Abstract
Amphetamine (AMPH) is a drug of abuse that modulates dopamine neurotransmission in the central nervous system. We recently showed that Nur77 expression is modulated by AMPH administration and that Retinoid X Receptor (RXR) ligands can modulate the effect of antipsychotic drugs. In the present study, we analyse the effect of HX531, a RXR antagonist, in wild type and Nur77 knockout mice in order to clarify the role of these transcription factors in AMPH-induced behaviors. We use the classic behavioral sensitization paradigm, which consists in a 5-day AMPH treatment followed by a 5-day washout period. Sensitization is evidenced with a subsequent AMPH challenge on day 11. Ambulatory movements are assessed in a flex field apparatus for a period of 2 h. AMPH induces a progressive increase (sensitization) in the locomotor activity of wild type and Nur77-deficient mice. The RXR antagonist reduces AMPH-induced locomotion, whereas it remains inactive in Nur77-deficient mice. The RXR antagonist also reduces basal locomotor activity of the mice and HX531 pre-treatment partially suppresses acute AMPH effect on ambulatory movements, again only in wild type mice. However, the locomotor sensitization observed following repeated exposure to AMPH is not modified by HX531. These results indicate that both RXR and Nur77 nuclear receptors (possibly as heterodimerization partners) are involved in AMPH-induced locomotor activity, but are not associated with the development of behavioral sensitization. Support contributed by the Canadian Institutes for Health Research (CIHR).
Published Version
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