THE NEUROPHARMACOLOGY OF ADDICTION
How do addictive substances alter the brain? How do they create addictive behaviors? All drugs of abuse (opioids, cocaine, methamphetamines, nicotine, etc) alter dopamine release in the brain. In the case of nicotine, the primary addictive component of tobacco products, dopamine neurons are altered so that more dopamine is released during their highly excitable (phasic) periods of activation.
The Neuropharmacology of Nicotine Addiction
Currently, our lab is studying how specific populations of neurons in the midbrain (dopaminergic, GABAergic, and glutamatergic) are altered by nicotine (the primary addictive compound in tobacco products) and how this changes dopamine signaling in the brain. To do this, the Henderson lab uses techniques in the fields of electrophysiology, microscopy, pharmacology, and neuroscience to understand how nicotinic acetylcholine receptors (the molecular target of nicotine) play a role in the addiction to nicotine.
With the advent of electronic cigarettes, additional flavors that have been banned in traditional cigarettes, are now available for smokers of all ages. Therefore, we also study how these flavors may alter the addiction to nicotine.
The Neuropharmacology of Opioid Addiction and the Co-Use of Tobacco with Opioids
Almost all opioid addicts (85 - 95%) exhibit high smoking rates. Opioid addicts undergoing treatment for addiction report significantly higher rates of cessation if they are non-smokers or if they choose to abstain from smoking during their treatment. Thus, there is an urgent need to understand how nicotine and opioids act synergistically in the brain. Our lab is beginning to examine the synergistic nature of nicotine and opioids by first examining reward-related behavior. Both opioids and nicotine, independently alter dopamine neurons in the ventral tegmental area (VTA) to provide rewarding and reinforcing properties. Therefore, our primary focus is the study of how nicotine, opioids, and both alter VTA dopamine neurons.
METHODS
Electrophysiology
Electrophysiology allows the study of neuronal excitability. In the Henderson lab, much of our focus is the examination of dopamine and GABA neurons in the ventral tegmental area. Other areas of interest are the medial habenula, interpeduncular nucleus, and nucleus accumbens.
Fluorescence Microscopy
By using mice genetically modified to contain fluorescent nicotinic receptors, we can use microscopy methods to study changes in neurobiology, following exposure to different drugs of abuse. Currently, we use mice that contain mCherry-tagged alpha4 and GFP-tagged alpha6 nicotinic receptors. These mice will be available soon through the MMRRC for any researcher that is interested (of course, this is delayed due to COVID-19…).
Fast Scan Cyclic Voltammetry (FSCV)
FSCV is an electrochemical technique that facilitates the identification and quantification of neurotransmitters. We use this method to measure dopamine release in the nucleus accumbens core and shell as well as the dorsal striatum. While we have used this in anesthetized mice, we chiefly use brain slice preparations as we can pair this with electrophysiology with habenular and VTA sections.
Fiber Photometry
We have hopped on the fiber photometry bandwagon and have no regrets. In fact, we should have started doing this years ago. Fiber photometry is a high temporal resolution method of detecting precise neurochemistry when paired with the correct viral expression method. We typically use fiber photometry paired with the dopamine sensor, dLight, to measure dopamine dynamics in the nucleus accumbens during vapor self-administration (first paper coming soon….hopefully).
E-Vape Self-administration
To model vaping behavior we use vapor (e-Vape) self-administration. Historically, many drug abuse researchers use intravenous self-administration (IVSA); but, this new methodology provides an advantage since it facilitates contingent inhalation of nicotine and other drugs of abuse using the same vape tanks used by consumers. Thus, this is relevant to vaping and all drugs of abuse that use inhalation.
These systems are custom built by La Jolla Alcohol Research, Inc (www.ljari.tech). While these systems are new and methods are continually modified to meet the changes of vaping-related behavior there is a growing research work group that works to share methods, protocols, and paradigms for varous drugs of abuse modeled in these inhalation systems (Vapor Research User Forum)
