UNC Bowles Center for Alcohol Studies Non-Profit Organization CB# 7178, Thurston-Bowles Building US Postage University of North Carolina at Chapel Hill PAID Chapel Hill, North Carolina 27599-7178 Permit No. 177 Chapel Hill, NC 27599-1800 Center Line Bowles Center for Alcohol Studies School of Medicine, University of North Carolina at Chapel Hill Our mission is to conduct, coordinate, and promote basic and clinical research on the causes, prevention, and treatment of alcoholism and alcoholic disease.

Volume 20, Number 3, September 2009 Malanga Lab Reveals the Basis of the “Buzz”

Many people drink alcohol for the receive electrical stimulation of the necessary to for animals to maintain “buzz”—those feelings of relaxation, ventral tegmental area, a component of responding to obtain intracranial geniality, and heightened interest that the mesolimbic system and part of the stimulation. Reductions in brain can accompany drinking in moderation. brain’s reward circuitry. It is thought that stimulation reward thresholds reflect In short, mild intoxication is pleasurable intracranial self-stimulation activates the pleasurable activation of the mesolimbic New Evidence for Metabotropic Glutamate Receptors and rewarding. How important is that brain’s reward circuitry to produce reward system, and the lowering of the As Targets for Alcoholism Therapy “buzz” in the development of feelings of pleasure and euphoria in the threshold for brain stimulation reward alcoholism? Is the “buzz” more same way as drugs of abuse. Animals is a means of quantifying the rewarding All drugs of abuse produce distinct interoceptive/subjective Center for Alcohol Studies and the pleasurable to some people than to work in order to have drugs of abuse and pleasurable effects of drugs in effects that are perceived by the individual and can be Department of Psychiatry, and others? Do inter-individual animals. In this model, the distinguished from a non-drug state. For example, after drinking colleagues have recently discovered that differences in the experience total amount of positive a glass of wine you may feel lightheaded, dizzy, sleepy or relaxed. mGlu5 receptors in the nucleus of alcohol-associated pleasure reinforcement (reward) is These subjective effects represent a major controlling process accumbens (a brain region known to and reward explain why some thought to arise from the that regulates drug-seeking behavior. Understanding the modulate drug reward) regulates the people become alcoholics and sum of the effects of the processes in the brain that affect these subjective effects is key subjective effects of alcohol. Using a others do not? Scientists who drug of abuse and those of to understanding how alcohol and other substances of abuse well characterized drug discrimination seek to shed light on the electrical brain stimulation gain control over behavior in addiction. procedure, rats were trained to answers to these questions by on activity of the The neurobiological mechanisms that regulate how the brain discriminate the subjective effects of a using animal models are faced mesolimbic reward circuit. Joyce Besheer, Ph.D. perceives alcohol are not yet fully understood. For decades, moderate dose of alcohol from water. with formidable challenges. With the drug of abuse in researchers have examined the glutamatergic system in the brain Besheer examined how the subjective effects of alcohol were Pleasure and reward, critical the animal’s system, the to better understand the effects of alcohol. Recently, a specific changed by compounds that are known to block or enhance motivators of alcohol amount of electrical current subtype of metabotropic glutamate receptors (mGlu5) has been mGlu5 receptor function. These studies, recently published in drinking, are difficult to needed to produce a given identified as a potential target for new therapies for alcoholism the Journal of Neuroscience, show for the first time that blocking measure in studies in Malanga Lab (left to right): Elliott Robinson, BS, Megan MacFarland McGuigan, BA, amount of pleasure or and other drugs of abuse. mGlu5 receptors within the nucleus accumbens blunts the animals. Unlike humans, Eric Fish, PhD, Elaina Howard, PhD, C.J. Malanga, MD, PhD, Thorfinn Riday, BA. reward is less than when Joyce Besheer, Ph.D., assistant professor at the UNC Bowles subjective effects of alcohol and activation of these receptors