Why Cocaine is So Addictive: Animal Model Study

Summary: Researchers replicate cocaine addiction in rats and obtain a better understanding about the underlying mechanisms of addiction.

Source: Wake Forest Baptist Medical Center.

Scientists at Wake Forest Baptist Medical Center are one step closer to understanding what causes cocaine to be so addictive. The research findings are published in the current issue of the Journal of Neuroscience.

Cocaine addiction is a debilitating neurological disorder that affects more than 700,000 people in the United States alone, according to the Substance Abuse and Mental Health Services Administration. With repeated use, tolerance may develop, meaning more of the drug is required to achieve the same euphoric effect. Cocaine addiction can be characterized by repeated attempts at abstinence that often end in relapse.

“Scientists have known for years that cocaine affects the dopamine system and dopamine transporters, so we designed our study to gain a better understanding of how tolerance to cocaine develops via the dopamine transporters,” said Sara R. Jones, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study.

“Currently there isn’t any effective treatment available for cocaine addiction so understanding the underlying mechanism is essential for targeting potential new treatments.”

Using an animal model, the research team replicated cocaine addiction by allowing rats to self-administer as much cocaine as they wanted (up to 40 doses) during a six-hour period. Six-hour-a-day access is long enough to cause escalation of intake and tip animals over from having controlled intake to more uncontrolled, binge-like behavior, Jones said.

Following the five-day experiment, the animals were not allowed cocaine for 14 or 60 days. After the periods of abstinence, the researchers looked at the animals’ dopamine transporters and they appeared normal, just like those in the control animals that had only received saline.

However, a single self-administered infusion of cocaine at the end of abstinence, even after 60 days, fully reinstated tolerance to cocaine’s effects in the animals that had binged. In the control animals that had never received cocaine, a single dose did not have the same effect.

Image shows the dopamine system in the brain.
“Scientists have known for years that cocaine affects the dopamine system and dopamine transporters, so we designed our study to gain a better understanding of how tolerance to cocaine develops via the dopamine transporters,” NeuroscienceNews.com image is for illustrative purposes only.

These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine, Jones said. This ‘priming effect,’ which may be permanent, may contribute to the severity of relapse episodes in cocaine addicts.

“Even after 60 days of abstinence, which is roughly equivalent to four years in humans, it only took a single dose of cocaine to put the rats back to square one with regard to its’ dopamine system and tolerance levels, and increased the likelihood of binging again,” Jones said. “It’s that terrible cycle of addiction.”

Jones added that hope is on the horizon through preclinical trials that are testing several amphetamine-like drugs for effectiveness in treating cocaine addiction.

About this neuroscience research article

Funding: The research was supported by National Institutes of Health grants RO1 DAO21325, RO1DAO30161, F31DAO37710 and T32AA00757565.

Source: Marguerite Beck – Wake Forest Baptist Medical Center
Image Source: This NeuroscienceNews.com image is credited to the NIH and is in the public domain.
Original Research: Abstract for “Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine” by Cody A. Siciliano, Steve C. Fordahl, and Sara R. Jones in Journal of Neuroscience. Published online July 27 2016 doi:10.1523/JNEUROSCI.4652-15.2016

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Wake Forest Baptist Medical Center. “Why Cocaine is So Addictive: Animal Model Study.” NeuroscienceNews. NeuroscienceNews, 1 August 2016.
<https://neurosciencenews.com/addiction-cocaine-neuroscience-4763/>.[/cbtab][cbtab title=”APA”]Wake Forest Baptist Medical Center. (2016, August 1). Why Cocaine is So Addictive: Animal Model Study. NeuroscienceNews. Retrieved August 1, 2016 from https://neurosciencenews.com/addiction-cocaine-neuroscience-4763/[/cbtab][cbtab title=”Chicago”]Wake Forest Baptist Medical Center. “Why Cocaine is So Addictive: Animal Model Study.” https://neurosciencenews.com/addiction-cocaine-neuroscience-4763/ (accessed August 1, 2016).[/cbtab][/cbtabs]


Abstract

Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine’s effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine’s effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse.

SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action, the dopamine transporter (DAT). Preclinical literature has shown that reduced cocaine potency at the DAT increases cocaine taking, highlighting the key role of tolerance in addiction. Addiction is characterized by cycles of abstinence, often for many months, followed by relapse, making it important to determine possible interactions between abstinence and subsequent drug re-exposure. Using a rodent model of cocaine abuse, we found long-lasting, possibly permanent, cocaine-induced alterations to the DAT, whereby cocaine tolerance is reinstated by minimal drug exposure, even after recovery of DAT function over prolonged abstinence periods.

“Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine” by Cody A. Siciliano, Steve C. Fordahl, and Sara R. Jones in Journal of Neuroscience. Published online July 27 2016 doi:10.1523/JNEUROSCI.4652-15.2016

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