Feature: The neuroscience of addiction: Combination therapies

Read part I of the neuroscience of addiction.

Read part II of the neuroscience of addiction.

Florey Neuroscience Institutes’ Professor Andrew Lawrence is hot on the trail of treatments for addiction. Some compounds that are showing promise as combination therapies with candidate mGlu5 inhibitors are already approved for treating addictive disorders, notably alcohol abuse and nicotine addiction.

There are still no registered therapeutic drugs for treating some common forms of addiction, such as addiction to cocaine. “And even though we have medications available for treating aberrant alcohol consumption or nicotine addiction, they’re not brilliant,” says Lawrence. “They work for some individuals, but not so well at a population level, so there is plenty of room for new therapies in the marketplace.”

The broader the range of therapies, the better the chances of finding combinations appropriate to each individual’s needs. But Lawrence says that will depend upon individuals with addiction problems being prepared to accept treatment. “Most people with hypertension will willingly seek treatment, but not all drug addicts will,” he said. “It’s not unusual for them to have co-morbidity problems, such as psychiatric disorders, that complicate treatment.”

Their reasons for avoiding treatment, or non-compliance with prescribed treatment, vary. In the case of smoking, some individuals are more prone than others to side effects from anti-smoking drugs that target the central nervous system, and the problem can be dose- related. “We’re genetically unique individuals, so not everyone responds in the same way to the same drug, or the same dosage.”

Addiction therapy is also complicated in heavy alcohol abusers. “If they have liver damage, then they may have an issue metabolising other drugs,” Lawrence says. Lawrence’s research group has replicated findings by several overseas groups that have linked consumption of sugar-laden soft drinks in childhood and teenage years with a propensity to consume alcohol in adulthood.

“We raised rats on a high carbohydrate diet, which involved them drinking a sucrose solution during a 12 hour period, then water for 12 hours in a repeating cycle. When the rats were given access to alcohol, they didn’t drink any more alcohol than a control group, but they developed a strong preference for alcohol much more readily. We’ve also confirmed that rats on a high-sucrose diet have an exaggerated response to amphetamines.”

While the metabotropic receptor for glutamate is strongly implicated in numerous forms of addiction, Lawrence says the mechanism that underlies the vulnerability of addicts to relapse years after they have ceased taking drugs, has yet to be identified. “There are several schools of thought,” he says. “One suggests that drug-taking causes persistent adaptation in the way the brain works.

“There’s some evidence to support that. A French research group allowed rats to self-administer cocaine, and then applied current human diagnostic criteria to confirm addiction. Amazingly, even after long-term use of cocaine, only 15 to 17 per cent of the rats fulfilled the criteria for addiction, which is about the same rate as in humans who have used cocaine. Furthermore, the French study showed that the minority of addicted rats exhibit persistent dysfunction of the corticostriatal synapse.

“But the majority of rats that self-administered cocaine showed only short- term dysfunction, before recovering spontaneously. The researchers suggested that understanding the mechanism by which non-addicted individuals recover normal synapse function could be crucial to understanding addiction.”

Another potential mechanism of long-term susceptibility is gene imprinting by methylation. “It’s an emerging area of study, but there’s some evidence that methylation is involved, and we’re currently involved in a collaboration with researchers at the Queensland Brain Institute to explore that avenue.”

One difficulty in providing combination drug therapies to treat addictive behaviours like gambling is that the current Diagnostic Statistics Manual, DSM4, which sets out guidelines for treating addiction, does not currently recognise these disorders as forms of addiction. “But I believe that revised guidelines in the next edition, DSM5, will define addiction more broadly, to possibly include behaviours like excessive internet use, problem gambling and certain eating disorders like anorexia and bulimia,” says Lawrence.

“While these disorders differ in a number of ways from addiction to alcohol, nicotine and illicit drugs, there are degrees of commonality. They’re all forms of compulsive behaviour, and one of the defining characteristics of addiction is that it involves behaviours that persist as long as a disorder remains untreated.”