ADVANCES IN GENETICS AND CELL BIOLOGY CREATE POSSIBLE TARGETS FOR TREATING ADDICTION
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ADVANCES IN GENETICS AND CELL BIOLOGY CREATE POSSIBLE TARGETS FOR TREATING ADDICTION.
ORLANDO, Monday, Nov. 4 - Major advances in genetics and cell biology are identifying many of the molecular targets of drugs of abuse and are leading to new hypotheses about addiction and new possible treatments.
New findings include the molecular neuroadaptations that occur from chronic administration of drugs; the role of receptors in addiction and their possible use as targets for therapy; and the discovery of genes that result in resistance and tolerance to alcohol. The new studies were reported today during the 32nd annual meeting of the Society for Neuroscience.
The economic costs of addiction are estimated at $161 billion in the United States, according to the National Institute on Drug Abuse. Many Western countries have made major investments in research directed towards its understanding and prevention.
Converging evidence by the early 1990s suggested that many, if not all, drugs of abuse, including 'stimulants' such as amphetamine and cocaine, opiates such as heroin, and even 'legal' drugs such as alcohol and nicotine, have commonalities in their modes of action which implicated brain dopamine systems, says Barry Everitt, PhD, a professor of behavioral neuroscience at the University of Cambridge. His lecture at this meeting addresses the neural and psychological mechanisms underlying drug addiction.
"Although these drugs can mimic the actions of several different chemical neurotransmitter systems in the brain through their actions at specific receptors, e.g. opiate receptors in the case of morphine and heroin, many of these primary effects were secondarily shown to influence the activity of a group of dopamine neurons in the midbrain which send their projections to interconnected forebrain structures including the prefrontal cortex, the so-called 'limbic system' and the striatum."
Everitt notes that a ventral region of the striatum, the nucleus accumbens, (contrasting with the more dorsal regions that are implicated in neurological disorders such as Parkinson's and Huntington's diseases) is generally agreed to be the key zone for mediating the rewarding effects not only of drugs such as amphetamine and cocaine - which directly potentiate dopamine neurotransmission by various actions at the molecular level - but all drugs of abuse including opiates, cannabis, nicotine and alcohol.
Recent discoveries of molecular neuroadaptations induced by chronic administration of cocaine, heroin, nicotine and alcohol that occur downstream of dopamine receptors in the nucleus accumbens neurons and elsewhere, have encouraged a view of drug addiction as gradual brain adaptations to chronic drug exposure, possibly triggered by a drive to homeostasis, i.e. the regulation of activity of brain systems affected by self-administered drugs within certain defined limits. These neuroadaptations are the product of both decremental (tolerance and withdrawal) and incremental (sensitization) pharmacological effects.
There is little doubt that phenomena such as sensitization and withdrawal contribute significantly to the persistence and resistance to treatment of addictive behavior. But an important question remains of the precise relevance of neurochemical and molecular changes produced by drug exposure to the clinical reality of drug addiction in humans. For these discoveries to be useful, we need a much more sophisticated understanding of the process of addiction at the cognitive, behavioral and neuropsychological levels.
The process of associative learning by which the drug abuser connects specific cues with drug-induced states now seems likely to depend upon structures in the so-called 'emotional brain' or 'limbic system' with strong anatomical links to the nucleus accumbens, including the amygdala and orbitofrontal cortex.
Everitt and his colleagues have successfully modeled these processes and explored their neural basis in rats. Thus, rats with lesions of the amygdala will readily self-administer cocaine but never acquire the capacity to learn long sequences of behavior to gain access to it. Cocaine addicts exhibit a functional activation of several interconnected areas including the amygdala when they are presented visually with the paraphernalia commonly associated with cocaine administration, giving clear evidence of homology between species. Rats with inactivation of the nucleus accumbens simply cannot tolerate delays to drug or food reinforcement; they become impulsive - another feature of addictive behavior in humans.
