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

Abstract

Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with “cognitive enhancer” use by individuals treated with SSRIs. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of SSRIs 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+SSRI-induced “cocaine-like” effects.

Selective Regulation of 5-HT1B Serotonin Receptor Expression in the Striatum by Dopamine Depletion and Repeated L-DOPA Treatment: Relationship to L-DOPA-Induced Dyskinesias

“…Our recent studies show that serotonin agonists (i.e., selective serotonin reuptake inhibitors, SSRIs) co-administered together with the psychostimulant methylphenidate, a dopamine reuptake blocker, potentiate methylphenidate-induced gene regulation in striatal projection neurons [12,13]. This effect is also mediated at least in part by the 5-HT1B receptor [14].…”

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review

“…MP effects on the serotonin receptor subtype, 5-HT1B, on gene regulation, were previously examined using the selective serotonin 5-HT1B receptor agonist, CP94253, on the common genes Zif268/Egr1, c-fos, and Homer1a. 36 The agonist’s role is to potentiate the serotonin reuptake subunit, which will then affect the striatal availability and serotonin uptake. In combination with MP, this agonist and gene in particular were examined with specific interest in whether it would have an effect on combination exposures, such as the MP and fluoxetine (FLX), a serotonin uptake inhibitor (SSRI), together contributing to its heightened effects.…”

“…To do this, male rats were injected with the agonist, 5-HT1B (CP94253) or a vehicle; 15 minutes later they received another injection of either the vehicle, MP alone, or MP with FLX combination injection of 5 mg/kg. 36 FLX alone was not tested on the genes due to previous studies indicating no effect. 36 The 5-HT1B agonist was not detected to have an affect on the Homer1a, through MP induced gene regulation; however, it did potentiate rostral, middle, and caudal striatal Zif268/Egr1, c-Fos, and locomotor activity.…”

“…PSD family: Homer1, Shaknk2, and MAGUK Other: Homer2, Homer3, PSD-95, Htr2a, Drd1, Drd2 0 or 2 mg/kg I.P. once daily Subchronic; 16 days Neurotransmitter receptors ↑ PSD family ↑ Other: ∅ [ 29 ] Grik2, Htr7 2 mg/kg/day Chronic ↑ of both [ 28 ] Zif268/ Egr1, c-fos, and Homer 1a with agonists: CP94253, 5-HT1B MP and FLX 5 mg/kg Acute 5-HT1B agonist: ∅ Homer 1a, ↑ zif268 and c-Fos [ 36 ] Htr-7, Grik2CAMKII, C-FOS 3 mg/kg MP or vehicle Acute effects vs Chronic; 14 days ↑ of Htr7, Grik2 Gene expression; MPH ↓ expression of DA D1/D2 receptors, CAMKII and c-FOS [ 35 ] Zif268 and Homer 1a with D1R antagonist: SCH-23390 2 μg/kg or 10 μg/kg I.P. 10 days SCH-23390: ↓ both [ 37 ] ADRA2A 0.5, 0.65 mg/kg Acute ∅ for Arp2 mRNA or protein expression [ 30 ] IRSp53, Cdc42, Arp2 (genes associated with neuroplasticity) 2.0 mg/kg MP, twice daily for 15 days Chronic; 15 days IRSp53, Arc, IPSp53, Cdc42, Arp2 expression ↑ Arc and IRSp53 were ↓ in the cerebellum [ 20 ] Potassium channels (TASK-1, TASK-5), intracellular junctions, connexin30, neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A); Homer 1, MAGUK MPP3, Shank2 2 mg/kg Sub-chronic; 16 days ↑ suggesting the therapeutic effects on behavioral plasticity but potentiating genes involved with synaptic plasticity and dendritic formation of dendritic spines [ 38 ] …”

“…autoradiogram, measuring the areas of gene expression in the right and left hemispheres. 36 Generally, this research study looked to find the mechanisms involved that allow for the MP to potentiate gene expression in combination with SSRIs.…”