Expired PA-13-194: Mechanisms of Alcohol and Nicotine 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 Nicotine Co-Addiction (R01)
Activity Code	R01 Research Project Grant
Announcement Type	Reissue of PA-09-099
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. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013. April 24, 2013 - See Notice NOT-DA-13-024. Notice of NIDA's Participation.
Funding Opportunity Announcement (FOA) Number	PA-13-194
Companion Funding Opportunity	PA-13-193, 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 neurobiological and behavioral mechanisms contributing to concurrent alcohol and nicotine co-addiction.

Key Dates

Posted Date	April 12, 2013
Open Date (Earliest Submission Date)	September 5, 2013
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, by 5:00 PM local time of applicant organization.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	September 8, 2016
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

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourages grant applications to examine mechanisms contributing to concurrent alcohol and nicotine dependence. Co-occurring alcohol and nicotine dependence is common. Research suggests that alcohol dependence and nicotine dependence have similar genetic, neurochemical and behavioral characteristics. It is not well understood, however, whether common mechanisms underlie the comorbidity of alcohol and nicotine use and dependence. The purpose of this funding opportunity announcement is to promote research to study neurobiological and behavioral mechanisms of dependence and how alcohol and nicotine use interact through these mechanisms to promote dependence. Such an understanding is essential to guide the development of better prevention and treatment strategies for alcohol and nicotine co-abuse.

Background

Alcohol and nicotine are the most commonly misused non-therapeutic drugs in the United States. Nearly 50 million Americans smoke cigarettes; almost 20 million Americans are alcohol dependent or regularly drink alcohol in harmful quantities. These are not mutually exclusive populations. As many as 88% to 96% of alcoholics are also smokers, and approximately 60% of smokers binge drink or consume significant amounts of alcohol. Individuals who co-abuse alcohol and nicotine have worse clinical outcomes than individuals who use either drug alone. Thus, there is a need to better understand neurobiological and behavioral mechanisms underlying alcohol and nicotine co-dependence.

Human twin studies and studies using selected strains of laboratory animals suggest a shared genetic predisposition to develop alcohol and nicotine dependence. In addition to seeking further research on common genetic determinants of alcohol and nicotine dependence, we also seek proposals to examine how genetic factors contribute to the development of common intermediate traits (e.g., risk taking, novelty seeking, and sensitivity to stress) that predispose one to alcohol and nicotine dependence. Furthermore, studies of how these common intermediate phenotypes impact alcohol and nicotine dependence are encouraged.

Human and animal studies have found that alcohol and nicotine exert both synergistic and antagonistic effects on behavior which may contribute to their concurrent use. For example, preclinical studies have shown that nicotine’s stimulant effects may offset alcohol’s acute sedative effects and cognition-impairing effects. Early postnatal exposure to alcohol enhances nicotine’s analgesic and reinforcing effects in adolescent rats, suggesting that early exposure to alcohol influences the strength of subsequent reinforcing effects of nicotine in later developmental stages. In humans, alcohol pretreatment increases cigarette smoking and craving as well as self-reported subjective rewarding effects of nicotine. A transdermal nicotine patch enhanced alcohol’s subjective rewarding and pharmacological effects in humans. The mechanism underlying such effects, and whether the combination of alcohol and nicotine has a greater effect than either drug alone have not been thoroughly investigated.

Role of nicotinic acetylcholine receptors in alcohol and nicotine co-addiction

One of the most probable targets for alcohol and nicotine to interact is nicotinic acetylcholine receptors (nAChRs). Several different types of nAChRs are involved in nicotine addiction. For example, cigarette smoking resulted in nearly complete occupancy of alpha4/beta2 nAChRs and was accompanied by a reduction in cigarette craving, indicating involvement of alpha4/beta2 nAChR in nicotine’s reinforcing effects. Alcohol enhances alpha4/beta2 nAChR function, but inhibits the activity of alpha7 nAChRs in vitro. By potentiating or inhibiting the function of different nAChRs, alcohol affects nicotine’s affinity for these receptors. A recent study using alpha4 nAChR knock-out (KO) mice points to a direct involvement of alpha4 nAChRs in modulating alcohol reward. In addition to alpha4, other studies have implicated alpha7 nAChRs in mediating alcohol’s (but not nicotine s) ability to disrupt contextual learning. It remains to be determined whether and how nicotine and alcohol interactions at nAChRs contribute to their co-dependence.

