Rat Race to Recovery: Uncovering the Secrets of Relapse

Kareena & Aditya

Introduction

A 2023 survey from the National Center For Drug Abuse Statistics reported almost one million deaths from substance abuse overdose since the year 2000, with opioids involved in at least 7 out of 10 overdose deaths. Additionally, more than 91% of people who abused opiates in the past had an episode of relapse, where a person resumes drug use after a period of abstinence or sobriety. Relapse is complicated, not only due to its nature, but because of the many ways it can occur. Social environments, mood states, and internal structural and functional changes in the brain can all potentially contribute to the onset of relapse. While there are a variety of programs and therapies available to help those experiencing relapse, there are no approved drugs to mitigate its onset.

Many people may associate addiction solely with the image of immediate and continuous drug use. However, a more nuanced perspective of addiction relies on characterizing it as not just a disease but as a conceptualization of the way the brain can change over time. Addiction, and subsequently relapse, develops through the creation of a long-lasting memory; they are not unique, isolated, and solitary experiences. Rather, the neuronal network transforms in inextricable and complicated ways, which scientists do not fully understand. Unearthing the secrets behind why addiction and relapse develop requires an understanding of neuroplasticity, the brain’s ability to constantly reorganize its neuronal network and activity in response to stimuli. As a result, many labs seek to understand the synaptic underpinnings of drug addiction and relapse, including the Martin-Fardon Lab.

Priming and Pathways: The Basics Behind Addiction Research

In drug addiction research, the addiction circuit pathway, though heavily studied, remains complicated. Like a racetrack where race cars travel in the same loop over and over until they cross the finish line, the reward circuit is where specialized neurons send their neurotransmitters to these in order, traveling from one brain region to another to reach their targets. An established addiction pathway in the brain flows from portions of the ventral tegmental area (VTA) to the nucleus accumbens (NAc), or the “pleasure center” of the brain. From here, these neurons eventually reach the prefrontal cortex and other areas, or the “finish line” for this circuit.

FIGURE 1 | BRAIN (Illustrated by Lindsey Kim)

On the other hand, the onset of relapse has been explored in two facets: conditional and stress induction. Following the self-administration of a drug via a lever-press, rodents are then placed in an extinction phase, where they are weaned off of the drug for a period of time until they no longer exhibit typical physiological signs of withdrawal such as teeth chattering, ptosis (drooping of eyelids), and body shaking. They are then placed in the reinstatement phase of drug seeking via drug priming, where rodents are reintroduced to a small dose of the drug to reactivate neural pathways. Here, behaviors associated with drug-seeking, drug cues or contexts, or certain stressors are assessed. Stress-induced reinstatement models are a popular choice due to a relatively simple protocol: rodents that have become dependent via self-administration of the drug are then put into an extinction phase, where they are weaned off of the drug. Then, the rodents are exposed to certain stressors, such as footshocks, and recurrent lever-pressing is assessed as a measure of relapse. Conditional-reinstatement models of drug addiction follow a similar methodology, but have a few key differences: rodents self-administer in a certain context (i.e. environment) that contains certain and identifying stimuli. During extinction, the rodents are removed from this context and placed into another context that does not contain the same identifying stimuli. When the rodents are introduced to the initial context again, recurrent lever-pressing is also assessed as a measure of relapse.

The Frontrunners: The Orexin System

At Scripps Research in La Jolla, CA, the Martin-Fardon Lab tackles many of the unsolved questions about relapse. Dr. Remi Martin-Fardon was originally interested in studying the effects of certain drugs, such as cocaine and PCP, on rodent behavior. Currently, the lab focuses on a fairly unknown yet important brain system that regulates sleep, feeding, arousal, stress, and other physiological functions: the orexin system. This neural network of substrates and receptors has piqued the interest of researchers for its potential role in characterizing the compulsive nature of drug-seeking behavior, particularly relapse.

How does the orexin system help researchers better understand addiction and relapse? Orexins are neuropeptides secreted from the brain’s lateral hypothalamus neurons. In 2002, researchers at Vanderbilt School of Medicine discovered that these neuronal orexins, or neuropeptides secreted from the brain’s lateral hypothalamus neurons, reach the dopamine neurons of the VTA. Furthermore, a 2006 study done by researchers UCSF demonstrated that when orexins can increase signaling through the VTA dopaminergic synapses by trafficking more NMDA receptors to the postsynaptic terminal, highlighting their connection and potential role in reward circuit underlying the neuroplasticity of addiction and relapse.