As a result of learning, behavior is often sustained for long periods in the absence of the original goal (in this case cocaine) and may lead to the development of a drug-seeking habit even in parallel with an apparent reduction in the subjective effects which encouraged its initial development. Rats with inactivation of the nucleus accumbens (in fact one specific part of it - the core region) are incapable of acquiring prolonged sequences of drug-seeking. "These new data reveal an otherwise unappreciated aspect of nucleus accumbens function that may be critical for the development of addiction," says Everitt.
Relapse is a further consequence of the conditioning process, occurring when the drug-seeking habit is triggered by salient, drug-related cues which may initially lead to the retrieval of devastatingly compelling memories of drug-related experiences but subsequently elicit further drug-seeking and taking behavior on an almost automatic basis.
"Our recent experimental work in animals reveals great potential for new pharmacological treatments for addiction that explicitly target the cravings, control over drug-seeking and relapse induced by drug-associated stimuli," Everitt says. "For example, our new data showing that drugs interfering with the actions of dopamine at one type of dopamine receptor, the D3 receptor, while being generally behaviorally inert nevertheless powerfully diminish drug-seeking and relapse induced by drug-associated cues in rats."
These drugs are currently undergoing evaluation in clinical trials. Drugs such as baclofen, which can indirectly decrease the activity of dopamine neurons through actions at a receptor for the inhibitory transmitter GABA, can both decrease cocaine- and heroin-seeking in rats and also block the activation of limbic areas by cocaine cues in cocaine addicts. Thus, there may be several ways to limit or prevent the impact of prior learning on the maintenance of, or relapse to, a drug-seeking habit.
Inhibitory processes in the brain normally hold potentially maladaptive behavior in check and presumably, similar processes also restrain many of us from over-indulging in drugs in the first place. Such self-control is usually attributed to neural networks involving the prefrontal cortex. In fact, some of the general behavioral and cognitive characteristics of drug abusers - including impulsivity, risk-taking and apparently poor decision-making abilities - resemble effects of damage to the frontal lobes.
It has recently been shown that chronic alcohol and cocaine abusers having been maintained free of drug for many months continue to show low levels of functioning of the prefrontal lobes of the brain and this may contribute not only to the above traits, but also the development of drug-taking as a compulsive habit. Everitt's group has shown that chronic amphetamine abusers show marked changes in their decision making abilities, making poor decisions in a gambling task that requires individuals to make judgments about the probability of an outcome. Thus, chronic abuse of addictive drugs may, temporarily or permanently - we simply do not know which - impair brain function in a way that contributes to the persistence and resistance to treatment of addictive behavior. These frontal lobe-dependent processes are also being investigated in rats seeking and taking cocaine and heroin.
In other work, researchers from the National Institutes of Health in Bethesda, MD and Alkermes, Inc. describe a new target for the development of therapies to treat drug abuse. The target is a protein, called the M5 muscarinic receptor that was discovered about 10 years ago. However, there was little interest in this receptor because it is not commonly found in the brain, and there were no chemicals (drugs) available to selectively activate or inhibit its function.
"We were able to shed light on the function of the M5 receptor by making mice with a specific deletion of the gene coding for this receptor (M5 knockout mice). We then used these mice to ask a number of questions about what this receptor does," says Anthony Basile, PhD, of Alkermes. Basile organized a symposium at this meeting on the mechanisms of reinforcement and relapse in drug abuse.
Previous work by other laboratories indicated that these receptors were located exclusively on neurons in the brain involved in the rewarding ("feel-good") properties of drugs of abuse. Using the M5 knockout mice, Basile and his colleagues directly tested if these receptors could modify the rewarding properties of one class of abused drugs, the opiates. Opiates, such as morphine, are clinically very useful drugs that suppress pain (analgesics). However, their use can also be addictive, due to the intensity of their rewarding properties (euphoria).
