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

Abstract

Use of psychostimulants such as methylphenidate (Ritalin) in medical treatments and as cognitive enhancers in the healthy is increasing. Methylphenidate produces some addiction-related gene regulation in animal models. Recent findings show that combining selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine with methylphenidate potentiates methylphenidate-induced gene regulation. We investigated the endurance of such abnormal gene regulation by assessing an established marker for altered gene regulation after drug treatments – blunting (repression) of immediate-early gene (IEG) inducibility – 14 days after repeated methylphenidate+fluoxetine treatment in adolescent rats. Thus, we measured the effects of a 6-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or their combination on the inducibility (by cocaine) of neuroplasticity-related IEGs (Zif268, Homer1a) in the striatum, by in situ hybridization histochemistry. Repeated methylphenidate treatment alone produced modest gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine given in conjunction with methylphenidate produced pronounced potentiation of methylphenidate-induced blunting for both genes. This potentiation was seen in many functional domains of the striatum, but was most robust in the lateral, sensorimotor striatum. These enduring molecular changes were associated with potentiated induction of behavioral stereotypies in an open-field test. 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. Key words: cognitive enhancer, dopamine, serotonin, gene expression, psychostimulant, SSRI antidepressant, striatum

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

“…FLX potentiates MP-induced regulation of Homer1a to a similar degree as regulation of Zif268 and c- Fos . This was demonstrated for acute IEG induction by MP+FLX (present results) as well as for blunting (repression) of IEG induction after repeated MP+FLX treatment (Beverley et al, 2014; Van Waes et al, 2014). …”

“…In contrast, repeated methylphenidate (dopamine) treatment produced robust Zif268 blunting, but had minimal or no effects for Homer1a (Cotterly et al, 2007). However, as discussed above, adding FLX (serotonin) to MP produced similar blunting for both Homer1a and Zif268 (Beverley et al, 2014; Van Waes et al, 2014). These results highlight the critical role for serotonin in Homer1a regulation.…”

“…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.…”

Genetic Signatures of Drug Response Variability inDrosophila melanogaster

“…Transcriptomic changes can occur within minutes or hours, and in response to most environmental changes; thus, it could be that some of the 64 differentially expressed transcripts are not directly related to the MPH response, but more generally to the ingestion of different food sources. However, transcriptomic responses to drugs have been reported in animal models (Yano and Steiner 2005;Adriani et al 2006;Beverley et al 2014) and in humans (Schwarz et al 2015), testing alcohol (Ghezzi et al 2013) and methamphetamine (Sun et al 2011) for example. Using a network-based approach, Sun et al (2011) found that methamphetamine, another commonly used drug in the treatment of ADHD (López 2006;Goodman 2007), led to alterations in the expression of genes involved in carbohydrate metabolism, which is consistent with results from our KEGG pathway analysis ( Figure 1D and Table S6).…”

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review

“…Zif268/Egr1 expression showed the greatest effect due to MP. 33 The combined group did show pronounced upregulation of MP-induced blunting for both genes; which concluded that SSRIs in combination with MP may increase the risk of developing addiction. 33 The MP+FLX group experienced heightened striatal gene regulation.…”