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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 who 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.

SUBMITTER: Van Waes V

PROVIDER: S-EPMC4250300 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Van Waes Vincent V Ehrlich Sarah S Beverley Joel A JA Steiner Heinz H

Neuropharmacology 20140916

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 who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combi ...[more]

PMID: 25218038

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Project description:Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with "cognitive enhancer" use by individuals treated with selective serotonin reuptake inhibitors. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of selective serotonin reuptake inhibitors potentiates these methylphenidate-induced molecular effects, thus producing a more "cocaine-like" profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers ( Zif268, c- Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c- Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate + selective serotonin reuptake inhibitor-induced "cocaine-like" effects.

Dataset Information

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

Publications

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

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