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Lowering the dose of key medicine can reduce stress-induced relapse

Posted by on Friday, April 3, 2020 in Discoveries, News .


By Sohini Roy

A gloved hand holding a little resealable baggie with cocaine inside it. The glove is blue and the background is white.
Despite stringent regulation under the Controlled Substances Act, cocaine use disorder is widespread throughout the United States. © Bits and Splits,

Cocaine is a highly addictive stimulant that is frequently abused in the United States despite stringent regulation under the Controlled Substances Act. Cocaine use disorder, a condition characterized by repeated and compulsive use and dependence on cocaine, often results in severe physiological and psychological problems, and can even result in death through overdose.

Cocaine works by targeting the critical neurotransmitter norepinephrine. Following its release from neurons, norepinephrine binds to autoreceptors—receptors on the very cells the neurotransmitter was released from—in a form of inhibitory regulation called negative feedback, eliminating excess norepinephrine and maintaining homeostasis. Cocaine deactivates these inhibitory receptors to increase the level of norepinephrine in the system, promoting CUD.

Although cocaine addiction is treatable, many people relapse before they can attain long-term sobriety. One of the major contributing factors in relapse is stress. At present, there are no medications approved by the U.S. Food and Drug Administration to treat CUD and consequent relapse. However, based on current knowledge, clinicians administer pharmacological agents that target various neurotransmitters to relieve withdrawal symptoms and help the patients feel relaxed.

One such drug administered in substance abuse patients is guanfacine. Although helpful for reducing stress-induced craving in patients in clinical trials, guanfacine has failed to curb CUD relapse rates. A recent publication from the lab of Danny Winder (Pharmacology), published in Nature Neuropsychopharmacology, investigated the molecular mechanism underlying the action of guanfacine to better understand how it modulates brain circuitry to induce stress-induced CUD relapse.

Guanfacine works by activating an inhibitory autoreceptor, α2a, to inhibit norepinephrine release from neurons. This prevents the activation of a key region in the brain known as the bed nucleus of the stria terminalis, which drives stress-induced relapse. However, a high dose of guanfacine can override the inhibitory signals and aberrantly stimulate α2a heteroreceptors, norepinephrine receptors responsive to the neurotransmitter if it arrives from non-self sources. The heteroreceptors, expressed on neurons and cells in the BNST, couple with different downstream signaling molecules to produce anxiety-like responses, thus dampening the clinical efficacy of guanfacine.

To understand the contribution of auto- versus heteroreceptors in stress-induced relapse, recent Ph.D. graduate and first author Rafael Perez genetically manipulated mice so that they expressed either α2aautoreceptors, both auto- and heteroreceptors or no α2a receptors. The mice then underwent a test in which relapse is indicated by the amount of time a mouse spends in a place associated with a stimulant, in this case, cocaine. Results showed that α2a heteroreceptors, and not autoreceptors, are required for stress-induced reinstatement of cocaine-seeking behavior since only a small fraction of mice lacking the heteroreceptors relapsed.

Next, using advanced neuroscientific experimental strategies, Perez and colleagues induced the acute activation of the BNST, mimicking the brain after a high or acute dose of guanfacine. BNST activation clearly resulted in stress-induced CUD relapse, suggesting that a high dose of guanfacine can override negative cues from autoreceptors and aberrantly activate the BNST, resulting in stress-induced CUD relapse. Excitingly, using a low dose of the drug did not stimulate the heteroreceptors and successfully blocked stress-induced relapse.

This study throws light on the importance of using optimal drug doses in treating substance use disorders. Although further studies are warranted, the current study encourages low versus high doses of guanfacine in clinical trials to prevent stress-induced cocaine relapse in patients.