animals do not smile when the drug of abuse is not enhances the subjective effects of alcohol. “We are excited about they experience pleasure, and they (e.g., cocaine) administered directly into in the animal’s system. For many years these findings, because they show that mGlu5 receptor activity The Bowles Center for cannot verbalize pleasurable sensations. certain mesolimbic brain sites in much it has been known that increased release in the nucleus accumbens is critical for the perception of alcohol,” Dr. C. J. Malanga, Assistant Professor the same way that they work to of dopamine, a neurotransmitter in the Alcohol Studies said Besheer. in the Department of Neurology and the administer intracranial self-stimulation. mesolimbic reward circuit, plays a key Tel. (919) 966-5678 While it is still unclear exactly how the interoceptive effects Fax. (919) 966-5679 Bowles Center for Alcohol Studies, While drugs of abuse may differ in role in the reward, attention and learning affect drug-seeking or addiction, the results of this research tackles the challenges in studying reward many respects, all of them—from associated with drug dependence. To become involved in our mission, call Elizabeth Thomas at (919) 966-4977 or email suggest that mGlu5 receptors could play a significant role. “The and pleasure in animals by using the alcohol to cocaine to meth- Increased electrical current increases [email protected]. nucleus accumbens is a central component of the brain’s reward method of intracranial self-stimulation, a amphetamine—potentiate the activity of brain dopamine and other reward For treatment information call UNC Health circuitry, so our results suggest the potential for overlap between way to study the effects of drugs on the the mesolimbic system. Furthermore, all transmitters providing an index of Care’s Alcohol and Substance Abuse Program drug reward processes and the interoceptive effects of drugs, neural circuitry that underlies brain drugs of abuse that have been tested to reward and reward seeking. at (919) 966-6039 or (888) 457-7457. especially in relation to the role of mGlu5 receptors,” said reward. In intracranial self-stimulation, date in the intracranial self-stimulation Intracranial self-stimulation has Besheer. “We believe this work also highlights the importance animals work in order to be reinforced paradigm lower the threshold for brain primarily been used in rats and larger www.med.unc.edu/alcohol of understanding the mechanisms that underlie the interceptive by delivery of electrical current directly stimulation reward. That is, drugs, such mammals. Dr. Malanga’s laboratory is effects of drugs.” „ into brain areas that mediate motivation as cocaine, that potentiate the activity one of only a handful that use the Center Line, Vol. 20, No. 3 Published quarterly to bring readers a greater understanding of alcoholism research and the Center’s mission. and reward, particularly the brain’s of the mesolimbic system and are technique in mice. The availability of A. Leslie Morrow, Ph.D., Editor-in-Chief; Elizabeth Thomas, Managing Editor; Jane Saiers, Ph.D., Science Writer mesolimbic system. For example, an pleasurable to humans reduce the many genetic models in mice allows his animal will spin a wheel in order to amount of electrical current that is This document is supported by subscriptions and donations to the Bowles Center for Alcohol Studies; All research partially funded by NIAAA. Continued on next page lab to study the genetic basis of differences the C57 mouse to the rewarding effects of alcoholics. Together these approaches point to the same brain in responding in the intracranial self- cocaine. The Director’s Column regions that underlie the motivation to consume alcohol. We stimulation paradigm. Dr. Malanga has used Dr. Malanga and his co-investigators are pleased to have these promising young scientists involved intracranial self-stimulation to explore in trained C57 and DBA mice to spin a wheel Fulton T. Crews, Ph.D. in our Center’s research program and intellectual environ- mice how prenatal exposure to drugs of to obtain rewarding electrical current into Director, ment. We expect continuing great progress from both of them. abuse, particularly cocaine, impacts the an area of the mesolimbic reward circuit. The Bowles Center for We are also pleased to honor one of our senior professors, rewarding effects of the drugs later