Vilazodone, a Novel SSRI Antidepressant with 5-HT1A Partial Agonist Properties: Diminished Potentiation of Chronic Oral Methylphenidate-Induced Dynorphin Expression in the Striatum in Adolescent Male Rats

• Published in: Molecular neurobiology
• Main Authors: Hrabak, Michael, Ahmed, Rania, Soriano, Michelle G, Powell, Aidan, Thanos, Panayotis K, Steiner, Heinz
• Format: Journal Article
• Language: English
• Published: United States 28.10.2024
• Subjects: SSRI; Striatum; Gene Expression; Fluoxetine; Dynorphin; Psychostimulant; Vilazodone; Methylphenidate
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-024-04569-8

Selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine are used in combination with the medical psychostimulant methylphenidate (Ritalin) in a variety of treatments in children and adults. Unintended co-exposure to these psychotropic medications also occurs in patients on SSRIs who abuse methylphenidate as a "cognitive enhancer" or recreational drug. Preclinical research shows that SSRIs such as fluoxetine when given in conjunction with methylphenidate potentiate addiction-related gene regulation by methylphenidate in the striatum, consistent with the known facilitatory role for serotonin in psychostimulant-induced neuronal and behavioral changes. Moreover, fluoxetine combined with methylphenidate also facilitated subsequent acquisition of cocaine self-administration in adolescent rats, suggesting an increased addiction liability for methylphenidate. In the present study, we investigated the impact of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation in adolescent male rats. In contrast to prototypical SSRIs such as fluoxetine, vilazodone also acts as a partial 5-HT1A serotonin receptor agonist and is thus proposed to temper serotonin input to the striatum. We compared the effects of chronic treatment (4 weeks) with vilazodone (10 mg/kg, twice daily) with those of fluoxetine (5 mg/kg, twice daily) on striatal dynorphin expression induced by oral methylphenidate treatment (30/60 mg/kg/day in drinking water, 8 h access daily). Our results demonstrate that, in contrast to fluoxetine, vilazodone had minimal or no potentiating effects on methylphenidate-induced dynorphin expression. This diminished impact on gene regulation was seen throughout the striatum, including the nucleus accumbens, where increased dynorphin expression has previously been associated with various aspects of addiction. Our findings suggest that vilazodone may serve as a better adjunct SSRI with reduced addiction-facilitating properties.