Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: Potential role for 5-HT1B receptor

Abstract

Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs that use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate 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, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.

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

“…Previously, we showed such potentiation of gene regulation for increases in opioid peptide expression (dynorphin, enkephalin [24]), as well as for blunting of IEG induction by a cocaine challenge [25]; these were measured within 1 day after the repeated treatment. The present study is the first to demonstrate that such potentiated gene blunting after repeated methylphenidate+fluoxetine treatment endures for at least 2 weeks past the treatment, similar to effects of repeated cocaine treatment [28].…”

“…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.…”

The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes

“…The probes had the following sequence: Zif268 ( Egr1 ), complementary to bases 352–399, GenBank accession number M18416; c-Fos , bases 207–254, X06769; Homer1a , bases 1493–1540, AB003726. Hybridization and washing procedures were as reported (Willuhn et al, 2003; Van Waes et al, 2015). The sections were apposed to X-ray film (BioMax MR-2, Kodak) for 5–9 days.…”

“…More specifically, combining MP with a selective serotonin reuptake inhibitor (SSRI; SERT) antidepressant, such as fluoxetine (FLX) or citalopram, in doses that by themselves have no effect on gene regulation, potentiates MP-induced gene regulation in the striatum (for review, see Van Waes and Steiner, 2015). This potentiating effect was demonstrated for acute induction of immediate-early genes (IEGs) such as Zif268 , c- Fos , and Homer1a by MP (Steiner et al, 2010; Van Waes et al, 2010), as well as for expression of neuropeptides (Van Waes et al, 2015) and blunting (repression; Renthal and Nestler, 2008) of IEG induction (Beverley et al, 2014; Van Waes et al, 2014), after repeated MP+FLX treatment.…”

“…Moreover, a facilitatory role for 5-HT1B in behavioral activation by MP has also been shown (Borycz et al, 2008). We previously investigated whether MP and/or FLX treatment regulated the expression of 5-HT1B in the striatum (Van Waes et al, 2015). Indeed, our results demonstrated that repeated treatment with MP also increases the expression of 5-HT1B (but not 5-HT2C) in striatal neurons and that this effect is also potentiated by co-treatment with the SSRI FLX (Van Waes et al, 2015).…”