Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam

Leggio, GM; Torrisi, SA; Castorina, A; Platania, CBM; Impellizzeri, AAR; Fidilio, A; Caraci, F; Bucolo, C; Drago, F; Salomone, S

Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam

Leggio, GM Torrisi, SA Castorina, A

Platania, CBM Impellizzeri, AAR Fidilio, A Caraci, F Bucolo, C Drago, F Salomone, S

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Publication Type:: Journal Article
Citation:: European Neuropsychopharmacology, 2015, 25 (9), pp. 1427 - 1436
Issue Date:: 2015-01-01

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Field	Value	Language
dc.contributor.author	Leggio, GM	en_US
dc.contributor.author	Torrisi, SA	en_US
dc.contributor.author	Castorina, A https://orcid.org/0000-0001-7037-759X	en_US
dc.contributor.author	Platania, CBM	en_US
dc.contributor.author	Impellizzeri, AAR	en_US
dc.contributor.author	Fidilio, A	en_US
dc.contributor.author	Caraci, F	en_US
dc.contributor.author	Bucolo, C	en_US
dc.contributor.author	Drago, F	en_US
dc.contributor.author	Salomone, S	en_US
dc.date.available	2014-11-04	en_US
dc.date.issued	2015-01-01	en_US
dc.identifier.citation	European Neuropsychopharmacology, 2015, 25 (9), pp. 1427 - 1436	en_US
dc.identifier.issn	0924-977X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/119192
dc.description.abstract	© 2014 Elsevier B.V. and ECNP. Increasing evidence indicates that central dopamine (DA) neurotransmission is involved in pathophysiology of anxiety, in particular the DA receptor subtype 3 (D<inf>3</inf>R). We previously reported that D<inf>3</inf>R null mice (D<inf>3</inf>R<sup>-/-</sup>) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D<inf>3</inf>R<sup>-/-</sup> than in wild type (WT) when tested in the elevated plus maze test (EPM). Here we tested the hypothesis that genetic deletion or pharmacological blockade of D<inf>3</inf>R affect GABA<inf>A</inf> subunit expression, which in turn modulates anxiety-like behaviour as well as responsiveness and tolerance to diazepam. D<inf>3</inf>R<sup>-/-</sup> mice exhibited tolerance to diazepam (0.5mg/kg, i.p.), assessed by EPM, as fast as after 3 day-treatment, performing similarly to untreated D<inf>3</inf>R<sup>-/-</sup> mice; conversely, WT exhibited tolerance to diazepam after a 14-21 day-treatment. Analysis of GABA<inf>A</inf> α6 subunit mRNA expression by qPCR in striatum showed that it was about 15-fold higher in D<inf>3</inf>R<sup>-/-</sup> than in WT. Diazepam treatment did not modify α6 expression in D<inf>3</inf>R<sup>-/-</sup>, but progressively increased α6 expression in WT, to the level of untreated D<inf>3</inf>R<sup>-/-</sup> after 14-21 day-treatment. BDNF mRNA expression in striatum was remarkably (>10-fold) increased after 3 days of diazepam-treatment in both WT and D<inf>3</inf>R<sup>-/-</sup>; such expression level, however, slowly declined below control levels, by 14-21 days. Following a 7 day-treatment with the selective D<inf>3</inf>R antagonist SB277011A, WT exhibited a fast tolerance to diazepam accompanied by a robust increase in α6 subunit expression. In conclusion, genetic deletion or pharmacological blockade of D<inf>3</inf>R accelerate the development of tolerance to repeated administrations of diazepam and increase α6 subunit expression, a GABA<inf>A</inf> subunit that has been linked to diazepam insensitivity. Modulation of GABA<inf>A</inf> receptor by DA transmission may be involved in the mechanisms of anxiety and, if occurring in humans, may have therapeutic relevance following repeated use of drugs targeting D<inf>3</inf>R.	en_US
dc.relation.ispartof	European Neuropsychopharmacology	en_US
dc.relation.isbasedon	10.1016/j.euroneuro.2014.11.004	en_US
dc.subject.classification	Psychiatry	en_US
dc.subject.mesh	Corpus Striatum	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Nitriles	en_US
dc.subject.mesh	Diazepam	en_US
dc.subject.mesh	Tetrahydroisoquinolines	en_US
dc.subject.mesh	Brain-Derived Neurotrophic Factor	en_US
dc.subject.mesh	Receptors, GABA-A	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Dopamine Antagonists	en_US
dc.subject.mesh	Anti-Anxiety Agents	en_US
dc.subject.mesh	Motor Activity	en_US
dc.subject.mesh	Anxiety	en_US
dc.subject.mesh	Drug Tolerance	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Receptors, Dopamine D3	en_US
dc.title	Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam	en_US
dc.type	Journal Article
utslib.citation.volume	9	en_US
utslib.citation.volume	25	en_US
utslib.for	111502 Clinical Pharmacology and Therapeutics	en_US
utslib.for	170101 Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)	en_US
utslib.for	11 Medical and Health Sciences	en_US
utslib.for	17 Psychology and Cognitive Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	9	en_US
pubs.publication-status	Published	en_US
pubs.volume	25	en_US

Abstract:

© 2014 Elsevier B.V. and ECNP. Increasing evidence indicates that central dopamine (DA) neurotransmission is involved in pathophysiology of anxiety, in particular the DA receptor subtype 3 (D3R). We previously reported that D3R null mice (D3R^-/-) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D3R^-/- than in wild type (WT) when tested in the elevated plus maze test (EPM). Here we tested the hypothesis that genetic deletion or pharmacological blockade of D3R affect GABAA subunit expression, which in turn modulates anxiety-like behaviour as well as responsiveness and tolerance to diazepam. D3R^-/- mice exhibited tolerance to diazepam (0.5mg/kg, i.p.), assessed by EPM, as fast as after 3 day-treatment, performing similarly to untreated D3R^-/- mice; conversely, WT exhibited tolerance to diazepam after a 14-21 day-treatment. Analysis of GABAA α6 subunit mRNA expression by qPCR in striatum showed that it was about 15-fold higher in D3R^-/- than in WT. Diazepam treatment did not modify α6 expression in D3R^-/-, but progressively increased α6 expression in WT, to the level of untreated D3R^-/- after 14-21 day-treatment. BDNF mRNA expression in striatum was remarkably (>10-fold) increased after 3 days of diazepam-treatment in both WT and D3R^-/-; such expression level, however, slowly declined below control levels, by 14-21 days. Following a 7 day-treatment with the selective D3R antagonist SB277011A, WT exhibited a fast tolerance to diazepam accompanied by a robust increase in α6 subunit expression. In conclusion, genetic deletion or pharmacological blockade of D3R accelerate the development of tolerance to repeated administrations of diazepam and increase α6 subunit expression, a GABAA subunit that has been linked to diazepam insensitivity. Modulation of GABAA receptor by DA transmission may be involved in the mechanisms of anxiety and, if occurring in humans, may have therapeutic relevance following repeated use of drugs targeting D3R.

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http://hdl.handle.net/10453/119192