Ton Schoffelmeer: unraveling the pharmacology of addiction
'Addiction is currently the most widely occurring psychiatric disorder, causing an enormous burden for our society. Addicted people suffer from a brain disease and it is possible to develop medicines to successfully treat those that are motivated to stop using drugs.’
Following his studies on opioid receptor heterogeneity in the brain as senior researcher with the Royal Netherlands Academy of Arts and Sciences (KNAW), psychopharmacologist Ton Schoffelmeer became interested in the long-lasting effects of the abuse of morphine and other drugs on the brain. About fifteen years ago, he was the first researcher in the Netherlands to study the long-term neurochemical as well as behavioural correlates of drug and alcohol addiction in rats at the Vrije Universiteit.
Schoffelmeer is proud of what his group has achieved thus far. For example, his group showed that persistent drug-induced neuroplasticity in the motivational system of the brain mediates long-lasting behavioural hypersensitivity to addictive substances and to drug-associated environmental stimuli (cues). ‘During drug abstinence, craving for cocaine or a cigarette is often initiated by cues previously associated with drug consumption, such as the street where a junk used to buy his heroin, a friend he used to smoke pot with, or simply an ashtray. In addicts, these cues trigger the persistently sensitised motivational system of the brain, leading to compulsive drug-seeking and to relapse to drug-taking during abstinence. Moreover, we and others showed that cognitive personality characteristics such as impulsivity determine the transition from recreational to compulsive cocaine or nicotine consumption and greatly enhance the individual’s vulnerability to cue-induced relapse.’
That is why Schoffelmeer considers addiction to be a neurological disorder. ‘Since addictive behaviour is the consequence of persistently altered communication between neurons in the brain of genetically vulnerable individuals, it is by definition a psychiatric disease. In fact, addiction is currently the most widely occurring psychiatric disorder, causing an enormous burden for our society. In this respect, I don’t judge people regularly smoking cigarettes or using other drugs such as cocaine, heroin and alcohol. All I’m saying is that people with an addiction suffer from a brain disease and that it is possible to develop medicines based on animal research in order to successfully treat addicts that are motivated to stop using drugs.’
What is so fascinating about addiction research, Schoffelmeer says, is that it is a brain disease which can be studied in great detail in laboratory animals such as rats, using behavioural animal models that closely resemble distinct aspects of human addictive behaviour. ‘Addictive behaviour can be adequately measured in operant animal models as opposed to, for instance, depression and schizophrenia. Thus, rats do not display a lack of interest to live or a wish to commit suicide as an expression of depression, nor do they appear to have paranoid delusions or irrational thoughts as an expression of psychosis. I think that this could be a reason for the lack of introduction of really innovative and powerful medicines against depression or schizophrenia on the market during the last couple of decades.’
Anti-craving medicine
In 2001, Schoffelmeer and colleagues published a Nature Medicine article on Rimonabant, a cannabinoid receptor antagonist that appeared to prevent cue-induced relapse to cocaine-seeking in rats without suppressing the pleasure gained from consuming cocaine. Subsequently, Rimonabant also appeared to attenuate relapse to heroin-, nicotine- or alcohol-seeking and to inhibit the motivation for high-calorie food in rats. Schoffelmeer: ‘In clinical studies, it appeared to prevent relapse in about 40 percent of the drug addicts tested, and to reduce overweight in obesity patients. Unfortunately, the compound also had the side effect of inducing depression in some people and was therefore recently taken off the market. Nevertheless, what is most important for us is that these clinical studies provided a proof of principle, in that it is apparently possible to design anti-craving medicines for human addicts based on behavioural pharmacological studies in rats.’
Schoffelmeer emphasises that this preclinical addiction research now has an excellent international reputation and that the success of this animal research has been made possible by the behavioural expertise of his co-workers Taco De Vries and Tommy Patty, and the long-standing collaboration with other groups of the VU, most notably the groups of his co-program leader Guus Smit and the group of Huib Mansvelder. ‘We share the same fundamental scientific drive and get along very well on the personal level, which I think is the key to an outstanding research program.’
He hopes and expects that the Neuroscience Campus Amsterdam will strengthen communication between clinicians and animal researchers. ‘I sometimes regret that I am not a clinician myself. I think that, using a fancy phrase, translational research can really make a difference in a research program. My dream is to establish an addiction centre at the VU entirely devoted to both scientific research and the treatment of addicts. The establishment of such a centre would indeed be the highlight of my career.’
