Objective 1.3: Establish the effects of drug use, addiction, and recovery on genes, molecules, cells, brain circuits, behavior, and health across the lifespan
Drug use has a broad range of direct and indirect consequences. The direct physiological effects on the user depend on the specific drug(s) used, dose, method of administration, and other factors. Acute effects can range from subtle molecular changes to overdose and death. While the major acute effects are known for many drugs, basic research is still necessary to understand the potential dangers of emerging drugs such as synthetic cannabinoids (e.g., K2, herbal incense) and synthetic cathinones (e.g., bath salts).
Chronic drug use can also have distinct effects on physical and mental health. Researchers are just beginning to understand the effects of chronic drug abuse on, for example, epigenetics, brain energetics, synaptic plasticity, and less-studied cell types, such as glia, that act to support neurons. All of these effects may vary across the trajectory of drug use and addiction. Drug use also has diverse indirect effects such as affecting a user’s nutrition51; sleep and circadian rhythms52,53; decision-making and impulsivity54; risk for trauma, violence, injury, and communicable diseases8,10,55–58; and outcomes such as educational attainment, employment, housing, relationships, and criminal justice involvement.59-63 These consequences can all contribute to the trajectory of addiction and may need to be considered independently and collectively when developing treatment interventions.
Approaches
- Explore the epigenetic consequences of drug use, addiction, and recovery
- Use established or novel behavioral models of each stage of addiction to more comprehensively characterize effects on genes, molecules, cells, circuits, and overall health across the lifespan
- Investigate the causal role of changes to brain circuit function in addiction using advanced transgenic technologies (such as optogenetics and DREADDs) to target cell types
- Utilize advanced technologies (such as multi-electrode arrays, multi-angle cameras, and mobile sensing and analytics tools) to investigate complex brain circuits, networks, and behaviors linked to drug use and addiction
Leveraging Research Technologies
The last few years have brought a steady stream of dramatic advances in technologies that can impact the neuroscience field by enhancing our ability to visualize or manipulate functional brain circuits and decode the complex language of the brain. One of the best recent examples is optogenetics, a technology that combines advanced genetic and optical techniques to allow scientists to insert light-sensing proteins into neurons and then use pulses of light to turn specific neuronal pathways on or off.64 By allowing precise optical control of cellular processes at high temporal (millisecond) and spatial (cell-specific) resolution, optogenetics has opened up completely new avenues for investigating biological systems in both healthy and diseased states.
New gene editing technologies hold even greater promise. Ever since the molecular basis of heredity was discovered, scientists have been looking for ways to edit the letters along the DNA double helix to both study the function of specific genes and to cure disease. Many such techniques have been developed over the years, but creating animals or cells with specific genetic modifications remained a tedious and expensive proposition until just 3 years ago, when a game-changing technology called CRISPR was developed.
CRISPR stands for clustered regularly interspaced short palindromic repeats. This refers to part of a very primitive bacterial defense system, which, as it turns out, can be easily adapted and coaxed to modify any desired gene for research or therapeutic purposes.
CRISPR technology has the potential to completely transform gene editing protocols. Because of its potential to help us understand complex biological systems, correct defective human genes, and eliminate disease, among other applications, CRISPR has swept through labs around the world.6 Although more research needs to be done before it can be deployed ethically, safely, and efficiently in humans, it and related technologies are heralding exciting future discoveries in the study of addiction and related fields.
Eliminating Hidden Reservoirs of HIV Virus in the Brain
The brain is a major target organ for the HIV virus. This explains why AIDS is associated with significant brain pathology and a wide range of neurological symptoms, including HIV-associated dementia.65 Many factors can influence the trajectory of these symptoms, but substance use, which commonly co-occurs with HIV infection, has been shown in many studies to hasten the progression of HIV infection and HIV-associated neurocognitive disorders. In turn, HIV-associated neurological dysfunction can increase the risk of SUDs.66
The introduction of antiretroviral therapy in the mid-1990s resulted in dramatic decreases in sickness and death in people infected with HIV. These drugs limit the HIV viral load and maintain a relatively healthy immune response, allowing the life expectancy of HIV-positive patients to approach that of the general population. Unfortunately, even with highly active antiretroviral therapy, HIV-1 viral proteins can still be expressed in so-called reservoir organs, which include the brain, causing persistent inflammation leading to continued neurological dysfunction and increased SUD risk.67
Thus, eradicating these hidden HIV reservoirs is absolutely critical to curtailing chronic brain inflammation and cutting the two-way connection between HIV infection and substance use. NIDA is actively encouraging researchers to explore the mechanisms responsible for the existence of HIV reservoirs as a way to identify additional vulnerabilities in the virus life cycle. To this end, NIDA is supporting basic studies of latency mechanisms behind HIV-1 reservoirs in a small pool of persistent, long-lived, and latently infected resting memory CD4 T cells; studies using nanotechnology to attack HIV where current medications do not penetrate; and investigations into the potential capability of anti-inflammatory drugs to attack latent viral reservoirs.
The knowledge we gain from these and related studies will lead to smarter approaches for targeting and purging HIV reservoirs, which could become a major component of an eventual cure for HIV.