in life. threshold for brain stimulation-reward was Alcohol Studies Dr. George Breese, with a John Andrews Distinguished Pro- His lab has recently extended their studies determined before and after an intoxicating fessorship. Dr. Breese is a leader in studies of the to alcohol and to the acute rewarding effects dose of alcohol was orally administered. The GABAmimetic effects of ethanol, unique brain region sensi- One question that has always interested me is whether C.J. Malanga, M.D., Ph.D. of alcohol in adult mice. results show that at baseline before alcohol tivity to alcohol and how alcohol abuse leads to anxiety and alcoholics experience a greater reward from drinking alcohol ------In a recent series of studies presented in was administered, the thresholds for brain craving for alcohol. He has made discoveries in neurophar- June 2009 at the Research Society on stimulation-reward were similar between than other individuals. Many recovered alcoholics have told macology for over 40 years. The distinguished professorship Affiliations Alcoholism in San Diego, Dr. Malanga, C57 mice and DBA mice. Alcohol me that they remember their first drink, which I do not. I have will support his continued research and scholarship so he can Assistant Professor of Neurology, postdoctoral researcher Dr. Eric Fish and significantly lowered the threshold for brain wondered if this memory resulted from therapy to recall all the focus on his studies of the mechanisms that underlie pro- Pediatrics and Psychology, bad things alcohol caused, one of the 12 steps of AA, or if the their colleagues investigated how differences stimulation-reward in both strains, a finding tracted ethanol withdrawal anxiety. John Andrews wanted to Department of Neurology and alcohol reward was so strong, it was unforgettable. Is it the Bowles Center for Alcohol Studies, in genetic background influenced the that demonstrates that acute alcohol support research that will lead to new treatments for alcohol- buzz that drives drinking individuals to progress from UNC School of Medicine; Graduate rewarding effects of alcohol and compared intoxication can be rewarding in mice ism. We believe that Breese’s work is likely to do just that.„ experimentation to abuse to addiction? Faculty Member, UNC Curriculum in the effects of alcohol with those of cocaine (Figure). At a dose of 0.6 g/kg, alcohol Neurobiology; Investigator, Neuro- Dr. C.J. Malanga has discovered that genetically different in the intracranial self-stimulation paradigm. lowered threshold by approximately 20% in developmental Disorders Research strains of mice show unique reward responses to alcohol, strongly This research is the first to use intracranial both mouse strains approximately 15 Center (NDRC), University of North suggesting genetic components of reward. This is almost im- Carolina at Chapel Hill. self-stimulation to investigate the reward- minutes after alcohol administration. The CONGRATULATIONS possible to do in humans because we have learned so much about potentiating effects of alcohol; previous timing of this effect mirrored the rising of to alcohol that our response is blurred by what we learned. For Education and Training studies with alcohol were done in rats. Two alcohol concentrations in the bloodstream Dr. George Breese example, those who have learned that alcohol or cocaine are Fellowship in Child Neurology, strains of mice with different genetic make- of these mice and is consistent with the dangerous will have more negative responses than those who on Receiving the Massachusetts General Hospital, ups and responses to alcohol were assessed: timing of euphoria reported after ingestion Boston, MA , 2002; Residency in have learned that these drugs make you feel good. Learned John R. Andrews C57B16/J (C57) mice and DBA2/J (DBA) of alcohol in humans. Neurology, Harvard Medical School, responses differ from innate biological responses and studies in Distinguished Professorship mice. The C57 mouse drinks relatively large While alcohol reduced the threshold for 2000; M.D., Ph.D., Medicine, adult humans cannot distinguish between them. Malanga has Pharmacology and Toxicology, West quantities of alcohol but is not as sensitive brain stimulation-reward in both mouse shown genetic differences in the innate reward response in the Virginia University School of as the DBA mouse is to alcohol’s rewarding strains, the strains