NEW RESEARCH GIVES ADDICTS HOPE THAT EFFECTS OF ADDICTION COULD BE REVERSED
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NEW RESEARCH GIVES ADDICTS HOPE THAT EFFECTS OF ADDICTION COULD BE REVERSED
ATLANTA, October 15, 2006 - Recent findings show that the effects of addiction on the brain potentially could be reversed and indicate a clearer understanding of the powerful effects of brain circuits, self-control, and environment on drug taking.
For years, addiction has been viewed simply as a weakness or defect in the addict, as reflected in the misguided "just say no" attitude. But gradually recent research has dispelled that myth, giving addicts and addiction the scientific and medical attention they deserve.
"New avenues of research may provide new strategies for developing treatments and medications to treat cocaine and other drug abuse and dependence," says Michael Kuhar, PhD, at Emory University. Kuhar is on the board of directors for AptoTec, Inc, which develops nutraceuticals to control and alleviate obesity and osteoporosis.
One new finding shows, for the first time, that an addict's inability to change their behavior is a consequence of taking drugs rather than a dysfunction or predisposition to addiction.
"Humans with a history of substance abuse or dependence frequently exhibit poor performance on neuropsychological tasks, particularly when those tests require planning or the ability to stop or change behavior," says David Jentsch, PhD, at the University of California, Los Angeles. "We believe that these impairments, measured in the laboratory, reveal a general inability to stop taking drugs, even when their internal motivation to do so is very strong. If that is true, it's critical to understand what causes these impairments to occur and how to correct them." Jentsch has received research support from private companies, including Pfizer, and has consulted for Rx-Gen.
To examine this issue, his group has undertaken studies of animal subjects exposed chronically to addictive drugs, including cocaine, methamphetamine, angel dust, and marijuana. "As a result of systematic investigations, we have been able to show that poor cognition is a consequence of drug intake," he says. "Specifically, animals exposed to addictive drugs show the same impairments in planning or changing or stopping behavior that people with substance abuse disorders do.
"The value of this knowledge is that people with substance dependence and abuse disorders are not necessarily dysfunctional people to begin with," he says, "their impairments are acquired as a consequence of drug intake and, as a result, these brain abnormalities can potentially be reversed or overcome."
Beyond this set of findings, Jentsch and colleagues have used sophisticated imaging and biochemical techniques to uncover the changes in the brain that underlie these behavioral impairments. Their results indicate that adaptations in the brain monoamine transmitters-dopamine, serotonin, and norepinephrine-are involved in these deficits, and they are beginning to test therapies that directly overcome those changes. "Our goal is to propose a new set of interventions designed to help people translate their intentions and desires to stop taking drugs into positive outcomes, and initial studies strongly support the feasibility of this approach," he says.
Other scientists, like Rita Goldstein, PhD, at Brookhaven National Laboratory, agree that addiction is not the fault of the addict. Her research results from several brain-mapping studies and neuropsychological tests support the idea that cocaine addicts have an impaired ability to perceive rewards and exercise inhibitory control due to disruptions in dopamine-mediated reward and control circuits in the brain's prefrontal cortex.
"Our findings provide the first evidence that the brain's threshold to responding to an abstract reward is modified in drug-addicted people and is directly linked to changes in the responsiveness of the prefrontal cortex," says Goldstein. "This dysfunctional interplay between reward processing and control of behavior could help to explain the chronically relapsing nature of drug addiction, and suggests new clinical interventions aimed at helping drug abusers to manage these symptoms as part of an effective treatment strategy."
Goldstein's theoretical model, called the Impaired Response Inhibition and Salience Attribution (I-RISA) model, suggests that drug-addicted individuals disproportionately attribute salience, or value, to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli. At the same time, these individuals exhibit a decrease in their ability to inhibit maladaptive drug use.
To test their hypothesis, Goldstein and colleagues monitored brain activity while subjecting cocaine-addicted and nondrug-addicted individuals to a range of tests of behavior, cognition, thought, and emotion.
In the first study, researchers monitored brain activity in cocaine-addicted individuals and matched nondrug-addicted individuals who were given a monetary reward for their performance on an attention task. Subjects were given one of three amounts-no money, one cent, or 45 cents-for each correct response, up to a total reward of $50 for their performance. The behavioral measurements were made during functional magnetic resonance imaging (fMRI) and recordings of event-related potentials (ERP) to simultaneously assess the changes in brain function in response to the monetary reward. Researchers also asked the subjects how much they valued different amounts of monetary reward, ranging from $10 to $1,000.
