Size	p. 8485-8490.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1103029108
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Article ; Online: TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity.

Proceedings of the National Academy of Sciences of the United States of America

2011 Volume 108, Issue 20, Page(s) 8485–8490

Abstract: The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising ... ...

Abstract	The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.
MeSH term(s)	Animals ; Benzodioxoles/pharmacology ; Biogenic Monoamines/metabolism ; Dopamine/metabolism ; Glutamine/metabolism ; HEK293 Cells ; Humans ; Mental Disorders ; Mice ; Phenylpropionates/pharmacology ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/deficiency ; Receptors, G-Protein-Coupled/metabolism ; Synaptic Transmission/physiology
Chemical Substances	4-(3-(6-(3-benzo(1,3)dioxol-5-yl-5-thiophen-3-ylphenoxy)hexyl)-2-(2-carboxyethyl)phenoxy)butyric acid ; Benzodioxoles ; Biogenic Monoamines ; Phenylpropionates ; Receptors, G-Protein-Coupled ; Glutamine (0RH81L854J) ; Dopamine (VTD58H1Z2X) ; Trace amine-associated receptor 1 (XMC8VP6RI2)
Language	English
Publishing date	2011-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1103029108
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Article: TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

Revel, Florent G. / Moreau, Jean-Luc / Gainetdinov, Raul R. / Bradaia, Amyaouch / Sotnikova, Tatyana D. / Mory, Roland / Durkin, Sean / Zbinden, Katrin Groebke / Norcross, Roger / Meyer, Claas A. / Metzler, Veit / Chaboz, Sylvie / Ozmen, Laurence / Trube, Gerhard / Pouzet, Bruno / Bettler, Bernhard / Caron, Marc G. / Wettstein, Joseph G. / Hoener, Marius C.

Proceedings of the National Academy of Sciences of the United States of America

Volume v. 108,, Issue no. 2

Abstract	The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and Î²-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HTâA receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1â»/â» mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.
Language	English
Document type	Article
ISSN	0027-8424
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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