Exposure to methylphenidate (a dopamine reuptake inhibitor) mimics several behavioral and molecular effects of cocaine. However, other """"""""cocaine-like"""""""" effects are minimal, possibly because serotonin is not elevated by methylphenidate. This notion is supported by recent findings produced in the applicants'laboratories, showing that elevating serotonin with selective serotonin reuptake inhibitors (SSRIs) potentiates methylphenidate-induced psychomotor activity and neuronal adaptations in brain regions implicated in psychostimulant addiction. It is currently unknown if increasing the serotonin transmission with SSRIs in conjunction with methylphenidate could also promote addiction. This is of concern because many individuals are being exposed to a drug combination of methylphenidate (Ritalin) plus an SSRI. The objective of this application is to determine how methylphenidate+SSRI exposure modifies indicators of cocaine addiction liability. The hypothesis is that SSRIs potentiate the effects of methylphenidate, making it more """"""""cocaine-like"""""""". Repeated exposure to methylphenidate+SSRI will thus facilitate the subsequent development of cocaine self-administration behavior, which is an indicator of cocaine addiction liability. This will be tested in rats, using paradigms that allow inferring sensitivity and """"""""motivation"""""""" to self-administer cocaine (Aim 1a) and """"""""compulsive"""""""" drug taking (Aim 1b). Exposure to methylphenidate+SSRI could also trigger relapse in ex-cocaine users. This will be tested in rats, using paradigms that measure reinstatement of drug seeking behavior (Aim 2). Successful completion of these aims is significant, as it will inform a decision of whether or not methylphenidate+SSRI drug combinations should be avoided in the future because of their potential to facilitate behavioral changes related to psychostimulant addiction.

Public Health Relevance

Serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs, Prozac) and dopaminergic agents such as methylphenidate (Ritalin) are widely used in mental health disorders such as attention-deficit hyperactivity disorder and depression. In addition, methylphenidate is frequently used as a cognitive enhancer. In these studies, we will establish if a combination treatment of methylphenidate (Ritalin) plus an SSRI (Prozac) produces cocaine-like behavioral changes indicative of increased addiction liability, and thus should be avoided.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA031916-02
Application #
8453351
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Volman, Susan
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$222,480
Indirect Cost
$78,480
Name
Rosalind Franklin University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Alter, David; Beverley, Joel A; Patel, Ronak et al. (2017) The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes. J Psychopharmacol 31:1078-1087
Van Waes, Vincent; Ehrlich, Sarah; Beverley, Joel A et al. (2015) Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: potential role for 5-HT1B receptor. Neuropharmacology 89:77-86
Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel et al. (2014) Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a. Addict Biol 19:986-95
Beverley, Joel A; Piekarski, Cassandra; Van Waes, Vincent et al. (2014) Potentiated gene regulation by methylphenidate plus fluoxetine treatment: Long-term gene blunting (Zif268, Homer1a) and behavioral correlates. Basal Ganglia 4:109-116
Steiner, Heinz; Warren, Brandon L; Van Waes, Vincent et al. (2014) Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior. Prog Brain Res 211:13-30
Van Waes, Vincent; Carr, Betsy; Beverley, Joel A et al. (2012) Fluoxetine potentiation of methylphenidate-induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons. J Neurochem 122:1054-64