Up-regulation of Oxidative Burden, NFκB, and D1 Receptor Is Involved in the Neuropsychotoxic Behaviors Induced by Camfetamine, a New Psychoactive Substance; Involvements of the Neuromodulation by GPx-1 Gene

초록

An analeptic camfetamine (CFA) is a psychostimulant with complex effects, however, its psychobehavioral characteristics are unclear. As escalating evidence suggests that psychostimulant-induced behaviors are associated with oxidative stress and dopaminergic alterations, we examined whether CFA-mediated psychobehavioral mechanism requires these alterations. Conditioned place preference (CPP) and behavioral sensitization (BS) induced by CFA (7.5 mg/kg, i.p.) were evaluated in male wild-type (WT) and glutathione peroxidase (GPx)-1 knockout (KO) mice. Redox parameters, dopamine D1/D2 receptor expression, and nuclear factor kappa B (NF kappa B) DNA binding activity were examined in the striatum. The D1 receptor antagonist SCH 23,390 and NF kappa B inhibitor pyrrolidine dithiocarbamate (PDTC) were applied to investigate the psychotoxic mechanism of CFA. CFA significantly enhanced superoxide dismutase (SOD)-1 and SOD-2 levels without compensative inductions of GPx/GPx-1 level, leading to increases in oxidative markers. CFA did not significantly affect D2 receptor expression, but significantly increased D1 receptor expression and NF kappa B activity. D1 receptor immunoreactivity and phospho-NF kappa B-immunoreactivity induced by CFA were co-localized in the same cells. These changes, along with CFA-induced CPP and BS, were more prominent in GPx-1 KO mice than those in WT mice, suggesting a protective role of GPx-1. SCH 23,390 and PDTC mitigated CPP and BS; PDTC attenuated CFA-induced D1 receptor upregulation, whereas SCH 23,390 did not affect NF kappa B activity, suggesting NF kappa B is an upstream molecule for CFA-induced D1 receptor activation. Combined results suggest that CFA-induced abnormal behaviors require oxidative stress, NF kappa B and D1 receptor activations. GPx/GPx-1 serves as a protective modulator against CFA-induced neuropsychotoxicity.

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