Abstract
The anterior insular cortex is hypothesized to represent interoceptive effects of drug reward in the service of goal-directed behavior. The insula is richly connected, but the insula circuitry in addiction remains poorly characterized. We examined the involvement of the anterior insula, amygdala, and nucleus accumbens, as well as the projections of the anterior insula to the central amygdala, basolateral amygdala (BLA), and nucleus accumbens core in voluntary alcohol drinking. We trained alcohol-preferring Alko Alcohol (AA) rats to drink alcohol during intermittent 2-h sessions. We then expressed excitatory or inhibitory designer receptors [designer receptors exclusively activated by designer drugs (DREADDs)] in the anterior insula, nucleus accumbens, or amygdala by means of adenovirus-mediated gene transfer and activated the DREADDs with clozapine-N-oxide (CNO) prior to the drinking sessions. Next, to examine the role of specific insula projections, we expressed FLEX-DREADDs in the efferent insula → nucleus accumbens core, insula → central amygdala, and insula → BLA projections by means of a retrograde AAV-Cre vector injected into the insula projection areas. In the anterior insula and amygdala, excitatory Gq-DREADDs significantly attenuated alcohol consumption. In contrast, in the nucleus accumbens, the Gq-DREADD stimulation increased alcohol drinking, and the inhibitory Gi-DREADDs suppressed it. The Gq-DREADDs expressed in the insula → nucleus accumbens core and insula → central amygdala projections increased alcohol intake, whereas inhibition of these projections had no effect. These data demonstrate that the anterior insula, along with the amygdala and nucleus accumbens, has a key role in controlling alcohol drinking by providing excitatory input to the central amygdala and nucleus accumbens to enhance alcohol reward.
Highlights
Corticolimbic regulatory systems have long been thought to be the primary neural substrates in addictive behaviors
The mean intake of all included subjects was 0.80 ± 0.02 g/kg during the 10th acquisition week. In these Alko Alcohol (AA) rats, we first tested the involvement of the anterior insula, nucleus accumbens, and amygdala in alcohol drinking by expressing the stimulatory Gq- and inhibitory Gi-designer receptors exclusively activated by designer drugs (DREADDs), as well as the EGPF protein as a control in these brain areas using adenovirus-mediated gene transfer
In contrast to the insula and amygdala manipulation, in the nucleus accumbens, the effects were bidirectional. We found both a significant 59% increase in alcohol drinking by the stimulatory Gq-DREADDs (t(10) = 2.67, p = 0.024) and a 36% decrease by the inhibitory Gi-DREADDs (t(9) = 2.99, p = 0.015), indicating that the failure to see effects by Gi-DREADD-mediated neuronal inhibition in the insula and amygdala was not due to the Gi-DREADD vector used
Summary
Corticolimbic regulatory systems have long been thought to be the primary neural substrates in addictive behaviors. The insula is hypothesized to represent the interoceptive effects of drug taking and integrate them with emotional. Insula Circuits in Alcohol Reward and decision-making processes (Naqvi and Bechara, 2009; Droutman et al, 2015b). Lesions of insula suppressed smokingrelated urges in smokers (Naqvi et al, 2007) and decreased both the conditioned drug effects and drug self-administration in various animal models of addiction (Contreras et al, 2007; Scott and Hiroi, 2011; Cosme et al, 2015; Pushparaj and Le Foll, 2015; Pushparaj et al, 2015). Human addicts displayed lower insula activation while performing decision-making and risk evaluation tasks (Li et al, 2009; Stewart et al, 2014). The apparently discordant findings show that insula may exhibit either sensitized or desensitized functions depending on the behavioral context and possibly the stage of addiction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
