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

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^-/-) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D<inf>3</inf>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 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^-/- 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^-/- 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^-/- than in WT. Diazepam treatment did not modify α6 expression in D<inf>3</inf>R^-/-, but progressively increased α6 expression in WT, to the level of untreated D<inf>3</inf>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 D<inf>3</inf>R^-/-; 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.