Alkoholbruk trots negativa konsekvenser: En translationell strategi

Alcohol addiction leads to continued alcohol use despite adverse consequences (“compulsivity”).

We have found that a minority of outbred rats show punishment-resistant, compulsive-like alcohol self-administration, and that altered Central Amygdala (CeA) function is a key determinant of this behavior.

To uncover the molecular basis of individual susceptibility to compulsivity, we analyze CeA neurons of compulsive rats, and those from post-mortem brain tissue from patients with alcohol addiction for differential gene expression. For functional validation, we will knock down prioritized candidates resulting from this search in rats.

We will also examine the general, drug-independent role of PKCδ+ CeA neurons in compulsive reward-taking, using optogenetic self-stimulation of dopamine neurons, combined with chemogenetic manipulation of PKCδ+ cells. GABA-B positive allosteric modulators (PAMs) rescue compulsivity, making them candidate therapeutics.

To accelerate clinical development of GABA-B PAMs, we will develop a human biomarker of GABA-B target engagement using a transcranial magnetic stimulation paired-pulse inhibition protocol.

This will be validated with the prototypical GABA-B agonist baclofen in a double-blind, placebo-controlled study in non-treatment seeking heavy drinkers.

Once established, this biomarker will allow us to initiate experimental medicine studies to advance novel GABA-B PAMs coming out of a collaboration with a drug company.