Drug Addiction and Mood Disorders: The Effect of Cholinergic Receptor Blockade on Relapse and Anxiety

Serena Thaw-Poon | serena.thaw-poon@yale.edu January 23, 2020

Drug Addiction and Mood Disorders: The Effect of Cholinergic Receptor Blockade on Relapse and Anxiety

To explain what we take for granted, that is one of the fundamental tenets of science. One such experience that is often accepted as true is the association between drug relapse and the prevalence of mood disorders. Dr. Nii Addy, Associate Professor in Psychiatry, and his lab, though, examine the relationship between mood disorders, like depression and anxiety, and substance abuse in order to elucidate their biological connections. His current work focuses on the impact of acetylcholine and the blockade of receptors that are activated by it. Acetylcholine is a versatile neurotransmitter involved in processes ranging from higher cognition to muscle contraction. In Addy’s research, though, its primary relevance is in how it alters the release of dopamine in the brain, a neurotransmitter associated with pleasure and reward. With this connection in mind, the lab decided to block cholinergic receptors in rodent models that would otherwise be activated by acetylcholine.

In order to do this, Addy and his team isolated different regions of rodent brains, using surgical targeting, to see if there were specific brain regions that were more responsive to the drug, cocaine. Rodents were then placed in an operant chamber in which there were two levers: one would give no solution, and the other would give a solution with the drug, display a light, and cue a tone. The researchers added these cues as a method of communication. Though scientists may be able to examine the physiology of animals, they are limited in communication. “We can’t ask if a rat is anxious, but we can use certain types of test to get at that,” noted Dr. Addy. Rodents associated cues with receiving the drug, therefore, if they continued to crave drugs when forced into sobriety, they would press the lever just to receive the drug-associated cue. When the acetylcholine receptors were blocked, however, the rodents would press the lever less, suggesting that their craving for drugs had decreased.

Not only, though, was their drug craving reduced, but so too was their anxiety. Another method for investigating the mood-related behavior of rodents is the elevated plus maze. This is a T-shaped place in which two of the arms are more closed and two are more open. It takes advantage of natural rodent behavior; rats and mice naturally prefer to be in darker and more closed off spaces out of fear. Therefore, when they venture into more open areas of the maze, it suggests that the rodents are experiencing lower levels of anxiety. The results of this experiment showed that rodents with blocked cholinergic receptors spent more time in open areas. That one physiological change affected both the levels of relapse and mood shift is remarkable and opens the door for new ways of addressing addiction.

The reduced craving and anxiety resulting from the blockade offers exciting therapeutic possibilities for human addiction recovery. Other attempts have targeted relapse and mood disorders separately, but Dr. Addy believes that, “interventions that won’t isolate only one or the other but ones that will deal with both simultaneously,” are the way forward. His current projects include taking the rodent work and applying it to human studies by taking advantage of and disrupting the same pathway. Though such work is only in its infancy, the potential impact of this discovery should not be undervalued. As more research is conducted, we hope that treatments for addiction can become more effective and comprehensive.

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