Effects of Cocaine on c-Fos and NGFI-B mRNA Expression in Transgenic Mice Underexpressing Glucocorticoid Receptors

Abstract

Numerous evidences suggest that stress and stress-related hormones can modulate the activity of the brain reward pathway and thus may account for individual vulnerability towards the reinforcing effects of drugs of abuse. Transgenic (TG) mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, were used to assess the role of GR dysfunction on cocaine (COC)-induced c-fos and Nerve-Growth Factor Inducible-B (NGFI-B, or Nur77) gene expression. These two genes belong to different families of transcription factors and have been shown to be modulated by various dopaminergic drugs. TG and wild-type (WT) mice were both acutely and repeatedly treated with COC (20 mg/kg, i.p.). In the chronic experiment, mice received a 5-day treatment of COC and were challenged 5 days later with COC or vehicle. Locomotor activity was assessed during the entire chronic experiment in the mouse home cages. Animals were sacrificed 1 h after the last injection and NGFI-B and c-fos mRNA levels in the prefrontal cortex, the nucleus accumbens and the striatum were measured by in situ hybridization. Acute COC administration led to significantly smaller c-fos increases in TG mice compared to WT, whereas repeated COC treatment potentiated c-fos induction both in TG and WT mice to equivalent levels. TG mice displayed higher basal NGFI-B expression in the nucleus accumbens and the level of NGFI-B mRNA was differently modulated by COC in TG mice compared to WT mice. In accordance with data on c-fos expression, behavioral data indicate a blunted locomotor effect on the first COC injection in TG mice, a phenomenon corrected by the repeated COC treatment. These results suggest that an alteration of the hypothalamus-pituitary-adrenal axis can modify COC-induced regulation of the transcription factors c-fos and NGFI-B, and that these changes parallel those seen at the behavioral level. It also demonstrates that the differences at the behavioral and molecular levels noted between TG and WT mice after acute COC injection disappear following repeated COC administration, suggesting that repeated COC has a greater impact in TG mice underexpressing GRs.

The transcription factors Nur77 and retinoid X receptors participate in amphetamine-induced locomotor activities

“…Psychostimulants, such as AMPH and cocaine, strongly induce Nur77 expression in striatal cells (Bhardwaj et al 2003;Gonzalez-Nicolini and McGinty 2002;St-Hilaire et al 2003;Werme et al 2000). We previously observed that Nur77 gene knockout and RXR antagonist treatment were associated with exacerbated D 2 antagonist responses in mice (Beaudry et al 2000;Ethier et al 2004a, b).…”

Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover

“…On the other hand, Nur77 and Nor-1 are highly expressed in target areas of DA neurons, such as the striatal complex and prefrontal cortex (Beaudry et al 2000;Werme et al 2000a;Zetterström et al 1996). In these areas, strong modulation of Nur77 and Nor-1 has been observed after manipulation of DA neurotransmission with DA receptor antagonists (neuroleptics) or psychostimulants, or after DA denervation (Beaudry et al 2000;Ethier et al 2004a;St-Hilaire et al 2003a;2003b;Werme et al 2000a;2000b). In addition, we have shown that Nur77-deficient mice had an altered response after treatment with antipsychotic drugs (Ethier et al 2004a;2004b).…”

Nur77 and retinoid X receptors: crucial factors in dopamine-related neuroadaptation

“…These effects are reminiscent to the behavioural sensitization induced by psychostimulants in schizophrenic patients [34,35]. Nur77 and Nor-1 mRNA levels are also correlated with behavioural manifestations associated with cocaine and morphine administration (Table 1) [17,36,37].…”