Neurobiological mechanisms underlying alcohol and nicotine co-addiction

Nicotine and alcohol ultimately affect common neural circuits that support motivational and hedonic processes. Both drugs exert their reinforcing effects through complex interactions with many neurotransmitters including gamma-aminobutyric acid (GABA), glutamate, dopamine (DA), serotonin, opioid, cannabinoid, and acetylcholine. For example, drugs that block nAChRs reduce alcohol drinking suggesting that nicotine’s primary receptor target plays a role in supporting alcohol ingestion. Pharmacological blockade of nAChRs in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) attenuates alcohol consumption in rats. Varenicline, an alpha4/beta2 nAChR partial agonist, reduces alcohol drinking without affecting sucrose intake in rats. These interactions may be mediated by mesolimbic dopaminergic function. Further, naltrexone, an opioid receptor antagonist approved for treating alcohol dependence, decreases the number of cigarettes smoked daily by humans as well as self-reported satisfaction experienced during smoking, suggesting the role for endogenous opioid systems in smoking and drinking. Given the wide range of receptor systems through which alcohol and nicotine interact, additional research is needed to delineate specific contributions of these systems in mediating concurrent alcohol and nicotine dependence. Studies of other molecular adaptations (e.g., CREB and delta FosB) and their functional roles in alcohol and nicotine co-abuse are also encouraged.

Unlike mesocorticolimbic pathways, the habenulo-interpeduncular pathway has recently received much attention for its role in absence of reward in humans and monkeys. Nicotine activates this pathway through alpha5 nAChRs, triggering an inhibitory motivational signal that limits nicotine intake. Thus, nicotine’s action in the habenulo-interpeduncular pathway is the opposite of the mesocorticolimbic reward pathway. The involvement of this pathway following acute and/or chronic alcohol treatment as well as combined alcohol and nicotine use, and how such use translates into subsequent alcohol and nicotine intake remains to be determined.

Cross-tolerance may also play a role in co-occurring alcohol and nicotine use. For example, chronic administration of alcohol to mice induced tolerance to behavioral effects of alcohol as well as cross-tolerance to the hypothermic and bradycardiac effects of nicotine, and vice versa. This relationship may be especially important during adolescence in that adolescent nicotine exposure might facilitate alcohol use in adulthood. Further research examining nicotine and alcohol cross-tolerance across developmental stages is needed.

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

Cues associated with drugs can elicit feelings of craving and often trigger unintended relapse episodes in people trying to maintain abstinence. Alcohol and nicotine have well-defined stimulus properties. Thus, during alcohol and nicotine co-use, one drug may serve as a cue for the expectancy of the other. After abstaining from one drug, cues associated with ingesting the other, such as interoceptive discriminative stimulus effects, may precipitate craving and relapse. This possibility has received very little experimental attention, but may have important implications for designing treatment plans. Alternatively, in operant behavior studies, when two behaviors are consistently reinforced concurrently in the same environment, as is the case with concurrent smoking and drinking, discontinuing one reinforcer (e.g., smoking) can trigger the resurgence of behaviors directed toward the other reinforcer (e.g., drinking). Additional experimental research is needed to examine the consequences of discontinuing or administering one drug (i.e., either alcohol or nicotine) on reinstating the ingestion of the other.

Role of neuroimmune factors in alcohol and nicotine co-abuse

Recent studies support the idea that a complex communication network exists between the central nervous and immune system. The interplay between these diverse systems occurs through a complex set of neurotransmitters, cytokines and hormones that act to modulate inflammation and restore homeostasis. Nicotine exposure exerts anti-inflammatory and immune modulatory effects in vivo, underscoring roles of nAChRs in CNS inflammatory and autoimmune responses. Chronic alcohol, on the other hand, is known to cause neurodegeneration and neuroinflammation. A recent study demonstrated a direct link between Toll-like receptor 4 (TLR4), an innate immune system molecule that contributes to the inflammation, and GABA(A) receptor in brains of heavy-drinking rats. Silencing the genes for TLR4 and GABA(A) receptor in the central amygdala inhibited binge drinking in rats, an effect that lasted for two weeks. These findings suggest a role for neuroimmune factors in modulating a variety of neuronal functions associated with alcohol and/or nicotine exposure. Additional research is needed to examine how neuroimmune factors regulate neurotransmitter and neuropeptide systems involved in alcohol and nicotine co-abuse, or vice versa, how alcohol and nicotine co-use influences neuroimmune factors and associated signal transduction pathways in targeted brain regions.

