Cerebral Hemispheres 2
NEUROSCIENTIFICALLY CHALLENGED

NEUROSCIENCE MADE SIMPLER

Changes in Gene Expression and Addiction


As I discussed in a post last week, addiction seems to correspond to abnormalities in dopamine (DA) transmission throughout the reward areas of the brain. Specifically, initial uses of a drug tend to correlate with low levels of dopamine receptor availability in the nucleus accumbens (NAc), while long-term use affects DA transmission throughout the entire striatum (the NAc is located in the ventral portion of the striatum, or the part nearer the front of the brain).

The striatum is a subcortical region of the brain, and part of the mesocorticolimbic DA pathway, which is integral to the evaluation and appreciation of rewards (like drugs). Striatum is from Latin, and means striped. It is so named because the entire region has a striped appearance, due to the alternating bands of gray and white matter that make it up.

The changes that occur in the striatum are postulated to be responsible for the long-lasting behavioral changes that drug addicts can experience, such as cravings for drug use, an inability to enjoy previously rewarding experiences, and proneness to relapse. It has been suggested that these changes must be preceded by some sort of synaptic remodeling in order to have such a long-lasting effect, and those synaptic changes could be a result of fluctuations in DA transmission. How exactly they occur, however, has yet to be elucidated.

A study to be published in an upcoming issue of Nature may shed some light on the mechanism behind these changes. It involves gene expression, and a phosphoprotein known as DARPP32 (dopamine-and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa).

A phosphoprotein is a protein that has had a phosphate group attached to it, through a process known as phosphorylation. Phosphorylation is an important event in cells, as it often is the catalytic process that activates enzymes and receptors. Dephosphorylation can “turn off” these enzymes, and involves proteins called phosphatases.

When dopamine 1 receptors (D1R) are stimulated, they in turn activate DARPP32, which inhibits a phosphatase known as protein phosphatase 1 (PP1). This signaling cascade affects the phosphorylation of numerous proteins in the cytoplasm and nucleus of a cell.

In the Nature study, the researchers found that the administration of amphetamine, cocaine, or morphine to mice caused DARPP32 to accumulate in the nuclei of striatal neurons. Further studies of neural cultures indicated that dopamine prevents a specific DARPP32 phosphorylation site, Ser97, from being phosphorylated. Ser97 appears to be responsible for exporting DARPP32 from the nucleus of the cell, thus DARPP32 builds up inside the nucleus.

When DARPP32 accumulates in the nucleus, it causes the phosphorylation of a histone, H3. Histones are proteins that DNA winds around to make chromatin, the protein and DNA complex that makes up chromosomes. Phosphorylation of histones often affects chromatin structure, and gene expression as a result.

Mice with mutations in the Ser97 site demonstrated long-lasting aberrations in their behavioral responses to drugs and other rewards. They showed decreased acute locomotor responses to morphine administration, along with a reduced locomotor sensitization to cocaine. Their motivation to obtain a food reward was also diminished.

Thus, this signaling pathway may be responsible for one of the most potent behavioral changes in addiction, when euphoria achieved from the drug diminishes along with the pleasure once obtained from other rewards. This change can contribute to compulsive drug seeking, as an addict obsessively continues to seek the pleasure once associated with their drug of choice. If altered gene expression is responsible for these changes, it would help to explain why they can persist for such a long period of time after the cessation of drug use—sometimes continuing to affect the behavior of an addict for years, and often making their efforts to stay sober much more difficult.

YOUR BRAIN, EXPLAINED

Sleep. Memory. Pleasure. Fear. Language. We experience these things every day, but how do our brains create them? Your Brain, Explained is a personal tour around your gray matter. Building on neuroscientist Marc Dingman’s popular YouTube series, 2-Minute Neuroscience, this is a friendly, engaging introduction to the human brain and its quirks using real-life examples and Dingman’s own, hand-drawn illustrations.

  • Dingman weaves classic studies with modern research into easily digestible sections, to provide an excellent primer on the rapidly advancing field of neuroscience. - Moheb Costandi, author, Neuroplasticity and 50 Human Brain Ideas You Really Need to Know

  • An informative, accessible and engaging book for anyone who has even the slightest interest in how the brain works, but doesn’t know where to begin. - Dean Burnett, PhD, author, Happy Brain and Idiot Brain

  • Reading like a collection of detective stories, Your Brain, Explained combines classic cases in the history of neurology with findings stemming from the latest techniques used to probe the brain’s secrets. - Stanley Finger, PhD, Professor Emeritus of Psychological & Brain Sciences, Washington University (St. Louis), author, Origins of Neuroscience

  • ...a highly readable and accessible introduction to the operation of the brain and current issues in neuroscience... a wonderful introduction to the field. - Frank Amthor, PhD, Professor of Psychology, The University of Alabama at Birmingham, author, Neuroscience for Dummies

BIZARRE

This book shows a whole other side of how brains work by examining the most unusual behavior to emerge from the human brain. In it, you'll meet a woman who is afraid to take a shower because she fears her body will slip down the drain, a man who is convinced he is a cat, a woman who compulsively snacks on cigarette ashes, and many other unusual cases. As uncommon as they are, each of these cases has something important to teach us about everyday brain function.

  • A unique combination of storytelling and scientific explanation that appeals to the brain novice, the trained neuroscientist, and everyone in between. Dingman explores some of the most fascinating and mysterious expressions of human behavior in a style that is case study, dramatic novel, and introductory textbook all rolled into one. - Alison Kreisler, PhD, Neuroscience Instructor, California State University, San Marcos

  • Dingman brings the history of neuroscience back to life and weaves in contemporary ideas seamlessly. Readers will come along for the ride of a really interesting read and accidentally learn some neuroscience along the way. - Erin Kirschmann, PhD, Associate Professor of Psychology & Counseling, Immaculata University

  • Bizarre is a collection of stories of how the brain can create zombies, cult members, extra limbs, instant musicians, and overnight accents, to name a few of the mind-scratching cases. After reading this book, you will walk away with a greater appreciation for this bizarre organ. If you are a fan of Oliver Sacks' books, you're certain to be a fan of Dingman's Bizarre. - Allison M. Wilck, PhD, Researcher and Assistant Professor of Psychology, Eastern Mennonite University

  • Through case studies of both exceptional people as well as those with disorders, Bizarre takes us on a fascinating journey in which we learn more about what is going on in our skull. - William J. Ray, PhD, Emeritus Professor of Psychology, The Pennsylvania State University, author, Abnormal Psychology