Incubation of methamphetamine craving in punishment-resistant individuals is associated with activation of specific gene networks in the rat dorsal striatum

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Hot Off the Press – April 24, 2024

Published in Molecular Psychiatry by Atul Daiwile and Jean Lud Cadet, et al. from the NIDA IRP Molecular Neuropsychiatry Section.

Summary

Methamphetamine also called METH, crank, ice etc. is a powerful stimulant that has caused addiction in a lot of people in the world. Humans who take too much methamphetamine develop many negative problems on the brain. Some people develop major psychiatric problems, but there is no approved treatment for the problems caused by methamphetamine. This might be because how methamphetamine works in the brain to cause addiction. Our laboratory has been studying how methamphetamine can cause changes in the way the brain functions in rats with a history of methamphetamine use. In this paper, rats that have experience giving themselves methamphetamine were given the opportunity to earn or to stop taking the drug when they were exposed to footshocks through an electrical grid on the floor of a cage where they take methamphetamine. We also tried to figure out if some rats would continue or stop taking the drug after they had not had access for a period of time. We did this because some users will stop taking the drug by themselves or because they are forced to stop because they are hospitalized or arrested by the police. This is the first time that any group of scientists has found that animals that kept taking methamphetamine in the face of punishment with footshocks will continue to take methamphetamine even if their access to the drug was blocked for a period of time. We also found that some rats that had decreased their methamphetamine taking behaviors in the presence of punishment will now take the drug even when they face adverse consequences after a period of not having access to drug. Importantly, we also found that the 3 groups of rats have different changes in the expression of several genes in a brain area called dorsal striatum which is involved in some aspects of addiction. One of these genes is called brain-derived neurotrophic factor (BDNF) which is influenced by an epigenetic enzyme called histone deacetylase-2 (HDAC2). This animal model of methamphetamine use disorder (addiction) has the potential to help us understand the way animals, and by extension, humans, take drug non-stop even when they are faced with bad medical or legal consequences.

Publication Information

@article{pmid38351172,

title = {Incubation of methamphetamine craving in punishment-resistant individuals is associated with activation of specific gene networks in the rat dorsal striatum},

author = {Atul P Daiwile and Michael T McCoy and Bruce Ladenheim and Jayanthi Subramaniam and Jean Lud Cadet},

url = {https://pubmed.ncbi.nlm.nih.gov/38351172/},

doi = {10.1038/s41380-024-02455-2},

issn = {1476-5578},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {Mol Psychiatry},

abstract = {Methamphetamine use disorder (MUD) is characterized by loss of control over compulsive drug use. Here, we used a self-administration (SA) model to investigate transcriptional changes associated with the development of early and late compulsivity during contingent footshocks. Punishment initially separated methamphetamine taking rats into always shock-resistant (ASR) rats that continued active lever pressing and shock-sensitive (SS) rats that reduced their lever pressing. At the end of the punishment phase, rats underwent 15 days of forced abstinence at the end of which they were re-introduced to the SA paradigm followed by SA plus contingent shocks. Interestingly, 36 percent of the initial SS rats developed delayed shock-resistance (DSR). Of translational relevance, ASR rats showed more incubation of methamphetamine craving than DSR and always sensitive (AS) rats. RNA sequencing revealed increased striatal Rab37 and Dipk2b mRNA levels that correlated with incubation of methamphetamine craving. Interestingly, Bdnf mRNA levels showed HDAC2-dependent decreased expression in the AS rats. The present SA paradigm should help to elucidate the molecular substrates of early and late addiction-like behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}