Expired PA-13-339: Mechanisms of Alcohol and Stimulant Co-Addiction (R01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Mechanisms of Alcohol and Stimulant Co-Addiction (R01)
Activity Code	R01 Research Project Grant
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-13-339
Companion Funding Opportunity	PA-13-340, R21 Exploratory/Developmental Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.273, 93.279
Funding Opportunity Purpose	This FOA encourages R01 applications from institutions/organizations that propose to study the neurobiological and behavioral mechanisms that might explain how alcohol and stimulants interact at genetic, epigenetic, cellular, neurocircuitry and behavioral levels to promote co-addiction.

Key Dates

Posted Date	August 28, 2013
Open Date (Earliest Submission Date)	January 5, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	January 8, 2017
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) encourages grant applications to examine mechanisms underlying interactions between alcohol and stimulants. Co-occurring use of alcohol and stimulants is common. However, the behavioral and neurobiological reasons for polydrug use and emergence of concurrent dependence on alcohol and stimulants require further study. The purpose of this FOA is to promote research to study the neurobiological and behavioral mechanisms that might explain how alcohol and stimulants interact at genetic, epigenetic, cellular, neurocircuitry and behavioral levels to promote co-addiction.

Background

Many people who drink alcohol also use other psychoactive drugs such as nicotine, cocaine, amphetamine, methamphetamine and caffeine. According to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), one of the largest surveys of its kind, people who are dependent on alcohol are much more likely than the general population to use drugs, and people with drug dependence are much more likely to drink alcohol. Interestingly, polydrug use is most common in teens and young adults.

Given the common use of alcohol and stimulants in combination and a lack of known causal factors leading to this outcome, there is a need to better understand the mechanisms that underlie their co-use and co-addiction. This phenomenon could occur as a chance intersection where the use of one drug has no influence on the use of the other. However, some findings suggest that it may be the result of a number of interactive influences such as genetic, epigenetic, pharmacological, neuroadaptive, or behavioral factors. For example, specific genes may be predictive of both alcohol and stimulant use, these drug combinations may produce synergistic subjective drug effects, or the use of one drug may offset the undesired effects of the other. While there is some evidence for each of these hypotheses, the mechanisms underlying such interactions have not been thoroughly investigated.

Genetic and epigenetic mechanisms of alcohol and stimulant co-addiction

The heritability of alcohol and stimulant addiction has been convincingly demonstrated by family, twin and adoption studies over the last forty years. Heritability estimates for alcohol dependence range from 40 to 60%, while stimulant addiction including cocaine, amphetamine, methamphetamine and caffeine range from 40 to70%. Therefore, it is clear that genetic factors may play a substantial role in susceptibility to alcohol and stimulant addiction. However, whether there are common genetic factors that influence susceptibility to alcohol and stimulant addiction has not been thoroughly studied, even though alcohol and stimulant addiction frequently co-occur in the same individual. Candidate gene association studies have shown that genetic variation in a number of genes that are expressed in the brain is correlated with both alcohol and stimulant abuse/dependence. Likewise, family based studies have identified genes that may be common genes associated with alcohol and stimulant addiction. In addition to direct genetic factors, epigenetic factors could also underlie the common biological mechanisms of co-abuse of alcohol and stimulants. This FOA encourages applications that examine the common genetic factors that influence both alcohol and stimulant addiction. In addition, this FOA seeks applications that examine epigenetic factors that may have a common influence on alcohol and stimulant addiction.

Neurotransmitter and neuropeptide mechanisms underlying alcohol and stimulant co-addiction

Human and animal studies have shown that many addictive drugs affect common brain targets. Alcohol and stimulants exert their reinforcing effects through complex interactions with many neurotransmitters including dopamine, GABA, glutamate, serotonin and acetylcholine. This avails a range of receptor systems through which alcohol and other drugs may interact to enhance their ingestion.