Basile's group investigated the role of M5 receptors in morphine addiction by administering doses of morphine to M5 knockout and normal mice, and measured the intensity of morphine-induced reward using behavioral and biochemical techniques. The intensity of the reward associated with increasing doses of morphine was very high in normal mice with the M5 receptor gene. However, the reward effect was almost completely absent - 90 percent reduction in conditioned place preference, 88 percent reduction in dopamine release in the nucleus accumbens - in M5 knockout mice.
In addition to suppressing the intensity of morphine-induced reward, knocking out the M5 receptor also reduced the severity of morphine withdrawal. Normal and M5 knockout mice were addicted to morphine by giving them daily doses for one week. Giving these mice the morphine blocker naltrexone then precipitated the morphine withdrawal syndrome. Mice withdrawing from morphine typically jump, and develop episodes of tremor, shaking, and teeth chattering. However, the number of jumps and the episodes of shaking and other withdrawal behaviors were substantially reduced - less than 70 percent reduction in jumping - in morphine-withdrawn M5 knockout mice.
Despite the suppression in morphine-associated reward and withdrawal behaviors observed in the M5 knockout mice, tests of the analgesic actions of morphine revealed that removing the M5 receptor had no effect on the painkilling properties of morphine.
"These results suggest that a drug that selectively blocks the M5 receptor may be developed that can reduce the addictive properties of morphine without altering its valuable ability to suppress pain," says Basile. "Such a drug may also reduce the severity of withdrawal symptoms in opiate addicts, allowing them to get off and stay off drugs. Finally, this treatment may be able to reduce the rewarding effects associated with many other drugs of abuse, such as cocaine, alcohol and nicotine, thereby making it more difficult to become dependent or addicted to them.
"Because of the restricted localization of the M5 muscarinic receptor in the brain, and its virtual absence from other organs, a therapeutic agent may be developed that has limited or no side-effects."
In research on alcoholism, researchers have found that those with a genetically determined increased resistance to intoxication by alcohol are at higher risk to become alcoholics. While the mechanisms by which this occurs are not understood, it is possible that people that can tolerate more alcohol, drink more, and consequently become addicted. Alternatively, the mechanisms that underlie addiction and ethanol resistance may be shared. It is extremely difficult to find the gene or genes that determine this behavior in humans.
Ulrike Heberlein, PhD, and her colleagues at the University of California at San Francisco are using the fruit fly Drosophila, to identify genes that confer resistance to ethanol. They believe that their findings with flies will be relevant to humans because there is a high degree of conservation between the genes of both organisms. In addition, they have shown that the behavior of flies when inebriated is very similar to that of humans, suggesting that the effects of ethanol in the brain are mediated by similar mechanisms.
When exposed to low ethanol doses, flies become hyperactive and their patterns of movement become more erratic. At higher doses, flies become uncoordinated, they fall on their sides and backs, and eventually fail to right themselves. Interestingly, the doses of ethanol that make flies hyperactive are very similar to those that cause behavioral disinhibition and euphoria in humans. Ethanol doses that sedate flies also sedate humans. In addition, they have found that flies develop tolerance when exposed to ethanol multiple times. Tolerance is a well known phenomenon that accompanies excessive drinking in humans. They have devised assays that allow them to measure these various aspects of the behavior of intoxicated flies with high resolution.
Heberlein's approach to identify and isolate the genes that mediate resistance and tolerance to alcohol is to use genetic screens for mutations that alter the mentioned behaviors. The availability of a mutation that disrupts a certain gene allows the isolation of the gene fairly quickly.
"We have already isolated several mutant flies that display the desired defects and we have begun isolating the corresponding genes" Heberlein says. "Several of these genes have obvious homologs in mammals, including humans. Perhaps more importantly, there is now evidence that mutations in the same gene change ethanol-induced behaviors in flies and mice. These genes will hopefully become candidate genes for genetic studies of alcoholism in humans."
