Insular neural system controls decision-making in healthy and methamphetamine-treated rats

Significance Patients with addiction have a greater tendency to engage in risk-taking behavior. However, the neural substrates responsible for these deficits remain unknown. Here we demonstrated that chronic methamphetamine-treated rats preferred high-risk/high-reward actions and assigned higher value to high returns, indicative of altered decision-making. Pharmacological studies revealed that the insular neural system controls decision-making in both healthy and methamphetamine-treated rats. We further confirmed the role of the insular cortex in decision-making using designer receptor exclusively activated by designer drug technology. Because decision-making is a cognitive process that influences many aspects of daily living and both mental and physical health, the findings of this study have broader implications. Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

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