Although common substrates may be involved in the reinforcing effects of many drugs, the possibility that other distinct actions of these drugs contribute to antagonistic effects must also be considered. For example, methylphenidate, at doses which do not affect locomotion, increased the locomotor stimulating effects of ethanol and decrease alcohol drinking. Because reinforcing effects were not directly measured in this study it is not possible to conclude whether reduced drinking after methylphenidate treatment reflected enhanced or decreased rewarding effects. Nonetheless, these results suggest a potentially complex interaction of common and/or distinct neurobiological mechanisms underlying the effects of methylphenidate and alcohol. A study in monkeys did not find additive or interactive effects of alcohol and cocaine, but instead suggested that when alcohol and cocaine are combined, alcohol decreased the reinforcing efficacy of cocaine, as indexed by rates of responding and elasticity of demand curves. This finding suggests that use of alcohol in combination with psychomotor stimulant drugs may not be due to an ability of alcohol to enhance the reinforcing effects of these drugs (or vice versa). Thus, when alcohol and other drugs are used in combination, it is important to examine both common and separate molecular mechanisms that could contribute to their co-use. Studies of other molecular targets (e.g., CART peptides, opioid and cannabinoid receptor system) and their functional roles in alcohol and stimulant co-use and addiction are also encouraged.

Role of neuroimmune factors in alcohol and stimulant co-addiction

Alcohol and stimulants have both neuronal and central immune modulatory signaling properties that can combine to induce reward and dependence behaviors that are associated with repeated exposure. For example, evidence from alcohol and cocaine literature provide a link to the possible role of Toll-like receptor 4 (TLR 4), an innate immune system molecule, in initiating the proinflammatory central immune signaling that may contribute to their abuse potential. Similarly, there is substantial evidence linking central immune signaling to methamphetamine and amphetamine behavioral responses including reward. For example, co-administration of amphetamine with minocycline (i.e., a tetracycline antibiotic that interacts with brain glutamate and dopamine neurotransmission) in humans revealed that glial attenuation blocked the reward, specifically the high and good effects experienced following amphetamine. Studies have also investigated the effects of pharmacological glial attenuators on methamphetamine behavioral responses. A recent study using ibudilast, an antiinflammatory drug which acts as a phosphodiesterase inhibitor, attenuated methamphetamine relapse in rats under prime- and stress-induced models. A Phase I safety interaction trial is currently underway to determine the possible clinical use of ibudilast as a novel treatment for methamphetamine dependence. These findings suggest that methamphetamine and amphetamine both contribute to alterations in proinflammatory central immune signaling which may interact with reward neurocircuitry in fashion that will drive reinforcement and promote further drug abuse. It remains to be determined, however, how neuroimmune factors regulate the neurotransmitter and neuropeptide systems involved in alcohol and stimulant co-abuse and how alcohol and stimulant co-use can influence neuroimmune factors and associated transductions pathways in targeted brain areas.

Role of conditioned and discriminative stimuli in alcohol and stimulant co-addiction

Situational cues associated with drugs can elicit feelings of craving and trigger relapse in people trying to maintain abstinence. Similarly, alcohol and stimulants produce well-defined interoceptive states that can prime further drug use such as when a priming dose of alcohol reinstates pressing a lever previously reinforced by alcohol. Ingesting two (or more) drugs in close temporal proximity raises the possibility that: (a) internal stimulus effects of one drug precipitates the ingestion of the second drug, and (b) the interoceptive states produced by each drug combine to form a compound stimulus that triggers further drug and stimulant use. These possibilities require further experimental attention. Additional studies suggest alcohol may alter stimulus effects of stimulants. For example, alcohol intoxication may increase attentional bias for cocaine cues in individuals who regularly use the drugs together since the interoceptive effects of alcohol have been repeatedly paired with the effects of cocaine. Therefore, the experience of these discriminative stimulus effects may increase attentional bias for cocaine cues through a classical conditioning process such that during abstinence from one drug, cues associated with ingesting the other could precipitate subjective craving and relapse. This possibility has received very little experimental attention, but may be important for designing future treatment plans. An additional treatment concern in cases of multiple drug addiction is that the stress of quitting one drug could trigger or escalate use of the other drug. Animal studies have shown when two behaviors are reinforced concurrently in the same environment (as is often the case with stimulant use and drinking), the discontinuation of one reinforcer (e.g., a stimulant) can trigger the resurgence of behaviors directed toward the other reinforcer (e.g., drinking). In light of the examples given above, this FOA encourages studies to examine the consequences of discontinuing or administering one drug (i.e., either alcohol or stimulant) on reinstating ingestion of the other.

