Pia Steensland´s research group
Experimental Neuropsychopharmacology - Dependence Disorders
Our research aims to increase the understanding of the underlying mechanisms in the brain during the development and maintenance of alcohol use disorder (AUD), with the ultimate goal to identify potential novel effective medications.
In Sweden, about one million people drink excessive amounts of alcohol, risking negative health effects and about 300.000 of these are addicted to alcohol. Alcohol use disorder is a relapsing psychiatric disorder characterized by loss of control over drinking and physiological dependence. The alcohol-related socioeconomic cost has been estimated to a staggering 49 billion SEK per year (Missbruksutredningen (SOU 2011:6)). Despite the severity of AUD, only four medications are available and the prescription rates are low, possibly due to modest clinical efficacy of the available medications. There is thus a great need for new and more efficacious AUD medications.
To identify and evaluate potential AUD medications, we have established a preclinical development program, consisting of a battery of validated models of long-term voluntary alcohol consumption. In fact, AUD is one of the few psychiatric disorder which can be modelled using preclinical methods with clear face validity, i.e. methods with a distinct resemblance to the clinical condition. The predictive validity of our preclinical development program is highlighted by the rapid transition of evaluated drug candidates (such as e.g. varenicline (Champix®)), from the laboratory to successful clinical trials in patients.
The current main target of our research is dopamine - a core neurotransmitter involved in the development and maintenance of AUD. Dopamine is also the main neurotransmitter modulating the brain reward system to stimulate us to act in the interests of our own survival. Since dopamine creates a feeling of wellbeing when we are exposed to “natural rewards”, such as when we exercise, eat good food or have sex, the memory associates the two so that we will repeat the behavior.
When we drink alcohol, the brain reward system releases more dopamine than after exposure to natural rewards, creating a pleasant euphoric sensation. However, over time with repeated intoxications, the reward system is desensitized and less dopamine is released creating a new more negative, depressive-like general state of mind. Greater volumes of alcohol are now needed to cause intoxication and to attain a state of physical and emotional normality – addiction has set in.
Based on the role of dopamine in AUD, we are currently evaluating the potential of the dopamine stabilizer (-)-OSU6162 (OSU6162) as a novel AUD medication. This is a collaborative project with Nobel Laureate Arvid Carlsson who invented the compound in the 1980’s. OSU6162 has a unique ability to increase or decrease the dopamine activity depending on the endogenous dopaminergic tone, we therefore hypothesize that the compound may normalize the dopamine activity in the brain reward system, in both the acute and the abstinence phase of alcohol abuse.
In a successful series of preclinical experiments, we have showed that OSU6162 decreases alcohol intake, motivation to seeking alcohol, relapse behavior and withdrawal symptoms as well as counteract the alcohol-induced dopamine deficiency in the brain reward system – all desirable characteristics of an AUD medication. Recently, we published, in collaboration with Professor Johan Franck and Assistant Professor Nitya Jayaram-Lindström, a “proof-of-concept” study in alcohol dependent patients showing that OSU6162, compared to placebo, attenuated craving for alcohol after drinking one glass of an alcoholic beverage. Interestingly the treatment effect was driven by those individuals that had the highest level of baseline impulsivity.
We are currently conducting preclinical experiments investigating the mechanisms behind OSU6162’s ability to attenuate alcohol-mediated behaviors as well as the role of impulsivity in the development of AUD to understand whether OSU6162 might be most valuable for treatment of specific subgroups of alcohol dependent individuals, i.e. for example those with higher level of impulsivity.
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- The influence of impulsivity on excessive alcohol consumption and the effects of OSU6162 on impulsive behavior after long-term drinking
- The effect of long-term alcohol intake on dopamine receptors in reward related brain regions using molecular assays
- Evaluation of the potential of the dopamine D3-receptor as a novel treatment target for AUD
The effects of the monoamine stabilizer (-)-OSU6162 on craving in alcohol dependent individuals: A human laboratory study.
Eur Neuropsychopharmacol 2015 Dec;25(12):2240-51
The monoamine stabilizer (-)-OSU6162 attenuates voluntary ethanol intake and ethanol-induced dopamine output in nucleus accumbens.
Biol. Psychiatry 2012 Nov;72(10):823-31
Evaluation of guanfacine as a potential medication for alcohol use disorder in long-term drinking rats: behavioral and electrophysiological findings.
Neuropsychopharmacology 2015 Mar;40(5):1130-40
Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats.
Alcohol. Clin. Exp. Res. 2008 Oct;32(10):1816-23
|Pia Steensland||Senior researcher, Research team leader|
|Thatiane de Oliveira Sergio||Associated|