Manic Mice Show Heightened Sensitivity to Rewards

During episodes of mania, people with bipolar disorder become avid seekers of new experiences, and some binge on psychostimulants such as cocaine and amphetamine. A NIDA-funded animal study suggests that mania promotes these and other extreme behaviors by enhancing sensitivity to rewards, both natural and drug-related. Mutant mice that exhibit behaviors resembling mania seemed to get a bigger kick than normal mice from sugar water, cocaine, and electrical stimulation of the brain's reward center. The finding implicates the manipulated gene, which is called Clock, in the mood disorder, vulnerability to substance abuse, and perhaps their co-occurrence.

Pleasure Goes a Long Way

Dr. Colleen McClung and colleagues at the University of Texas Southwestern Medical Center and other institutions created a strain of mutant mice for use in studies to understand the neurobiology of circadian rhythms. They initiated the current study after observing that these mice exhibit behaviors often associated with heightened reward sensitivity and vulnerability to stimulant addiction. For example, compared with normal mice, the mutants explore novel environments more vigorously and spend significantly more time in an environment they associate with cocaine.

Dr. McClung and colleagues tested the responses of these mice to three types of rewards. In each instance, genetically engineered mice demonstrated more sensitivity to rewards than normal animals. For example:

• Given the opportunity to turn a wheel that sent electrical impulses to the pleasure pathway of their brains, the genetically engineered mice turned the wheel more often and responded to a lower current than normal mice, indicating that they found brain stimulation more rewarding.
• After a dose of cocaine, both normal and mutant animals pushed the wheel less often—a sign that they were feeling pleasure from the cocaine. But the genetically engineered mice reduced their wheel-turning responses more, indicating that they received more pleasure from the drug.
• Given a choice between water and a sugar solution, which mice find rewarding, the genetically engineered animals consumed more of the sweet drink than the normal animals.

In their heightened responsiveness to rewards, the genetically engineered animals resemble a subset of normal animals—those that show special interest in exploring novel environments. Compared with less active peers, novelty-seeking animals show greater sensitivity to drugs in behavioral protocols that mimic the early stages of addiction. High responsiveness to novelty predicts drug-related behavior so reliably that animal researchers often use it as a test for vulnerability to initiating drug abuse.

Building a Mouse Model

To produce the mice that have characteristics resembling bipolar patients' manic symptoms, Dr. McClung's colleagues at Northwestern University disrupted a gene called Clock. The gene is a critical regulator of daily rhythms—including sleep and wakefulness, body temperature, hormone levels, blood pressure, and heart activity. Particular variants of this gene have been linked with bipolar disorder in clinical research.

Dr. McClung's mutant mice mimic key symptoms experienced by bipolar patients in the manic phase of the disease. For example, the animals' hypersensitivity to rewards parallels the extreme euphoria seen in mania. In addition, the mice become hyperactive, have disrupted circadian rhythms, and sleep less than the wild-type mice. In a situation that provokes nervous behavior from normal rodents, the mutant mice show reduced anxiety—a trait that mimics bipolar patients' increased risk-taking during a manic phase. Like bipolar patients, the mice respond to mood-stabilizing drugs with reduced mood- and anxiety-related behaviors.

"My colleagues and I suspected that the animals might to some extent resemble patients with mood disorders, but we were surprised to find that they had such a complete profile of manic-like behaviors," says Dr. McClung.

In the long term, Dr. McClung is interested in determining the genetic roots of bipolar disorder, which is highly heritable: An estimated 80 to 90 percent of affected individuals have a relative with a mood disorder.

Rhythms and Reward: A Dopamine Connection?

Dr. McClung and colleagues plan to use the Clock mutant mice to elucidate the neurobiology underlying bipolar patients' proclivity to risky behaviors, particularly drug abuse, during manic episodes. Clinicians observe that both depression and manic episodes increase substance abuse: People tend to abuse stimulant drugs during a manic phase and alcohol during a depressive period. The lifetime rate of substance abuse is 38 percent for people with bipolar disorder, as compared with 10 percent for those without a psychiatric illness, according to a 2006 analysis by the National Epidemiologic Survey on Alcohol and Related Conditions. When bipolar patients abuse drugs, their risks for hospitalization and suicide increase—a fact that adds urgency to the task of devising means to prevent drug abuse among people with the disorder.

The Clock mutant mice differ from normal rodents not only in behavior but also in their neurobiology. Neurons in their ventral tegmental area (VTA)—the starting point for brain dopamine pathways, including the reward circuit—fire more frequently and strongly than in normal animals, resulting in greater dopamine release. Extra dopamine in the reward pathway is a critical factor in addiction and may influence vulnerability to both drug abuse and manic symptoms. In ongoing studies, Dr. McClung's team is examining whether restoration of the Clock gene normalizes dopamine release in the reward circuitry and behavioral sensitivity to reward. To date, this work has demonstrated that insertion of a normal Clock gene in the VTA of the genetically engineered animals eliminated their manic-like hyperactivity.

The researchers also plan to identify the mechanism by which a disrupted Clock gene leads to augmented dopamine in the reward pathway. Dr. McClung's team has found that Clock regulates some genes that affect neurochemical processes related to dopamine. One of these genes, for example, influences an enzyme that controls dopamine production.

When researchers learn how the Clock gene influences dopamine levels, they may be able to explain the frequent co-occurrence of drug abuse and bipolar disorder. The findings may also provide clues to new treatments for both bipolar disorder and drug abuse. Dr. McClung's team is already using Clock mutants to screen potential new medications.

A variety of human genes appear to increase the risk of bipolar disorder, says Dr. Minda Lynch of NIDA's Division of Basic Neuroscience and Behavioral Research. Dopamine may emerge as a common factor among the actions of such genes, some of which may also influence addiction vulnerability.

"Dr. McClung's research is relevant to co-occurring psychiatric and addiction disorders," says Dr. Lynch. "NIDA is trying to stimulate the development of such animal models because researchers might use them to elucidate the neurobiological underpinnings of co-occurring substance abuse and psychiatric disorders."

Sources

Falcón, E., and McClung, C.A. A role for the circadian genes in drug addiction. Neuropharmacology 56(1):91-96, 2009. [Abstract]

Roybal, K., et al. Mania-like behavior induced by disruption of CLOCK. Proceedings of the National Academy of Sciences 104(15):6406-6411, 2007. [Full Text (PDF, 517KB)]