Fluoxetine potentiation of methylphenidate‐induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons

Abstract

Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention-deficit hyperactivity disorder/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers. Results demonstrate that fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine-like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.

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

“…This notion is supported by our findings showing that the SSRIs fluoxetine or citalopram potentiate gene regulation by methylphenidate in the striatum [20]. Such potentiation of methylphenidate-induced gene regulation was first demonstrated for acute induction of immediate-early genes (IEGs; c- Fos, Zif268 ) [21,22] and neuropeptides (substance P, dynorphin) [23]. Further studies showed that fluoxetine also potentiates increases in dynorphin, enkephalin and 5-HT1B receptor expression [24], as well as blunting of IEG induction [25], produced by repeated methylphenidate treatment, in striatal neurons.…”

Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a

“…This hypothesis is supported by our recent findings showing that serotonin-enhancing drugs - selective serotonin reuptake inhibitor (SSRI) antidepressants - potentiate acute gene regulation by methylphenidate in the striatum (Steiner & Van Waes 2013). Thus, administering an SSRI (fluoxetine, citalopram) together with methylphenidate potentiated the acute induction of immediate-early genes (c-Fos, Zif268) and neuropeptides (substance P, dynorphin) by methylphenidate in striatal neurons (Steiner et al 2010; Van Waes et al 2010; Van Waes et al 2012). …”

Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior

“…2C). These findings indicate that repeated combined treatment produces molecular changes in both striatal output pathways, unlike repeated treatment with MPH alone (Brandon and Steiner, 2003) or acute combined treatment (Van Waes et al, 2012), which both favor the direct pathway. These effects of repeated combined treatment are thus also more “cocaine-like” than those of MPH alone (Yano and Steiner, 2007).…”

“…FLX potentiated MPH-induced expression of substance P (Fig. 1B) and, to some degree, dynorphin, but had no effect on enkephalin (Van Waes et al, 2012). These findings thus suggested some selectivity for the direct pathway by the acute drug treatment.…”

“…Fluoxetine potentiation of acute methylphenidate-induced gene expression in the striatum (Van Waes et al, 2010; Van Waes et al, 2012). Illustrations of film autoradiograms depict expression of Zif268 ( A ) and substance P ( B ) in coronal sections from the middle striatum in animals that received an injection of vehicle (V), methylphenidate (MPH, 5 mg/kg), fluoxetine (FLX, 5 mg/kg) or MPH+FLX and were killed 40 min (Zif268) or 90 min after drug administration.…”