Abstract
The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.
Highlights
The insular cortex has been implicated in many neuropsychiatric disorders, including addiction
Change in alcohol and sucrose drinking induced by insula Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) activation
The key finding of the present study is that anterior insula stimulation suppressed reward-related behavior, alcohol, and sucrose consumption, without influencing deprivation-induced water drinking or locomotor activity in a rat model of high alcohol preference
Summary
The insular cortex (insula) has been implicated in many neuropsychiatric disorders, including addiction. Insula is hypothesized to retrieve the salient interoceptive effects associated with drug and natural rewards and to represent them in the service of goal-directed behavior[1,2]. Decreased addictive behavior produced by disruptions of insula function seems to contradict the human neuroimaging data showing that reduced insula volume or reactivity is associated with drug seeking and relapse to drug use following abstinence. Functional neuroimaging suggested that alcohol- and methamphetaminedependent patients exhibited lower insula activation while performing decision-making and risk evaluation tasks[16,17]. These data can be interpreted as desensitized insula function in drug-addicted individuals
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