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Transcranial direct current stimulation (tDCS) is a non-invasive method to modulate cortical excitability. This technique is a promising emerging tool to treat several neuropathologies, including addiction. We have previously shown in mice that repeated tDCS normalizes pathological behaviors associated with chronic nicotine exposure. Here, we evaluated, in adult female mice, the impact of tDCS on cocaine-induced behavior and gene regulation in corticostriatal circuits implicated in psychostimulant addiction. Anodal tDCS was applied transcranially over the frontal cortex. Three weeks after repeated tDCS, we investigated the induction of a gene expression marker (Zif268) by cocaine (25 mg/kg) in 26 cortical and 23 striatal regions using in situ hybridization histochemistry. We also assessed place preference conditioning by cocaine (5, 10 and 25 mg/kg). tDCS pretreatment increased basal expression and attenuated cocaine (25 mg/kg)-induced expression of Zif268 in specific corticostriatal circuits. Cocaine-induced locomotor activation (25 mg/kg) and place preference conditioning (5 and 25 mg/kg) were also reduced. These results demonstrate that tDCS can attenuate molecular and behavioral responses to cocaine for several weeks. Together, our findings provide pre-clinical evidence that such electrical brain stimulation may be useful to modify the psychostimulant addiction risk.

There is a growing use of psychostimulants such as methylphenidate (Ritalin; dopamine reuptake inhibitor) for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin reuptake inhibitors (SSRIs) including fluoxetine can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine in conjunction with methylphenidate in adolescent rats facilitated a gene regulation effect well-established for repeated exposure to illicit psychostimulants such as cocaine - blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs such as fluoxetine may increase the addiction liability of methylphenidate.

Transcranial direct current stimulation (tDCS) is a non-invasive method to modulate cortical excitability. This technique is a promising emerging tool to treat several neuropathologies, including addiction. We have previously shown in mice that repeated tDCS normalizes pathological behaviors associated with chronic nicotine exposure. Here, we evaluated, in adult female mice, the impact of tDCS on cocaine-induced behavior and gene regulation in corticostriatal circuits implicated in psychostimulant addiction. Anodal tDCS was applied transcranially over the frontal cortex. Three weeks after repeated tDCS, we investigated the induction of a gene expression marker (Zif268) by cocaine (25 mg/kg) in 26 cortical and 23 striatal regions using in situ hybridization histochemistry. We also assessed place preference conditioning by cocaine (5, 10, and 25 mg/kg). tDCS pretreatment increased basal expression and attenuated cocaine (25 mg/kg)-induced expression of Zif268 in specific corticostriatal circuits. Cocaine-induced locomotor activation (25 mg/kg) and place preference conditioning (5 and 25 mg/kg) were also reduced. These results demonstrate that tDCS can attenuate molecular and behavioral responses to cocaine for several weeks. Together, our findings provide pre-clinical evidence that such electrical brain stimulation may be useful to modify the psychostimulant addiction risk.