Neuroadaptation of circuits associated with alcohol and stimulant co-addiction

Repeated alcohol or stimulant use lead to tolerance, dependence, and sensitization resulting from neuroadaptation that may be associated with the transition from controlled to uncontrolled drug and alcohol use. Alcohol, stimulants, and most drugs of abuse have profound effects on the mesolimbic reward circuit. Most notably, consumption is associated with increased extracellular dopamine in the nucleus accumbens. Significant efforts toward understanding substance use and abuse have focused on this pathway and it is clear that major changes occur in this circuit during the transition from drug use to drug abuse. However, ongoing work suggests that neuroadaptations occur in other important networks including the extended amygdala, which is associated with negative affect resulting from repeated withdrawal episodes, and cortical control circuits that are associated with craving and relapse. Within each of these circuits specific neurotransmitter systems are implicated generally (e.g. reward circuit and dopamine, extended amygdala and corticotropin-releasing hormone), but little is known about how these circuits function or adapt in the presence of co-use. As an example, the use of Disulfiram has been recently explored for the treatment of alcohol- and cocaine-dependence separately or in combination. Disulfiram was historically used to treat alcohol dependence and thought to be effective through its inhibition of aldehyde dehydrogenase. However, more recent work has demonstrated that it can reduce craving for both alcohol and cocaine through blockade of dopamine beta hydroxylase, increasing dopamine implicating the reward circuit in co-abuse and treatment. Studies are encouraged to explore the circuits, neurotransmitter systems and neuroadaptations associated with the development, persistence, treatment and recurrence of alcohol and stimulant co-abuse.

Summary

Many factors can influence alcohol-stimulant interactions. For example, co-administration of alcohol and stimulants may increase their abuse liability via pharmacokinetic and/or pharmacodynamic properties, the production of new psychoactive metabolites, or through another mechanism(s) yet to be identified. There also may be a cross-tolerance between alcohol and the co-ingested substance. Moreover, genetic vulnerability and/or long-term alcohol use could perturb neural systems in ways that contribute to the dependence phenotype. Therefore, a multilevel analysis of genetic, neurocircuitry, and behavioral influences is needed to identify the range of shared and unique mechanisms involved in addiction to alcohol and stimulants. Such an in-depth approach will lead to more effective treatment and prevention strategies for alcohol and stimulant co-addiction.

Areas of Research Interest

Areas of research interest include but are not limited to:

Identifying genetic and epigenetic factors that underlie the joint vulnerability to alcohol and stimulant addiction.
Determining whether the reinforcement induced by the combination of alcohol and stimulants is additive or synergistic.
Determining whether the combined use of alcohol and stimulants diminishes negative effects associated with either substance.
Identifying the common or distinct molecular pathways, circuitry and neurotransmitter systems that mediate alcohol and stimulant co-use and addiction.
Determination of the functional roles of glutamate, opioid, and cannabinoid receptor systems in concurrent alcohol and stimulant use and addiction.
Examining the role of cross-tolerance as a common mechanisms underlying alcohol and stimulant (specifically, amphetamine, methamphetamine, and caffeine) co-addiction
Examining the role of conditioned cues and their interactions in concurrent alcohol and stimulant use and addiction.
Examination of discriminative stimuli for alcohol and stimulants and determining whether these stimuli interact to promote alcohol and stimulant use and relapse.
Determining how neuroimmune factors regulate the neurotransmitter and neuropeptide systems involved in alcohol and stimulant co-addiction and how alcohol and stimulant co-use can influence neuroimmune factors or associated transductions pathways in targeted brain areas.
Identifying neuroadaptations that occur in the presence of alcohol and stimulant co-use and addiction.

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover