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Serotonin receptors that potentiate addiction-related behavioral and molecular effects induced by methylphenidate plus SSRI exposure

Award Number: R01DA046794
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract: 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $337,634 )
2023	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	000	5	1/25/2023	NON-COMPETING CONTINUATION	$337,634
														Subtotal = $337,634

Issue Date FY: 2022 ( Subtotal = $337,869 )
2022	2022	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	000	4	1/7/2022	NON-COMPETING CONTINUATION	$304,082
2022	2022	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	001	4	3/18/2022	NON-COMPETING CONTINUATION	$33,787
														Subtotal = $337,869

Issue Date FY: 2021 ( Subtotal = $338,093 )
2021	2021	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	000	3	2/5/2021	NON-COMPETING CONTINUATION	$338,093
														Subtotal = $338,093

Issue Date FY: 2020 ( Subtotal = $338,306 )
2020	2020	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	000	2	1/16/2020	NON-COMPETING CONTINUATION	$338,306
														Subtotal = $338,306

Issue Date FY: 2019 ( Subtotal = $351,108 )
2019	2019	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Drug Abuse and Addiction Research Programs	000	1	3/14/2019	NEW	$351,108
														Subtotal = $351,108

Grand Total All Awards = $1,703,010

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Serotonin receptors that potentiate addiction-related behavioral and molecular effects induced by methylphenidate plus SSRI exposure

Award Number: R01DA046794

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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