NIH - Neuroscience Research on Drug Abuse (R01, R21)

The following description was taken from the R01 version of this FOA:

This FOA encourages basic neurobiological studies that use in vivo and in vitro model systems as well as studies in humans. Applicants are especially encouraged to include appropriate behavioral models and paradigms of behavioral components or stages of addiction in their research proposals, especially in response to chronic exposure to drugs, different drug administration regimens, withdrawal, or recovery. The subject of study can be at the level of a single protein or gene, neurobiological system, or the entire organism. Research may be conducted across multiple levels of analysis, and applications that incorporate changes over time and/or across multiple scales (e.g., gene to behavior, abuse to dependence, adolescence to adulthood) are sought. Multi- and inter-disciplinary studies are especially encouraged. Topics that would be appropriate to this FOA are described below, but they are not intended to be exhaustive or exclusionary.

Developmental Approaches

This FOA encourages the conduct of neurodevelopmental studies throughout the lifespan, such as:

Neonatal abstinence syndrome
Research that characterizes neural development and its interaction with abused substances during sensitive developmental periods, such as the peripubertal period
Research on the effects of abused drugs, and those that are potential treatments for drug abuse, on neurogenesis, cell differentiation, proliferation, migration and survival in young and adult animals, including assessment of consequences and reversibility of these alterations
Research during aging, particularly on interactions of drugs of abuse with therapeutic pharmaceuticals

Genetic, Molecular and Cellular Approaches

NIDA encourages the use of genetic, such as human genetics, molecular genetics, epigenetics, and pharmacogenetics, cellular and molecular approaches to identify and understand the neurobiological mechanisms underlying addiction. Research may include, but is not limited to:

Use of genome or epigenome editing technologies to investigate neuroplasticity-relevant gene expression changes
Functional comparisons of populations of subjects with different “gene dosing,” whether naturally-occurring (such as comparison of different strain along a dimension) or manipulated experimentally
Mapping of gene variants in either animals or humans using linkage or association studies
Genetic and epigenetic screening and analysis of addiction variations and genetic mechanisms using novel cellular systems, such as induced pluripotent stem cell (iPSC) derived from samples from SUD patients or substance-using participants
Nucleosynaptic signaling studies to understand the mechanisms by which nuclear processes can influence synaptic structure and how synapses can signal back to the nucleus
Identification and validation studies for novel targets or ligands on neurons and glia
The use of patient- and disease-specific inducible pluripotent stem cells as a model system for the study of unique cellular and molecular events that occur in individuals with SUDs for the purpose of developing therapeutic agents or screening drug toxicity
Functional studies of novel receptor-receptor interactions (homo- and hetero- dimerization of receptor subunits, or receptor mosaics) and their response to drugs. Functional studies of the effects of novel receptor-protein interactions, including those with scaffold, RGS, kinase, arrestin, GPCRs, TRP ion channels, and PDZ proteins
Investigations into cytoskeletal regulatory processes and how they can influence processes relevant to substance use disorders
Development, characterization, and validation of organoid models to answer questions relevant to substance use disorders

Neural Circuit and Systems Neuroscience Approaches

Applications using neural circuit and systems-level approaches are encouraged. Of particular interest are studies that address how drug exposure and/or withdrawal leads to persistent changes that underlie relapse to compulsive use. These approaches might include in vivo or in vitro studies of normal and drug-exposed tissues from humans and animals to determine the effects of abused

substances on neurophysiology, changes in distributions of receptors, or delineation of circuits through the use of neuroimaging or neuromodulation techniques such as two-photon imaging, photoacoustics, adaptive optics, in vivo spectroscopy, genetically encoded activators/inhibitors, PET or MR imaging, and Transcranial Magnetic Stimulation. Such studies might include, but are not limited to:

Examination of the temporal course of the addictive process on dendritic spine development and retraction in naïve, drug-treated, and drug-withdrawn tissues within specific brain regions and circuits, especially in compulsively using animals and those in recovery, linked to their physiological and behavioral outcomes
Modulation of neural systems by the neurochemical environment, including steroid hormones and peptides, trophic factors and cytokines/chemokines
Use of systems-level approaches to understand the effects of drugs on the biology of glia and neurons
The interaction of abused substances with the neuronal-glial interface, the study of glial-derived inflammatory and protective factors (neuroimmunology), and the linkage of the anatomy and physiology with outcomes
Comparison of the neural circuits and behaviors that are central to non-drug reward processes with those directly linked to drug-induced reward
Drug-induced modifications of glia that impact the function of the neural circuit, including synaptic excitability, alterations of neurotransmission, or the formation of synapses and/or synaptic elements such as spines
Investigation of brain regions or processes that underlie avoidance learning including those involved in behaviors and cognitive strategies maintained by negative reinforcement
Investigation of individual differences in neural circuitry underpinning SUD-related behavior and outcomes, including studies to understand the neurobiology underlying important risk factors for drug use and addiction (e.g., stress, impulsivity)
Resting state functional connectivity studies examining specific SUD-related neural circuits or large-scale network function in the context of SUDs, including those that predict SUD-related behavior and clinical outcomes
Modulation of SUD-related circuits using non-invasive brain stimulation to investigate neural mechanisms underlying cognition, behavior, and clinical outcomes relevant to substance use disorders
Studies investigating gene – environment interaction effects on SUD-related behavior and neural circuitry
Studies that further investigate hemispheric asymmetries in cognitive function, neurocircuitry, neurotransmitter concentration, and neuronal activation relevant to drug use and addiction
Studies of the relationship between glymphatics, circadian rhythm, and/or sleep on aspects of SUDs such as craving, relapse, susceptibility or resilience
Studies employing novel genetic tools to map circuits critical to the understanding of SUDs. These may include tools such as spatial-temporal, or conditional knockouts, receptor- or subtype-selective antagonists that can demonstrate conclusively the site, developmental stage, and the receptor type(s) involved in the action of drugs of abuse

