Long‐lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: effects on zif 268 and homer 1a

Abstract

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers (zif 268, homer 1a) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a, changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction.

CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants

“…The exact molecular basis for drug-induced stereotypies are not fully understood, but a large body of evidence suggests that this behaviour is mediated by fronto-striatal circuits of the dorsal striatum (Aliane et al 2009;Kelly et al 1975;Saka et al 2004), and long-lasting changes in gene expression have also been implicated (Saka et al 2004;Unal et al 2009). Our findings suggest that CREB1 expression within the dorsal striatum may normally counter amphetamineinduced stereotypies.…”

Potentiated gene regulation by methylphenidate plus fluoxetine treatment: Long-term gene blunting (Zif268, Homer1a) and behavioral correlates

“…We previously found that repeated treatment with methylphenidate alone produced some blunting of c- Fos and Zif268 inducibility, whereas another IEG, Homer1a , was minimally or not affected [26,27]. This latter finding is in contrast to effects of repeated cocaine treatment, which produces robust blunting for c- Fos and Zif268 , but also Homer1a [28]. Our further study demonstrated that adding fluoxetine to the repeated methylphenidate treatment robustly potentiated gene blunting for both Zif268 and Homer1a [25], thus mimicking cocaine effects.…”

“…For example, gene blunting produced by the 5-day repeated cocaine treatment endured for more than 3 weeks [28]. In our recent study [25], we examined IEG blunting one day after the repeated methylphenidate+fluoxetine treatment in adolescent rats, for comparison with our earlier findings [26].…”

Cocaine Modulation of Frontostriatal Expression of Zif268, D2, and 5-HT2c Receptors in High and Low Impulsive Rats

“…We therefore also investigated whether the duration of cocaine self-administration differentially recruited this marker of neural plasticity within the corticostriatal networks (Hearing et al, 2008;Unal et al, 2009) of HI and LI rats.…”