National Health Research Institutes

The National Health Research Institutes used zebrafish to establish animal models for drug addiction and relapse.

April 15, 2024

Drug addiction is a concern around the world. The laboratory of Dr. Hwei-Hsien Chen at the Neurobehavioral and Psychiatric Research Center of the National Health Research Institutes (NHRI) is one of the few teams in Taiwan that has been involved in long-term basic research on addiction. The long-term goal is to develop treatment strategies related to drug addiction.

Drug addiction involves an association between environmental stimuli and the rewarding effects of drugs, making it a process of learning and memory. Addicts often experience intense cravings when exposed to drug-related cues, which is a state of uncontrollable desire to use drugs.

“Conditioned place preference” (CPP) is a classical conditioning paradigm. After training with drug and environmental cues, animals link the euphoric effects of the related drug with the paired environmental cues, resulting in a preference behavior. It is a common model for studying drug addiction memory.

Currently, most CPP research is primarily focused on rats or mice. Although in recent years there have been studies attempting to use zebrafish to establish CPP, they have been limited to the expression of drug-induced CPP behavior, lacking investigation into the subsequent extinction and reinstatement of preference behavior.

A research team led by Dr. Hwei-Hsien Chen of NHRI used zebrafish to establish methamphetamine-induced CPP and to determine whether CPP behavior in zebrafish, similar to that of rats and mice, could gradually disappear through extinction training and could be reinstated under conditions of methamphetamine priming or stress.

The research results showed that methamphetamine could induce CPP behavior in zebrafish in a dose-dependent manner. The preference behavior could be gradually extinguished by extinction training. Under conditions of methamphetamine administration or stress induced by chasing or yohimbine, an α2A adrenergic receptor antagonist, reinstatement occurred. This means that the previously extinguished CPP behavior reappeared. Additionally, after a 14-day withdrawal period, methamphetamine or stress still could induce significant preference behavior again, similar to the situation of relapse in people with methamphetamine use disorders after long-term abstinence.

Additionally, the research team also observed that other drugs had similar effects on methamphetamine-induced CPP in zebrafish compared to rats and mice. For example, the dopamine D1 receptor antagonist SCH23390 could inhibit methamphetamine-induced CPP, the opioid receptor antagonist naltrexone could reduce methamphetamine-induced reinstatement, and the α2 adrenergic receptor agonist clonidine could prevent stress-induced reinstatement.

This study successfully used zebrafish to establish a methamphetamine-induced CPP addiction model, extending to the stages of extinction, withdrawal, and reinstatement. These findings reveal that the predictive validity of the zebrafish CPP model is similar to that of rats and mice. In the future, zebrafish can replace rats and mice in research on drug addiction, craving, and relapse, contributing to the development of addiction treatment drugs.