Aims

To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.

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Monday, February 26, 2007



National Institute on Alcohol Abuse and Alcoholism
Application Receipt Date: February 25, 2007

Executive Summary

Purpose: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications on the development of medications for alcohol abuse/dependence. Investigations are needed on pharmacological agents that prevent or reduce alcohol intake by, e.g., decreasing alcohol craving/urge to drink and/or alleviating the negative symptoms associated with drinking cessation.

  • Funds Available and Anticipated Number of Awards: NIAAA intends to commit up to $2 million for FY2007. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications. Approximately 3 to 6 awards will be made in response to this FOA.
  • Mechanism of Support: This FOA will utilize the STTR (R41/R42) grant mechanisms for Phase I, Phase II, Fast-Track and, Phase II Competing Renewal applications and runs in parallel with a FOA of identical scientific scope, RFA-AA-07-009 that solicits applications under the Small Business Innovation Research (SBIR) (R43/R44) grant mechanisms.
  • Eligible Institutions/Organizations: Only United States SBCs are eligible to submit STTR applications. A SBC is one that, on the date of award for both Phase I and Phase II funding agreements, meets ALL of the criteria as described in Section III.
  • Eligible Project Directors/Principal Investigators: Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their SBC 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. On an STTR application, the PD/PI may be employed with the SBC or the participating non-profit research institution as long as he/she has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the small business concern and that individual.
  • Number of Applications: Applicant SBCs may submit more than one application, provided each application is scientifically distinct.
  • Resubmissions. Applicants may submit a “resubmission” application, but such application must include an “Introduction” (1 page maximum for Phase I and 3 pages maximum for Phase II) addressing the previous peer review critique (Summary Statement).
  • Number of PDs/PIs. More than one PD/PI, or multiple PDs/PIs, may be designated on the application.
  • Application Materials: See Section IV.1 for application materials. The SF424 (R&R) SBIR/STTR Application Guide for this FOA is located at these Web sites:
  • General Information: For general information on SF424 (R&R) Application and Electronic Submission, see these Web sites:
  • Hearing Impaired: Telecommunications for the hearing impaired is available at: TTY 301-451-0088.



1. Research Objectives

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications on the development of medications for treatment of alcohol abuse/dependence. Investigations are needed on pharmacological agents that prevent or reduce alcohol intake.

Background

Recent advances in the development of medications to treat alcoholism are highlighted by FDA approval of naltrexone and acamprosate for this indication. (see review by Litten et al, 2005). Advances have also been made in understanding the biological mechanisms underlying alcohol drinking, with recognition that alcohol acts at numerous sites, and many of through many pathways. Many of these provide treatment targets. Naltrexone, for example, is an opiate antagonist and acamprosate apparently acts to stabilize glutamate function in the abstinent alcoholic. Multiple neurotransmitter, neuromodulator, and hormonal systems are involved in problematic drinking. These include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), glutamate, neuropeptide Y (NPY), cannabinoid, and hypothalamic-pituitary-adrenal (HPA) systems (Litten et al., 2005) This developing knowledge base has led to identification of many possible biological targets for testing novel pharmacological agents.

Two important clinical trials of naltrexone first demonstrated its efficacy in alcohol dependent patients and contributed significantly to its FDA approval (Volpicelli et al., 1992 and O'Malley et al., 1992). Naltrexone is not a cure for alcoholism, but appears to have a moderate effect in reducing drinking, particularly in reducing relapse to heavy drinking (Anton et al., 1999; Anton et al., 2005; Morris et al., 2001; Heinala et al., 2001). Patient compliance plays a significant role in the efficacy of naltrexone (Volpicelli et al., 1997; Chick et al., 2000; Monti et al., 2001), but even given compliance, naltrexone is not be effective for all alcoholics (Kranzler et al., 2000; Krystal et al, 2001). Several studies are currently being funded to address issues surrounding the clinical use of naltrexone, such treatment duration, optimal dose, identification of patient predictors of favorable treatment outcome, optimal combination with behavioral/psychosocial interventions, and efficacy in combination with other medications.

Acamprosate was studied extensively and approved in Europe years before approval in the US. Studies have consistently shown that individuals treated with acamprosate are more likely to complete treatment, have longer times to their first drink, have greater abstinence rates, and demonstrate longer cumulative abstinence periods than placebo-treated patients (Mason, 2005). Still, acamprosate does not work for everyone (Anton et al., 2006). Acamprosate's mechanism of action has yet to be definitively identified, although several studies suggest that it may modulate activity of the glutamate system (Mason, 2005)

The serotonergic system has also been implicated in drinking. The serotonin 3 (5-HT3) receptor regulates dopamine release in the mesolimbic area, particularly in the nucleus accumbens. Ondansetron, a 5-HT3 antagonist, reduces desire to drink in humans and augments stimulant and sedative effects of alcohol (Johnson et al., 1993; Swift et al., 1996). In a 12-week trial, ondansetron reduced frequency and quantity of alcohol consumption in early onset alcoholics, but not in late onset alcoholics. In a preliminary study, combination of ondansetron and naltrexone reduced alcohol craving and improved drinking outcome to a greater extent than had either compound alone (Johnson et al., 2000; Ait-Daoud et al., 2001).

