Scores of people are being exposed to drug combinations that include methylphenidate (Ritalin) plus a
selective serotonin reuptake inhibitor (SSRI). Such drug combinations are indicated for attention-deficit
hyperactivity disorder (ADHD)/depression or anxiety comorbidity (in up to 40% of pediatric ADHD) and other
psychiatric disorders. High-dose co-exposure also occurs, for example, in patients on SSRIs who abuse
methylphenidate as a “cognitive enhancer” or party drug. Many of these subjects are children or adolescents.
This is a public health concern because of potential long-term behavioral and neuronal changes induced by
these psychotropic drugs. Methylphenidate (a dopamine/norepinephrine reuptake inhibitor), given alone,
mimics some, but not other, molecular effects of cocaine. These effects are less robust presumably because
methylphenidate does not affect serotonin systems. Indeed, research in the applicants' laboratories shows that
treatment with an SSRI in conjunction with methylphenidate potentiates abuse/addiction-related behavior and
gene regulation, thus producing “cocaine-like” behavioral and molecular profiles. It is unknown which serotonin
receptor subtype(s) mediate these SSRI (serotonin) effects. The long-term goal of this project is to better
understand how serotonin and dopamine interact to induce their effects on drug addiction-related behavior and
neuronal processes. The objective of this application is to determine serotonin receptor subtypes and cell types
that mediate the effects of methylphenidate plus SSRI combinations on behavioral responses to cocaine and
gene regulation in striatum and nucleus accumbens in adolescent male and female rats. The central
hypothesis is that SSRIs potentiate methylphenidate effects on both cocaine-induced behavior and gene
regulation via activation of specific serotonin receptor subtypes. This hypothesis is based on preliminary data
from the applicants' laboratories. The rationale for the proposed work is the necessity to determine the involved
serotonin receptor subtypes and neuron populations, in order to lay the groundwork for identifying novel
pharmacological interventions that avoid these effects. The central hypothesis will be tested by pursuing three
specific aims: 1) Determine behavioral and neuronal consequences of combined methylphenidate+SSRI
(fluoxetine) treatment, comparing clinically relevant doses and “abuse doses”; 2) Determine serotonin receptor
subtypes that contribute to the methylphenidate+SSRI effects on behavior and gene regulation; 3) Determine
brain sites and cell populations that mediate these behavioral and molecular changes. Effects on behavior will
be determined using the cocaine-induced place preference conditioning (CPP) and sensitization models.
Effects on gene regulation will be assessed by in situ hybridization, RT-qPCR, and Western blot analyses.
These techniques are well-established in our labs. The proposed research is significant, because elucidating
the mechanisms by which serotonin potentiates psychostimulant-induced behavioral and neuronal changes will
inform the future development of novel antidepressants that avoid these potential health risks.