Behavioral Approaches

NIDA is committed to supporting behavioral neuroscience research on SUDs, conducted with human participants or using animal models that best mimic the complexity of the human condition. Research may include, but are not limited to:

The study of behavioral or cognitive processes (e.g., learning, memory, emotion), and their neurobiological mechanisms, as variables contributing to substance use initiation, escalation, maintenance, abstinence, or relapse
Characterization of transition points and stages in the development of SUDs, including the use of biomarkers or other neurobiological signatures that predict transition to more compulsive patterns of intake
Behavioral and neurobiological phenotyping to characterize patterns of vulnerability and resilience; to identify propensity for transition to more compulsive patterns of behavior and responsivity to interventions (i.e., malleability in SUD trajectories)
Vulnerability phenotyping that considers complex patterns or constellations of individual differences across multiple dimensions (e.g., cognitive processes, drug sensitivity, response to environmental stimuli including social stimuli, reward reactivity, punishment sensitivity) and levels of analysis (e.g., individual differences at genetic or neurobiological levels)
Influences on decision-making, risk-taking, attention or higher order executive functions involved in SUDs, including interactions with emotional processing involved in top-down or bottom-up control
Use and development of refined measures of behavioral choice in complex environments in preclinical models that mimic the human phenomenology of SUDs (e.g., value assessments, probability, flexibility, economic trade-off), including models of compulsive behaviors and behavioral dysregulation
Testing of environmental, behavioral or pharmacological manipulations that leverage potential treatment or prevention targets in all phases of drug taking behavior seen in the progression to development of SUDs, and identification of mechanisms of action
Investigation of individual differences in the role of negative affective processes and their associated neurobiological substrates to the progression through phases of abuse to the development of SUD

Development of Tools and Reagents for the Study of Substance Use

The study of the genetic, molecular, cellular, behavioral, and circuit-based mechanisms involved in SUDs, and the development of associated therapeutic strategies, will benefit from method, tool, and reagent development research and approaches as well. There is a need for:

Improved neuroimaging techniques as well as novel, innovative molecular probes/ligands for receptors, transporters, enzymes, and other neurobiological targets that permit non-invasive deep imaging of neuronal activity at the level of the single cell
Development and application of genetically encoded voltage sensors to map neural activity with circuits involved in SUDs and neuroplasticity
Development and use of high throughput screening methods and application of associated technologies to discover new endogenous ligands and critical biomarkers of known drug effects
Development of innovative technologies in the service of behavioral and neurobiological assessments and the assessment of novel therapeutic regimens aimed at producing favorable neuroadaptations
Classification of cell types by genetic and/or protein complement and activity before and after chronic exposure to/withdrawal from abused substances or therapeutics aimed at mitigating drug use
Single cell analysis-based approaches to study heterogeneities of the neurons that form identified circuits that underlie learning and motivation
Development of novel cellular and behavioral screens that predict treatment the response to potential medications for SUDs

Computational Modeling and Secondary Data Analysis

Development of computational models of neural function in the presence and absence of drug to integrate structural and behavioral neurobiology
Development of computational models of network-level neural function and connectivity in the context of substance use disorders0
Methods for analyzing and interpreting large data sets (preclinical and clinical data) related to substance abuse and its treatment using big data analytical tools
Secondary data analysis of molecular, preclinical, and clinical data

Additional Areas of Interest

HIV/AIDS and SUDs: There is a need to characterize the interactions and synergies of addictive drugs with the functional and structural alterations and neuroadaptations within the central nervous system produced by HIV-1 infection that cause the development and expression of neuroAIDS. This includes studies that examine the role of substance use in exacerbating the pathophysiology underlying HIV-associated neurocognitive disorder (HAND). Additionally, research to develop methods and approaches that protect and potentially repair neurons damaged or dysregulated by exposure to combined HIV-1 infection and drugs of abuse, anti-retroviral therapies (ARTs), and/or host inflammatory factors, is needed. Applicants are strongly encouraged to include relevant animal behavioral models or study substance abusing populations in their research proposals.

Chronic Pain: Studies are needed that aim at understanding the underlying neurobiological mechanisms of chronic pain and its treatment by opioid analgesics. Research might include the study of the changes that occur in response to chronic pain and exposure to its treatment; mechanisms that underlie the sex differences in the response to chronic pain; and the development of non-addicting analgesics for the control of chronic pain. For example, the development of non-opioid analgesics or analgesic approaches that combine different classes of drugs with opiates to reduce opioid abuse liability would be of interest.

Psychiatric Comorbidity and Polysubstance Abuse: The high incidence of comorbidity between SUDs and other psychiatric disorders, or the concurrent misuse of multiple substances by individuals, are well documented. The neurobiological mechanisms underlying these associations remain poorly understood. Preclinical and clinical studies could further our understanding of the extent to which these disorders do or do not share a common neurobiological etiology. Research is encouraged that incorporate comorbidity behavioral models or models of polysubstance use to discern the neurophysiological and neural circuitry similarities and differences between these co-occurring disorders.

Deadlines: standard dates apply

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Filed Under: Funding Opportunities

NIH – Neuroscience Research on Drug Abuse (R01, R21)