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Volume 20, Number 3, September 2009

Many people drink alcohol for the “buzz”—those feelings of relaxation, geniality, and heightened interest that can accompany drinking in moderation. In short, mild intoxication is pleasurable and rewarding. How important is that “buzz” in the development of alcoholism? Is the “buzz” more pleasurable to some people than to others? Do inter-individual differences in the experience of alcohol-associated pleasure and reward explain why some people become alcoholics and others do not? Scientists who seek to shed light on the answers to these questions by using animal models are faced with formidable challenges. Pleasure and reward, critical motivators of alcohol drinking, are difficult to measure in studies in animals. Unlike humans, animals do not smile when they experience pleasure, and they cannot verbalize pleasurable sensations.

Dr. C. J. Malanga, Assistant Professor in the Department of Neurology and the Bowles Center for Alcohol Studies, tackles the challenges in studying reward and pleasure in animals by using the method of intracranial self-stimulation, a way to study the effects of drugs on the neural circuitry that underlies brain reward. In intracranial self-stimulation, animals work in order to be reinforced by delivery of electrical current directly into brain areas that mediate motivation and reward, particularly the brain’s mesolimbic system. For example, an animal will spin a wheel in order to receive electrical stimulation of the ventral tegmental area, a component of the mesolimbic system and part of the brain’s reward circuitry. It is thought that intracranial self-stimulation activates the brain’s reward circuitry to produce feelings of pleasure and euphoria in the same way as drugs of abuse. Animals work in order to have drugs of abuse (e.g., cocaine) administered directly into certain mesolimbic brain sites in much the same way that they work to administer intracranial self-stimulation.

While drugs of abuse may differ in many respects, all of them—from alcohol to cocaine to meth-amphetamine—potentiate the activity of the mesolimbic system. Furthermore, all drugs of abuse that have been tested to date in the intracranial self-stimulation paradigm lower the threshold for brain stimulation reward. That is, drugs, such as cocaine, that potentiate the activity of the mesolimbic system and are pleasurable to humans reduce the amount of electrical current that is necessary for animals to obtain intracranial stimulation. Reductions in brain stimulation reward thresholds reflect pleasurable activation of the mesolimbic reward system, and the lowering of the threshold for brain stimulation reward is a means of quantifying the rewarding and pleasurable effects of drugs in animals. In this model, the total amount of positive reinforcement (reward) is thought to arise from the sum of the effects of the drug of abuse and those of electrical brain stimulation on activity of the mesolimbic reward circuit. With the drug of abuse in the animal’s system, the amount of electrical current needed to produce a given amount of pleasure or reward is less than when the drug of abuse is not in the animal’s system. For many years it has been known that increased release of dopamine, a neurotransmitter in the mesolimbic reward circuit, plays a key role in the reward, attention and learning associated with drug dependence. Increased electrical current increases brain dopamine and other reward transmitters providing an index of reward and reward seeking.

Intracranial self-stimulation has primarily been used in rats and larger mammals. Dr. Malanga’s laboratory is one of only a handful that use the technique in mice. The availability of many genetic models in mice allows his lab to study the genetic basis of differences in responding in the intracranial self-stimulation paradigm. Dr. Malanga has used intracranial self-stimulation to explore in mice how prenatal exposure to drugs of abuse, particularly cocaine, impacts the rewarding effects of the drugs later in life. His lab has recently extended their studies to alcohol and to the acute rewarding effects of alcohol in adult mice.

Malanga Lab (left to right): Elliott Robinson, BS, Megan MacFarland McGuigan, BA, Eric Fish, PhD, Elaina Howard, PhD, C.J. Malanga, MD, PhD, Thorfinn Riday, BA.