More than half of the cocaine abusers rated $10 as valuable as $1,000, demonstrating a reduced subjective sensitivity to relative monetary reward. "Such a 'flattened' sensitivity to gradients in reward may play a role in the inability of drug-addicted individuals to use internal cues and feedback from the environment to inhibit inappropriate behavior," says Goldstein, "and may also predispose these individuals to disadvantageous decisions," such as trading a car for a couple of cocaine hits. "Without a relative context, drug use and its intense effects-craving, anticipation, and high-could become all the more overpowering."
The behavioral data collected during the performance of the fMRI task implicate a disruption in the ability to perceive inner motivational drives in cocaine addiction, says Goldstein. The fMRI results also revealed that cocaine-addicted individuals' orbitofrontal cortex, a prefrontal region within the brain's reward circuit, was less responsive to changes in the amount of monetary reward offered than was the same region in non-addicted control subjects. That is, this region responded to the different monetary amounts in a graded fashion-the higher the potential reward, the greater the response-only in the non-addicted subjects.
"These results provide the first evidence that the brain's threshold to responding to an abstract reward (money) is modified in drug-addicted people," says Goldstein. "Further, our results implicate the prefrontal cortex in this modified sensitivity to reward, highlighting its monitoring role in awareness to inner motivation and in the ability to control behavior."
Goldstein hopes that the I-RISA model and results will provide advice based on results of this complex neuropsychoimaging data for clinical interventions aimed at helping drug abusers to manage their I-RISA related symptoms. "Our results also attest to the benefit of combining several neuroimaging methods with sensitive behavioral, cognitive, and emotional probes, including self-reported scales, to optimize the study of drug addiction, a psychopathology that only recently has been identified as a disorder of the brain."
Other research shows that repeated cocaine use produces long-term neuroadaptations in prefrontal cortical cells.
Brain imagining studies in human psychostimulant drug addicts provid evidence for altered activity within some brain regions, says Antonieta Lavin, PhD, at the Medical University of South Carolina. Among the diverse brain structures affected by the continuous exposure to drugs is the prefrontal cortex.
"The prefrontal cortex is a complex brain region," says Lavin, "and imaging and behavioral studies in humans and animals have shown that damage to the prefrontal cortex can result in irresponsibility, impulsivity, and perseveration in humans and impairment in the ability to modify behavior in primates." She adds that brain imaging studies indicate that cocaine users exhibit hypoactivity of the prefrontal cortex, and neuropsychological studies indicate that cocaine users exhibit deficits in executive cognitive functions ascribed to the prefrontal cortex, making "the study of the long-term effects produced by drugs of abuse in the prefrontal cortex very important in order to understand how the psychostimulants hijack the normal decision processes."
Lavin's studies show that repeated cocaine administration affects the physiological properties of the prefrontal cortical neurons. By measuring the electrical activity of the cells located on the prefrontal cortex, she and colleagues were able to assess how the cortical neurons of normal animals or cocaine-treated animals respond to different situations.
They found that the excitability of the prefrontal cortical cells in cocaine-treated animals is significantly reduced when compared to the activity found in normal animals. They also found that prefrontal cortical cells from cocaine-treated animals do not respond to the administration of selective dopaminergic D2 antagonists.
"This data suggest that the prefrontal cortical hypoactivity reported by imaging studies in human addicts could be related to a decrease in the excitability of some of cells that conforms the prefrontal cortex," says Lavin. "It appears that following repeated exposure to cocaine, the normal activity and consequent synchrony exhibited by prefrontal cortical cells in normal animals is severely disrupted, and this condition could contribute to the cortical dysfunctions that are a cardinal feature of cocaine abuse."
Scientists also report that learned associations between the effect of drugs and the environment in which the drugs are taken play a role in the level of sensitization to the drug.
Learned associations between environmental stimuli and cocaine chemical effects play major roles in a drug-induced behavior, says Bruce Hope, PhD, at the National Institute on Drug Abuse. Cocaine-associated stimuli in an addict's environment are known to stimulate craving for the drug. Hope examines this interaction between cocaine's chemical effects on the brain and the environment where the drug is administered.
