Aberrant insular cortex connectivity in abstinent alcohol‐dependent rats is reversed by dopamine D3 receptor blockade

Abstract

A few studies have reported aberrant functional connectivity in alcoholic patients, but the specific neural circuits involved remain unknown. Moreover, it is unclear whether these alterations can be reversed upon treatment. Here, we used functional MRI to study resting state connectivity in rats following chronic intermittent exposure to ethanol. Further, we evaluated the effects of SB-277011-a, a selective dopamine D3 receptor antagonist, known to decrease ethanol consumption. Alcohol-dependent and control rats (N = 13/14 per group), 3 weeks into abstinence, were administered SB-277011-a or vehicle before fMRI sessions. Resting state connectivity networks were extracted by independent component analysis. A dual-regression analysis was performed using independent component maps as spatial regressors, and the effects of alcohol history and treatment on connectivity were assessed. A history of alcohol dependence caused widespread reduction of the internal coherence of components. Weaker correlation was also found between the insula cortex (IC) and cingulate cortices, key constituents of the salience network. Similarly, reduced connectivity was observed between a component comprising the anterior insular cortex, together with the caudate putamen (CPu-AntIns), and the posterior part of the IC. On the other hand, postdependent rats showed strengthened connectivity between salience and reward networks. In particular, higher connectivity was observed between insula and nucleus accumbens, between the ventral tegmental area and the cingulate cortex and between the VTA and CPu-AntIns. Interestingly, aberrant connectivity in postdependent rats was partially restored by acute administration of SB-277011-a, which, conversely, had no significant effects in naïve rats.

Neuroimaging reveals functionally distinct neuronal networks associated with high-level alcohol consumption in two genetic rat models

“…including the infralimbic and prelimbic areas seems therefore genuine in msP rats, and a property that this line shares with the post-dependent model, in which rodents are exposed to high blood alcohol levels during chronic intermittent ethanol (Meinhardt and Sommer, 2015). Prolonged alcohol exposure caused a profound reprogramming in the mPFC, leading to molecular dysregulation (Heilig et al, 2017) and alterations in activity and connectivity (Scuppa et al, 2020) 14 that probably contribute to the alcohol-dependent phenotype. Similar alterations appear to preexist in the msP line (Bjork et al, 2010;Bifone et al, 2019).…”

The Influence of Stomach Back-Shu and Front-Mu Points on Insular Functional Connectivity in Functional Dyspepsia Rat Models

“…With regard to increased functional connectivity between the insula and CPu, S1BF, and PnO regions, research has shown that functional connections decreased between the insula and CPu in alcohol-dependent rats going through early withdrawal [ 46 ]. Both the insula and S1BF have also been shown to belong to the circuit which regulate gustatory information [ 47 ], and connections between the insula and PnO are yet to be explored, with more research required in these areas overall.…”

It’s more than just interoception: The insular cortex involvement in alcohol use disorder

“…Similar findings to alcohol use disorder are also evident in animal models. With regard to abstinence, aberrant or reduced, connectivity of the insular cortex is observed in post-dependent rats compared to naïve controls (Scuppa et al, 2020). Additionally, the insular cortex of conscious rats is activated following acute (six days) Pavlovian conditioning of alcohol-associated cues in an awake fMRI paradigm (Tsurugizawa et al, 2012).…”

“…As stated above, there is a strong projection between the insular cortex and the striatum. Indeed, recent imaging studies have shown alcoholdependent rats have altered insular cortex activity and connectivity which can be partially restored by systemic dopamine D 3 receptor antagonism (Scuppa et al, 2020). Alcohol also disrupts µ-opioid receptor-mediated long-term synaptic depression at anterior insular cortex-dorsolateral striatum synapses (Munoz et al, 2018).…”