Greg MillerAssociate Professor
- Center for Drug Discovery
- Department of Pharmaceutical Sciences
- School of Pharmacy
Office: Mugar Hall 338
Addiction Sciences Laboratory
Drugs of abuse are chemical imposters in the brain that mimic our own natural neurotransmitters, but they do so in ways that cause changes in the brain that can last a lifetime. People respond to drugs of abuse in different ways. No one chooses to become a drug addict, and only a fraction of users become addicts. This attests to the power of drugs of abuse to control one’s mind, body and behavior. Scientific research on addiction is central to the field of neuroscience. Drugs of abuse alter the way we walk, talk, think, feel and learn. Knowledge on addictions is essential for everyone, and is particularly important for health practitioners.
Drug addiction causes personal devastation, health deterioration and has extreme societal cost. An estimated 208 million people internationally use illegal drugs, and nearly 25 million Americans aged 12 or older—9.4 percent of the population—have used an illicit drug in the past month. About 570,000 people die annually in the U.S. due to drug use. To put this in perspective, each year 12.7 million people discover they have cancer, and approximately 570,000 people die each year. Drug addiction has an estimated societal cost of $700 billion annually, as compared to cancer at $88.7 billion. The Substance Abuse and Mental Health Services Administration estimates that the market for addiction treatment is about $35 billion per year, yet there is a paucity of available medical treatments—most chemical addictions have no pharmacological treatment.
The Addiction Sciences Laboratory at Northeastern University focuses on the neurobiology, immunology and genetics associated with acute and chronic exposure to drugs of abuse. Its goals are to understand the science of how drugs work in the brain and the body, to create new pharmacological treatment strategies for people who are addicted and motivated to recover from their addiction, to take a leadership role in educating students and the public on the science of addiction, and to work diligently towards preventing drug addiction. The lab takes an eclectic approach, but the major scientific focus is on the neurochemical mechanisms by which drugs act on the brain and body, and how genetic, epigenetic and environmental factors alter drug responses to predispose or protect an individual from becoming addicted.
One of our areas of focus is Trace Amine Associated Receptor 1 (TAAR1), a major target in the brain and immune system of psychostimulant drugs including amphetamine, methamphetamine, MDMA (ecstasy) and LSD. TAAR1 modulates neurons and immune cells, and is a potential therapeutic target for addiction medications.
G protein-coupled receptors (GPCRs) play an inordinately large role in human health. They are the targets of many clinically relevant medications and are also candidate therapeutic targets under current investigation for a wide spectrum of diseases. Discovered in 2001, TAAR1 is a G protein-coupled receptor that is important in regulating the dopamine system, reward behaviors and the action of amphetamine-like drugs of abuse. The receptor has a wide agonist spectrum, including common biogenic amines such as dopamine, rare “trace amines” such as b-phenylethylamine, as well as amphetamines. Our lab cloned the TAAR1 receptor from primates and pharmacologically characterized its action. A major area of focus has been on how TAAR1 regulates dopamine. We found that upon activation, TAAR1 drives intracellular phosphorylation cascades that trigger changes in dopamine transporter (DAT) kinetic and internalization functions, leading to changes in extracellular dopamine and consequent behaviors. This is intimately tied to the way drugs of abuse work, as well as the neurochemistry which underlies a spectrum of neuropsychiatric and neurodegenerative disorders.
The TAAR1 receptor is expressed in monoaminergic brain regions and co-localizes with the dopamine transporter (DAT) in Substantia nigra dopaminergic neurons. Upon activation by agonists, such as methamphetamine (METH), the ability of DAT to take up dopamine following its release is reduced, which in turn elevates extracellular dopamine.
Our lab has also identified and pharmacologically characterized TAAR1 in immune cells. Through screening a wide range of signaling pathways for their upregulation, we identified two transcription factors, CREB and NFAT, which are upregulated via phosphorylation of PKA and PKC following TAAR1 activation. The high levels of TAAR1 that we observed on lymphocytes are inducible and fully functional, capable of transmitting a signal likely via PKA and PKC activation following ligand binding. More importantly, an increase in TAAR1 receptor expression is concomitant with lymphocyte immune activation, suggesting a role for TAAR1 in the generation or regulation of an immune response.
A Cignal45 assay (Qiagen) was used to determine which cellular signaling pathways are upregulated upon activation of TAAR1. The NFAT (Ca++/PKC) and CREB (cAMP/PKA) pathways were activated in response to methamphetamine (METH; TAAR1 agonist) treatment.
A. Double-label immunofluorescence and confocal laser microscopy of TAAR1 positive cells in the spleen. TAAR1 single positive cells (green) do not co-express macrophage marker CD68 (red). B. TAAR1 protein is detected in TAAR1-transfected HEK293 cells compared with immortalized B lymphocyte cell lines. C. Upregulation of phosphorylation of PKA and PKC is observed following stimulation with the TAAR1 agonist methamphetamine, which is blocked by pretreatment with the TAAR1 antagonist EPPTB. D. Quantification of C.
All students follow a Graphic Syllabus (click here)
I have designed a mentoring program that teaches students approaches and strategies for originating and performing biomedical research. My goal is to mentor students who are strongly motivated towards scientific research, providing them with a laboratory environment and a faculty mentor who can guide them forward throughout their educational experience at NU. Working independently and then in teams, students develop the ability to conceive, critique and execute a research aim of high scientific significance and impact. Each student first gets introduced to how to search the biomedical literature and use library resources to help them target in on significant publications in areas of addiction research. They get access to a community database of folders containing scientific literature by topic, as a guide to help them with their selection of an area of initial research interest. A student can add literature to any folder, or can create their own folder. Students who share the same primary interest focus are then recruited into an interest focus team, and I mentor each team in the context of a research community.
Each team works towards identifying a major scientific problem of high significance where there is an identifiable “gap” in scientific knowledge. How impactful would “filling the gap” be? Would filling the gap make a vertical leap in the scientific field? Students share ideas with each other and draft a hypothesis, a goal and a specific aim as a group output. This creates a “think tank” where ideas get generated that otherwise wouldn’t have surfaced, and in doing so students build enthusiasm, comradery and a team mentality. In addition to specific laboratory techniques, there is a spectrum of knowledge and skills that students learn related to productive lab work, research methods and ethics, and data analysis and presentation (summarized in the graphic syllabus). Most notably, students learn how to work collaboratively together on a project, develop laboratory skills, data organization and record keeping, issues related to the use of animal models in biomedical research, data analysis, data presentation, scientific writing and how to present data. Leadership skill development and community outreach is an additional component. Students become educated in addiction as a societal and economic problem throughout this process, and learn to become “ambassadors” who disseminate scientific knowledge on drug addiction into their communities.