This notice of funding opportunity (NOFO) will support projects proposing mechanistic studies that will transform our understanding of polysubstance use in addiction. These hypothesis-based, exploratory projects may investigate mechanisms of polysubstance use at the behavioral, cognitive, cellular, circuit, genetic, epigenetic, pharmacological and/or computational levels. Research on substance use disorders (SUDs) has primarily focused on individual substances although polysubstance use is prevalent. Polysubstance use is the use of more than one addictive substance within a defined interval; the use may be sequential (use of multiple substances on separate occasions), or concurrent/simultaneous. Limiting studies to an individual addictive substance overlooks potential interactions between substances and could influence the translational potential of preclinical research findings.

Results from several studies have demonstrated that the use of multiple addictive substances produces pharmacokinetic and behavioral profiles that are distinct from those produced by a single substance. Despite this recognition, little is known about the precise pharmacological mechanisms and interactions that may contribute to such outcomes, or co-morbidities resulting from co-use. There is also a significant lack in our understanding of how the activity of discrete cells, genes, circuits, expression of receptors, ion channels, intrinsic excitability or signaling mechanisms in the reward systems synergize when exposed to distinct classes of drugs simultaneously or sequentially. Even less is known about these mechanisms in brain regions and circuits that underlie negative reinforcement, or how neurotransmitters, neuromodulators or stress interact within these circuits to contribute to the behavioral and pharmacological profiles observed following polysubstance use. In addition, there is a need for behavioral models of polysubstance use that have translational potential.

Research Objectives: The National Institute on Drug Abuse (NIDA) seeks to stimulate innovative research that will transform our understanding of the basic mechanisms that underlie polysubstance use in addiction. These studies will investigate novel neurobiological, pharmacological and/or behavioral mechanisms underlying the biobehavioral outcomes of polysubstance use.

Research areas and questions of programmatic interest include, but are not limited to:

Identification and/or characterization of molecules, genes, cells (including non-neuronal cells), neural pathways, circuits, receptors, ion channels, intrinsic excitability, pharmacological and signaling mechanisms mediating the effects of polysubstance use.
Mechanisms underlying the association of early adolescent polysubstance use with SUD’s in adulthood.
Sex differences in the development and trajectory of polysubstance use. What are the roles of organizational and activational effects of sex steroids on discrete brain regions and neural circuits, and how is this altered with exposure to polysubstance use?
What are the developmental determinants? Are there developmental windows during which polysubstance use would be facilitated?
What are the pharmacologic, pharmacokinetic and pharmacodynamic interactions that can impact toxicity, or the SUD trajectory?
How do environmental factors interact with brain circuits to influence the development and trajectory of SUDs involving polysubstance use?
How does stress interact with brain circuits to influence the development and trajectory of SUDs involving polysubstance use?
Are there neurobehavioral risk phenotypes for progression to polysubstance use? What are the neurocognitive and neurobehavioral changes that occur through experience with different patterns of polysubstance use?
Applications Not Responsive to this Notice of Funding Opportunity (NOFO)

The following types of studies are not responsive to this NOFO and will not be reviewed:

The major goal of the project is not targeted at delineating the basic mechanisms underlying polysubstance use in addiction.
Projects limited exclusively to the phenomenology of polysubstance use, consequences of polysubstance use, or those focused exclusively on the development of tools or animal models.
Projects that do not focus on combinations of two or more addictive substances with well-justified translational and public health relevance.
Projects that do not include a psychostimulant, opioid, or cannabinoid in the polysubstance combination. Alcohol may be included in the polysubstance combination.
Research that does not pertain to at least one of the stages of the substance use trajectory, including, but not limited to initiation, escalation, withdrawal and/or relapse.
Other application considerations:

Collaborative research teams to foster the sharing of conceptual and/or technical expertise are strongly encouraged.
Applicants using animal models are encouraged to use models reflective of chronic and voluntary drug intake.
Preliminary data are not required but may be included if available. In the absence of preliminary data, a strong premise should be provided for testing a novel hypothesis based upon the scientific literature as well as evidence of the team’s ability to carry out the proposed studies through published or technical preliminary data.