Serotonin-dopamine interactions in psychostimulant-induced gene regulation: SSRI antidepressants potentiate gene regulation by methylphenidate (Ritalin) in the striatum and enhance behavioral profile indicative of addiction liability in rodents

Abstract

Selective serotonin reuptake inhibitor (SSRI) antidepressants are used in combination with the medical psychostimulant methylphenidate (Ritalin), a dopamine reuptake inhibitor, in a variety of treatments in children and adults. Unintended co-exposure to these medications also occurs in patients on SSRIs who abuse methylphenidate as a “cognitive enhancer” or recreational drug. This review summarizes a series of studies on the neurobehavioral effects of such drug combinations, administered either orally (mimicking clinical doses) or intraperitoneally (abuse doses), in adolescent rats. Prototypical SSRIs such as fluoxetine (Prozac) given together with methylphenidate produce various behavioral changes, including facilitated acquisition of cocaine self-administration and increased reinstatement of cocaine seeking (model for relapse). Consistent with these behavioral effects, prototypical (but not novel atypical) SSRIs potentiate abuse/addiction-associated gene regulation by methylphenidate in dopamine target areas such as the striatum. Studies investigating the mechanisms underlying these effects revealed that 5-HT1A and 5-HT1B serotonin receptors inhibit and facilitate, respectively, such gene regulation. These findings indicate that combining methylphenidate with prototypical SSRIs may increase the abuse/addiction liability for psychostimulants, and that 5-HT1A and 5-HT1B receptors may serve as pharmacological targets to alleviate this risk.