Oxytocin attenuates neural response to emotional faces in social drinkers: an fMRI study.

INTRODUCTION: Oxytocin is a key mediator of emotional and social behavior that seems to be of relevance for the development and maintenance of addictive behaviors. We thus investigated the effect of oxytocin on neural response and behavior during a face-matching task in a sample of social drinkers. METHODS: Thirteen social drinkers underwent a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging face-matching task with and without prior intranasal application of 24 international units oxytocin. Effects of oxytocin and task condition (faces, shapes) on brain activation and individual task performance were assessed. RESULTS: Face-matching compared to shape-matching trials resulted in higher brain activation in the bilateral amygdala, hippocampus and parts of the occipital gyri. Oxytocin application vs. placebo reduced activation in bilateral amygdala, parts of the frontal gyri, and the parietal lobe. Region of interest analyses indicated that the oxytocin-induced attenuation of amygdala response was specific to face-stimuli and associated with lower subjective alcohol craving, and a lower percentage of heavy-drinking days (defined as ≥ 5 standard drinks/day). CONCLUSION: For the first time, we could show that a larger oxytocin-induced attenuation of amygdala response to fearful faces is associated with lower subjective craving for alcohol and percentage of heavy drinking days in social drinkers. Modulation of amygdala activation, induced by emotional stimuli, might represent a neurobiological substrate of oxytocin's protective effects on drug seeking behavior.

Oxytocin modulates alcohol-cue induced functional connectivity in the nucleus accumbens of social drinkers.

The brain oxytocin system is involved in a wide range of addictive behaviors, inhibiting prime- and cue-induced relapse in preclinical models of substance use disorders. Especially the ability of oxytocin to modulate connectivity between the nucleus accumbens (NAc) and cortical regions has been identified as a factor likely to be critical to its effects on relapse. We thus investigated the effect of oxytocin on NAc functional connectivity during an alcohol cue-reactivity task. Thirteen male social drinkers participated in a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task with and without prior intranasal application of 24 IU oxytocin. Effects of oxytocin and functional connectivity during presentation of alcohol cues were assessed using ROI-to-ROI generalized psychophysiological interaction analyses. Oxytocin application significantly reduced NAc connectivity with the cuneus and thalamo-occipital connectivity, while enhancing connectivity between the paracingulate gyrus and precentral gyrus. This effect was specific to the alcohol presentation and was not found during processing of neutral pictures. In addition, the NAc-cuneus connectivity significantly correlated with alcohol cue-induced craving during the scanning session. For the first time, we could show that oxytocin selectively attenuates NAc connectivity during an alcohol cue-reactivity task which was related to changes in subjective craving for alcohol. This might reflect an attenuation of alcohol-cue saliency by oxytocin, which improves inhibitory control over craving and cue reactivity.

Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans.

Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol-dependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([125I]OVTA binding), and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol-dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positively affect treatment outcomes in alcoholics.