Drug effects are mediated by a complex interaction of external and internal stimuli. The interoceptive system, including the insular cortex, is involved in homeostatic and emotional processing of internal states. It is this system that allows one to discriminate a heroin high from an amphetamine high. Animals can do this too. Pharmacologists use animal drug-discrimination experiments to group compounds of abuse into different classes. Such tasks depend upon the actions of the insular cortex, where the nervous system develops a subjective state with discriminative stimulus qualities to differentiate one drug from another. Changes in this interoceptive system can lead to the development of addiction and underlie the negative affective states, such as anxiety and depression, which often occur during drug abstinence.

In a recent paper (available here), Marco Contreras, Francisco Ceric, and Fernando Torrealba examined the role of insular cortex in drug craving and affective states. Amphetamine-experienced rats were trained to exhibit conditioned place preference for an amphetamine-associated compartment. Conditioned place preference illustrates how a drug-induced subjective experience can become associated with environmental cues. A brief description of the methodology: animals are given injections of a drug, in this case amphetamine, and placed in a chamber with distinct contextual cues. Other animals are given saline and placed in neutral chambers. After several injections, the animals are then placed in a third compartment, one with clear access to either of the first two chambers, and allowed to choose where to spend their time. If a drug produced a subjective state that is rewarding, animals will spend more time in the drug-associated chamber. This method provides an indirect measure of reinforcement and allows researchers to determine how well animals can differentiate the internal states that different drugs create.

In the current study, amphetamine-treated animals preferred the amphetamine chamber, as expected. Researchers then reversibly inactivated their insular cortices with lidocaine, a sodium channel blocker. Inactivated animals reversed place preference to the non-amphetamine-associated chamber, exhibiting preference similar to saline controls (controls preferred the non-amphetamine-associated chamber because it was darker). This effect reversed again after the lidocaine wore off, with the amphetamine-experienced rats returning to the amphetamine chamber. Lidocaine injections into the adjacent somatosensory cortex did not disrupt conditioned preference for the amphetamine chamber. The researchers conclude that insular inactivation reduced drug craving; rats spent less time in the amphetamine chamber because they no longer felt the subjective state that made amphetamine rewarding.

To examine insular involvement in the development of aversive internal states, researchers induced a “malaise-like” state with lithium chloride (LiCl). Inactivation of the insular cortex blocked the malaise-inducing behavioral effects of LiCl. In rats, this state is characterized by a sagging posture and decreased locomotion. Lithium chloride is often used to treat the mania aspect of human bipolar disorder.

Specificity of insular activation was tested with Fos immunoreactivity. Fos is the protein product of the immediate early gene c-Fos often used as a marker of neuronal activity. Conditioned place preference to amphetamine and LiCl administration significantly increased Fos protein expression in the insular cortex relative to controls. Utilization of axonal tracers verified that lidocaine injections were effective at inactivating the primary insular cortex, which includes the posterior granular insula and projections to visceral-thalamic, limbic, and prefrontal regions.

If the insula is important for generating motivation to take drugs, its inactivation should decrease drug craving, as the researchers note. The authors cite a recent human finding showing that subjects with insular damage were able to easily quit smoking. This relationship between drug craving and insular activity has also been backed up by neuroimaging studies. The insular cortex is active when addicts are exposed to environmental cues that signal craving. Interestingly, humans with insular damage do not report decreased food craving or intake. The authors suggest this implicates the insula as part of a system for measuring state of well being. Strong deviations from homeostasis, like those elicited by drugs, activate the insula in part to mediate motivation and aversion.

Given these findings, it is clear that the involvement of the insular cortex in drug craving and affective states is important for the study of addiction. Most drugs of abuse act on natural homeostatic and reward pathways, changing them in ways that promote compulsive drug craving and seeking. In humans, such changes can persist for years, making relapse a perpetual danger. Future research will need to examine how the insula, through interactions with mesolimbic dopamine pathways, prefrontal cortex, and memory systems, acts to develop and maintain subjective drug experience.

Discussion Questions:

5. The idea that the insula is a “well-being detector” has interesting evolutionary implications. Why would this system have evolved to be so susceptible to compounds of abuse, which initially provide some signal of well being, but later cause such deleterious consequences?