For fourth-year undergraduate Colin He, drug addiction research was an unsuspecting step forward. He, a pharmacological chemistry major minoring in general biology at UCSD, soon discovered that the Martin-Fardon Lab’s approach to research aligned closely with his interests in drug development and pharmacology research. Currently, He explores the pharmacological characteristics of Survarexit (SUV), an FDA-approved drug that treats insomnia. The lab has previously shown that when administered orally, SUV reduces the onset of relapse in oxycodone and alcohol-dependent rats. Due to popular interest in the posterior paraventricular nucleus of the thalamus (pPVT), where orexin transmission modulates reward-seeking behavior, the lab postulates that intravenous SUV can function as an orexin receptor antagonist, meaning that SUV could potentially be used to prevent the onset of relapse in opioid use disorder by blocking orexin receptors.

Under the guidance of Dr. Martin-Fardon, He and his colleagues began assisting on a project working directly with rats under the influence of oxycodone, an opioid. There were two starting groups of rodents: one group given oxycodone, and the other given sweetened condensed milk (SCM) for comparison. He assisted investigators in setting up 21 sessions of oxycodone and SCM administration, where rats could press a lever to self-administer. Every week, the rats entered an extinction phase, where they were unable to administer the drug. After the 17th session of self-administration, the oxycodone group was then divided into two groups: the control group and the group to receive SUV. The researchers then surgically inserted a catheter implant into the pPVT to direct SUV doses to the pPVT area of the brain.

To induce reinstatement to see if the rodents would display signs of relapse, the control and SUV groups of rodents were divided once again into two groups: the conditional-reinstatement (CIR) group and the stress induced reinstatement (SIR) group. The conditional-reinstatement group was placed into their original contexts (with stimuli present during the original self-administration), and the researchers counted the number of times the rats pressed the lever to administer the drug. For the stress-induced reinstatement group, He helped give the rats a foot shock over a 15 minute timespan to induce a stress response. The results for the SIR group were recorded similarly to the CIR group.


FIGURE 2 | STRESS REINSTATEMENT (Illustrated by Lindsey Kim)


FIGURE 3 | CATHETER CLOSEUP (Illustrated by Lindsey Kim)

The study found that rodents taking SUV were less likely to relapse when exposed to stress-stimuli than if exposed to context present-stimuli. These results suggest that the orexin signaling in the PVT plays an important role in the onset of relapse While it is still unknown how exactly stress versus context stimuli alter neuroplasticity when the orexin system is blocked, these results shine light on the differing conditions that affect whether rodents will exhibit relapse, as it supports the notions that there is indeed pairing between specific stimuli and opioid use. Furthermore, these “addiction-extinction” models of relapse in rodents are useful for future research to better understand how a multitude of factors, such as rodent behavior, addiction, and memory, all play a role in the onset and prevention of relapse.

Continuing the Race?

Unfortunately, there are no successful and approved treatments for relapse available today. However, He, like Dr. Martin-Fardon, believes that his lab’s research is extremely valuable as it helps encourage future translational research efforts to test if certain FDA-approved drugs that are already on the market can potentially be used to treat relapse. Going forward, He hopes they can further expand on their work with stress and conditional-reinstatement rodent models in different brain areas connected to the orexin system. Their ongoing research delving further into the orexin system holds promise for advancing our understanding of relapse mechanisms, paving the way to continue the race for new relapse therapies.

 

For Faculty, this is the abstract for this study that I was given from the lab (for your reference):

Background: The orexin (OX) system has received great interest as a potential target for treating drug use disorder. It was shown that OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT)– an area activated by highly salient stimuli that are both reinforcing and aversive– mediates cue- and stress-induced reinstatement of reward-seeking behavior. We showed that oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. Aims: This study tested whether blockade of OXRs in the pPVT using SUV could reduce oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. Methods: Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 mL, dilution 2:1 v/v, 30 min/day) and after extinction, the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress was tested. Results: The rats acquired oxycodone and SCM self-administration and oxycodone intake correlated with signs of physical opioid withdrawal confirming dependence. Following extinction, presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking, nor stress-induced reinstatement of SCM seeking. Conclusions: The results endorse that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking further corroborating OXRs as treatment target for opioid use disorder.

 

Quote Pulls

A more nuanced perspective of addiction relies on characterizing it as not just a disease but as a conceptualization of the way the brain can change over time.

Orexins are neuropeptides secreted from the brain’s lateral hypothalamus neurons.

SUV could potentially be used to prevent the onset of relapse in opioid use disorder by blocking orexin receptors.

Advancing our understanding of relapse mechanisms