Neuroadaptive mechanisms of alcohol and nicotine co-abuse

As alcohol and nicotine use transitions from initiation to occasional, habitual and compulsive use, it is important to explore whether and how either of these drugs produce mutual transition to dependence. In rats, repeated cycles of alcohol intoxication and withdrawal promote neuroadaptations in many neural circuits leading to hyperexcitability and to long-lasting changes in measures of stress and anxiety once alcohol administration is discontinued. Dysregulation of CRF neurons in the central nucleus of the amygdala mediates elevated drinking in post-dependent animals. Similarly, intermittent exposure to unlimited access to nicotine produced large and rapid intake of nicotine in rats. Many of the underlying neuroadaptive changes in response to chronic nicotine exposure remain unclear. Given that neuroadaptation is a key element in development of drug dependence and vulnerability to relapse, its role in conjoint alcohol and nicotine abuse needs further examination.

Areas of Research Interest

Appropriate topics for investigation under this FOA include, but are not limited to:

Elucidation of genetic factors that underlie the joint vulnerability to alcohol and nicotine dependence (e.g., gene-gene interactions; gene-environment interactions). For example, study how genetic variance contributes to risk of alcohol and nicotine co-abuse.
Studies of how common intermediate phenotypes such as risk taking, novelty seeking and sensitivity to stress impact alcohol and nicotine co-abuse.
Identification of common brain circuitry and molecular pathways underlying alcohol and nicotine co-dependence. For example, what neural substrates are implicated in cognitive deficits induced by combined use of alcohol and nicotine? Further, study the role of habenulo-interpeduncular pathway in alcohol-nicotine co-abuse.
Determining whether drug reinforcement induced by the combination of alcohol and nicotine is additive or synergistic in nature.
Elucidation of nAChRs and their role in concurrent alcohol-nicotine use. For example, how chronic alcohol and nicotine use alone or in combination modulates expressions of different nAChRs?
Determination of the functional roles of glutamate, opioid and cannabinoid receptor systems as well as transcription factors in concurrent alcohol and nicotine dependence.
Elucidation of the role of cross-tolerance as a common mechanism underlying alcohol and nicotine co-dependence. For example, study the involvement of adolescent nicotine use in induction of tolerance to alcohol and facilitation of alcohol use in adulthood. Further, study how nicotine (or alcohol) exposure leads to development of cross-tolerance to reinforcing effects of alcohol (or nicotine) and subsequent increase in alcohol (or nicotine) use.
Individuals that do not initiate alcohol and/or tobacco use prior to adulthood very rarely ever become dependent on either alcohol or nicotine. Studies of mechanisms during the early initiation of drinking and smoking that would lead to subsequent predisposition to either alcohol or nicotine abuse or their combination.
Determination of the role of conditioned cues and their interactions in concurrent alcohol and nicotine dependence and elucidation of relevant receptor and neural mechanisms.
Examination of discriminative stimuli for alcohol and nicotine and how these stimuli interact to promote alcohol and nicotine use and relapse.
Examination of how neuroimmune factors regulate neurotransmitter and neuropeptide systems involved in alcohol and nicotine co-abuse, or vice versa, how alcohol and nicotine co-use influences neuroimmune factors and associated signal transduction pathways in targeted brain regions.
Determining whether neuroadaptive mechanisms (e.g., neuropeptides involved in post-dependent stress and anxiety responses) contributing to concurrent alcohol and nicotine dependence are additive or synergistic in nature.
Determination of the optimal timing of alcohol and smoking cessation in treatment programs (i.e., concurrent vs. separate treatment).

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	Scope of the proposed project should determine the project period. The maximum 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.

SF424(R&R) Cover