"We and others have found that when we repeatedly administer cocaine to rats in one environment, there is a progressive enhancement, called sensitization, of the behavioral effects of the drug," says Hope. "If rats are injected with cocaine in the same environment, then rats exhibit sensitized locomotor behavior for as long as 6 months after repeated drug exposure. However, if these rats are injected with cocaine in an environment that was not previously associated with cocaine exposure, then rats respond as though they had no prior experience with cocaine."
The sensitized drug-induced behavior is dependent on the environmental context and appears to be due in part to learned associations between drug effects and the drug administration environment.
"It is thought that such learned associations are mediated by environmental stimuli selectively activating small numbers of sparsely distributed neurons or synapses and altering them in a way that represents the association between drug effects and the drug administration environment," says Hope.
One problem, he says, has been how to study modifications in only these selectively activated neurons as opposed to all neurons in a given brain region. "It's a lot like trying to study needles in a haystack," he says. "Nearly all current molecular and cellular techniques do not address this issue of specificity."
To address this problem, Hope's laboratory uses transgenic rats that have been modified with the addition of a gene that is activated in only strongly activated neurons. Activation of this gene produces a protein called beta-galactosidase that can be detected and manipulated in behaving animals and in live tissue.
Hope and his collaborators focused their efforts on a brain region called the nucleus accumbens, which is thought to mediate many of cocaine's effects on behavior, and determined that a small set of neurons is uniquely selected by the environment to be modified by repeated cocaine administration.
"We are currently using these rats to more fully characterize molecular and cellular alterations in this unique set of selectively activated neurons," says Hope. "Our goal is to identify how repeated cocaine exposure alters neurons and synapses during learning of more complicated drug-associated behaviors such as drug-seeking in rat models and in human addicts."
Another avenue of research shows that discharges from specific neurons can increase arousal and may have a connection with addiction.
"Orexin-containing neurons discharge during active waking and through their influence upon multiple other systems, including the sympathetic nervous system and the hypothalamo-pituitary-adrenal axis (HPA), have the capacity to stimulate arousal along with peripheral autonomic and hormonal changes that support such arousal," says Barbara Jones, PhD, at McGill University.
Orexin is a highly excitatory neuropeptide hormone associated with regulating sleep-wake cycles. Jones says that some scientists believe that Orexin can enhance stress, which, in turn, induces reinstatement of drug-seeking behavior. Other research holds that Orexin neurons function as a reward system.
In her studies, Jones and her team of researchers employed special procedures to record and identify Orexin neurons in the hypothalamus of naturally sleeping-waking rats. In order to identify recorded neurons, they needed to use fine glass micropipettes that could be filled with a chemical for labeling the neurons. Yet they could not be used in freely moving animals. So, Jones and her colleagues immobilized the rat's head so that it would not move during the recording but so it would be relaxed enough to be able to fall asleep.
Jones recorded neuronal activity in association with electroencephalographic (EEG) activity from the cortex and electromyographic (EMG) activity from the neck muscles during active waking, quiet waking, slow wave sleep (SWS), and REM sleep. During the recording they moved the pipette filled with the chemical marker Neurobiotin to a position next to the cell being recorded and passed a current through the pipette so that the Neurobiotin was ejected out of the pipette and through the membrane of the recorded cell.
At the end of the experiment, the rats' brains were examined by staining sections for the Neurobiotin to locate the recorded-labeled cell. Then, by double staining for Orexin, they were identified as being immuno-positive or immuno-negative for Orexin (Orx+ or Orx-).
"We discovered that neurons which discharged at high rates only during waking were Orx+, whereas those that discharged at high rates during both waking and REM sleep were Orx," says Jones. The Orx+ neurons discharged maximally during active waking and minimally during SWS and REMS. During active waking their firing was often relatively slow and regular, she adds, but could also increase phasically in association with movement or decrease transiently with immobility.
"These new findings indicate that Orx neurons discharge during active waking and are virtually silent during sleep, including REM sleep and associated muscle atonia," says Jones. "The Orx neurons must play a critical role in maintaining waking by exciting multiple central systems that subtend muscle tonus and movement during active waking."
These central systems are known to include neurons in the cortex, basal forebrain, thalamus, brainstem, and spinal cord that are excited by Orx and innervated by Orx neurons. From its central position, the Orx neurons can mobilize all neurons of the arousal systems, including glutamatergic, cholinergic, histaminergic, and noradrenergic neurons, while also directly stimulating cortical activation, motor activity, and sympathetic activity to promote and sustain an alert and active waking state. Jones concludes that Orx neurons normally prevent mammals from falling asleep by keeping them awake, active, and responsive.