differed in their sensitivity brain. Reward thresholds provide insight into how reward im- Medicine, Morgantown, WV, 1997; effects. The DBA mouse does not drink to alcohol effects. Alcohol doses exceeding This professorship recognizes leaders in B.A., Biology, Swarthmore College, pacts the addiction process. significant amounts of alcohol (largely 0.6 mg/kg reduced brain stimulation-reward PA, 1989. Dr. Joyce Besheer uses animals to identify the brain circuits alcohol research for their outstanding work in because it does not like the taste and/or smell thresholds even further in DBA mice, that determine how alcohol “feels.” What makes alcohol con- finding cures, genes, causes and treatments for of alcohol) but appears to be more sensitive suggesting continued reward with increasing Publications sumption a unique experience? What alcohol responses are alcoholism and alcohol use disorders. than the C57 mouse to its rewarding effects. blood alcohol levels. Surprisingly, they were Alcohol, Cocaine and Brain Stimula- learned with drinking experience? Understanding those learned tion-Reward in C57Bl6/J and DBA2/ The DBA mouse is also more sensitive than ineffective in C57 mice. This pattern of J Mice. Fish, E.W., Whitman, B., responses will help understand the drive that takes control over McGuigan, M.M., Faccidomo, S., Hodge. C.W., and Malanga. C.J. Continued from previous page ACER, 2009 (In Press). results suggests that the degree to which alcohol is perceived us to measure changes in brain reward repeatedly and across Augmentation of cocaine-sensitized a as rewarding in the intracranial self-stimulation paradigm different drugs and multiple drug doses. We are now in a dopamine release in the nucleus differs between the mouse strains. position to investigate the pharmacological mechanisms for accumbens of adult mice following Dr. Malanga and his colleagues assessed the effects of the effects of alcohol and cocaine on the brain reward circuits. prenatal cocaine exposure. We also want to explore the consequences of prenatal or Malanga, C.J.,C.J. Ren, J.Q., Guerriero, cocaine, as well as alcohol, on the threshold for brain R.M., Kosofsky, B.E. Dev Neurosci. stimulation-reward in these studies. By studying cocaine, a drug repeated or chronic alcohol adult exposure in this model, and 31(1-2):76-89, 2009. of abuse with a different mechanism of action than alcohol, the impact of other experiences that would be expected to the investigators sought to determine whether their results with alter the brain’s sensitivity to reward. Our findings will help Prenatal exposure to cocaine in- us define the neural and pharmacological substrates of alcohol creases the rewarding potency of alcohol were specific to alcohol or reflected generalized cocaine and selective dopaminergic differences in the responsiveness of the mesolimbic dopamine drinking, which we can then explore further with agonists in adult mice. Malanga, C.J.C.J., system to drugs of abuse regardless of pharmacological neuroanatomical and in vitro electrophysiological methods. Riday, T.T., Carlezon, W.A. Jr., mechanism of action. They found that, like alcohol, cocaine By knowing better how drinking is motivated, we will know Kosofsky, B.E. Biol Psychiatry. lowered the brain stimulation-reward threshold in both mouse better how to use tools and interventions that affect perception 15;63(2):214-21, 2008. Figure: Brain stimulation reward thresholds at selected time points after administration of alcohol in C57 mice (circles) and DBA mice (triangles). Brain stimulation reward thresholds are expressed as strains but was more potent in DBA mice than in C57 mice. of reward to curb drinking when it is excessive. With the Website mean percent change from the pre-injection baseline. Each panel represents the effects on brain “We have shown with the intracranial self-stimulation mouse models, we also have the opportunity to further explore www.med.unc.edu/alcohol/ stimulation reward thresholds during a 15-minute interval following the injection. Asterisks denote paradigm that mild alcohol intoxication potentiates the the genetic determinants of motivation to drink. The sky is malanga significance (p<0.05) versus no alcohol (0 g/kg). Arrows denote significance (p<0.05) versus C57 mechanisms of brain reward,” says Dr. Malanga. “The the limit.” „ mice. intracranial self-stimulation method is powerful in that it allows