In a recent series of studies presented in June 2009 at the Research Society on Alcoholism in San Diego, Dr. Malanga, postdoctoral researcher Dr. Eric Fish and their colleagues investigated how differences in genetic background influenced the rewarding effects of alcohol and compared the effects of alcohol with those of cocaine in the intracranial self-stimulation paradigm. This research is the first to use intracranial self-stimulation to investigate the reward-potentiating effects of alcohol; previous studies with alcohol were done in rats. Two strains of mice with different genetic make-ups and responses to alcohol were assessed: C57B16/J (C57) mice and DBA2/J (DBA) mice. The C57 mouse drinks relatively large quantities of alcohol but is not as sensitive as the DBA mouse is to alcohol’s rewarding effects. The DBA mouse does not drink significant amounts of alcohol (largely because it does not like the taste and/or smell of alcohol) but appears to be more sensitive than the C57 mouse to its rewarding effects. The DBA mouse is also more sensitive than the C57 mouse to the rewarding effects of cocaine.

Dr. Malanga and his co-investigators trained C57 and DBA mice to spin a wheel to obtain rewarding electrical current into an area of the mesolimbic reward circuit. The threshold for brain stimulation-reward was determined before and after an intoxicating dose of alcohol was orally administered. The results show that at baseline before alcohol was administered, the thresholds for brain stimulation-reward were similar between C57 mice and DBA mice. Alcohol significantly lowered the threshold for brain stimulation-reward in both strains, a finding that demonstrates that acute alcohol intoxication can be rewarding in mice (Figure). At a dose of 0.6 g/kg, alcohol lowered threshold by approximately 20% in both mouse strains approximately 15 minutes after alcohol administration. The timing of this effect mirrored the rising of alcohol concentrations in the bloodstream of these mice and is consistent with the timing of euphoria reported after ingestion of alcohol in humans.
While alcohol reduced the threshold for brain stimulation-reward in both mouse strains, the strains differed in their sensitivity to alcohol effects. Alcohol doses exceeding 0.6 mg/kg reduced brain stimulation-reward thresholds even further in DBA mice, suggesting continued reward with increasing blood alcohol levels. Surprisingly, they were ineffective in C57 mice. This pattern of results suggests that the degree to which alcohol is perceived as rewarding in the intracranial self-stimulation paradigm differs between the mouse strains.

Dr. Malanga and his colleagues assessed the effects of cocaine, as well as alcohol, on the threshold for brain stimulation-reward in these studies. By studying cocaine, a drug of abuse with a different mechanism of action than alcohol, the investigators sought to determine whether their results with alcohol were specific to alcohol or reflected generalized differences in the responsiveness of the mesolimbic dopamine system to drugs of abuse regardless of pharmacological mechanism of action. They found that, like alcohol, cocaine lowered the brain stimulation-reward threshold in both mouse strains but was more potent in DBA mice than in C57 mice.

“We have shown with the intracranial self-stimulation paradigm that mild alcohol intoxication potentiates the mechanisms of brain reward,” says Dr. Malanga. “The intracranial self-stimulation method is powerful in that it allows us to measure changes in brain reward repeatedly and across different drugs and multiple drug doses. We are now in a position to investigate the pharmacological mechanisms for the effects of alcohol and cocaine on the brain reward circuits. We also want to explore the consequences of prenatal or repeated or chronic alcohol adult exposure in this model, and the impact of other experiences that would be expected to alter the brain’s sensitivity to reward. Our findings will help us define the neural and pharmacological substrates of alcohol drinking, which we can then explore further with neuroanatomical and in vitro electrophysiological methods. By knowing better how drinking is motivated, we will know better how to use tools and interventions that affect perception of reward to curb drinking when it is excessive. With the mouse models, we also have the opportunity to further explore the genetic determinants of motivation to drink. The sky is the limit.”

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 mean percent change from the pre-injection baseline. Each panel represents the effects on brain stimulation reward thresholds during a 15-minute interval following the injection. Asterisks denote significance (p<0.05) versus no alcohol (0 g/kg). Arrows denote significance (p<0.05) versus C57 mice.