Results of selective serotonin reuptake inhibitors (SSRIs) in human alcohol trials have yielded inconsistent on alcohol drinking measures (Pettinati, 1996, Kranzler, 2000). It has been suggested that subpopulations of alcohol dependent patients respond differently to the SSRIs. For example, Kranzler et al. (1996) and Pettinati et al. (2000) found that higher-risk/severity type B alcoholics had less favorable treatment outcome to SSRIs than lower-risk/severity type A alcoholics. Cornelius et al. (1997) found that fluoxetine reduced depressive symptoms and alcohol intake in severe inpatient populations of alcoholics with major depression and suicide risk. In contrast, Pettinati et al. (2001) and McGrath (1998) reported that fluoxetine and sertraline were no better than placebo in improving depression and reducing drinking in a less severely affected sample of depressed alcoholics.

Because the medications developed to date show, at best, small to medium effect in reducing or preventing drinking, developing and evaluating new, more efficacious medications remains a high priority. Several promising agents could lead to clinical testing. These include, but are not limited to, memantine, a non-competitive NMDA antagonist (Holter et al., 1996); kudzu and its purified active components (e.g., puerarin) (Keung and Vallee, 1993; Lin et al., 1996); corticotropin-releasing factor (CRF) antagonists (Bell et al., 1998; Richter et al., 2000); opioid receptor antagonists such as delta2 antagonist naltriben (June et al., 1999); synthetic neurosteroids (Morrow et al., 1999); FG 5974 (and its analogues) a 5-HT1A/5HT2A antagonist (Roberts et al., 1998); agents with selective affinity to GABAA alpha1 or GABAA alpha 5 receptor subunits (June et al., 2001, Harvey et al., 2002), mGluR5 antagonists (Backstrom et al. 2004); mGluR2/3 agonists (Baptista et al., 2004); cannabinoid CB1 antagonists (Serra et al., 2001; Columbo et al., 2004); NOP agonists (Ciccocioppo et. al, 2004); and NPY Y2 antagonists (Rimondini et al., 2005)

A spectrum of neurotransmitter systems (e.g., GABA, NMDA, 5-HT, dopamine), neuropeptide systems (neuropeptide Y, leptin), signal transduction pathways (PKA, PKC), and gene transcription factors (delta fosB) have been implicated in alcohol dependence and craving. New therapeutic compounds may act on known ethanol targets, or may act upon newly identified therapeutic targets not yet examined in relation to alcohol. As basic research reveals promising targets relevant to alcohol abuse and its consequences, analogs acquired from existing libraries, or newly-synthesized analogs developed through computational and combinatorial chemistry can be screened in vitro or in standardized behavioral assays for potential therapeutic efficacy.

Advances in molecular genetics (e.g., microarray analysis, targeted mutations, and proteomics) offer powerful approaches for identifying molecular participants in the neurobiological processes of adapting to alcohol and adapting to its subsequent absence. Changes in gene expression and protein concentration can be identified in specific brain regions in temporal relation to alcohol exposure. Such studies may identify biochemical pathways and brain circuits which are preferentially involved in development of alcohol dependence. Receptors or pathways involved in alcohol drinking and other alcohol effects can be blocked selectively with targeted knockout strategies. Targets for modification of the neurological changes underlying craving and alcohol-seeking after periods of prolonged abstinence can be identified.

SPECIFIC AREAS OF INTEREST INCLUDE

NIAAA is committed to the development and assessment of pharmacological agents to treat alcohol use disorders as well as the more prevalent and severe medical conditions associated with chronic drinking. Compounds may be new, “off the shelf,” or already approved for another medical disorder. Pharmacological agents of interest can be categorized by function as follows:

  • Agents to reduce drinking and/or agents to prolong abstinence.
  • Agents to decrease craving or urge to drink including drinking maintained through positive and negative reinforcement mechanisms.
  • Agents to attenuate the negative hedonic symptoms of chronic drinking, sometimes referred to as protracted abstinence or protracted withdrawal. This includes targeting pathways responsible for stress and anxiety.
  • Agents that restore the impaired cognitive function associated with chronic heavy drinking.
  • Agents to diminish drinking by alleviating co-occurring psychiatric pathology and other drug use.
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