Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam
- Publication Type:
- Journal Article
- Citation:
- European Neuropsychopharmacology, 2015, 25 (9), pp. 1427 - 1436
- Issue Date:
- 2015-01-01
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© 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 (D3 R). We previously reported that D3 R null mice (D3 R-/-) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D3 R-/- 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 D3 R affect GABAA subunit expression, which in turn modulates anxiety-like behaviour as well as responsiveness and tolerance to diazepam. D3 R-/- mice exhibited tolerance to diazepam (0.5mg/kg, i.p.), assessed by EPM, as fast as after 3 day-treatment, performing similarly to untreated D3 R-/- 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 D3 R-/- than in WT. Diazepam treatment did not modify α6 expression in D3 R-/-, but progressively increased α6 expression in WT, to the level of untreated D3 R-/- 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 D3 R-/-; such expression level, however, slowly declined below control levels, by 14-21 days. Following a 7 day-treatment with the selective D3 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 D3 R 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 D3 R.
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