Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats.

Jean Lud Cadet,Donna Walther,Subramaniam Jayanthi,Irina N Krasnova,Daniel Collector,Michael T Mccoy,Bruce Ladenheim,Oscar V Torres,Christie Brannock,Ndeah Terry

doi:10.1038/srep37002

Jean Lud Cadet, Donna Walther + Show 8 more

Open Access

https://doi.org/10.1038/srep37002

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Abstract

Addiction is associated with neuroadaptive changes in the brain. In the present paper, we used a model of methamphetamine self-administration during which we used footshocks to divide rats into animals that continue to press a lever to get methamphetamine (shock-resistant) and those that significantly reduce pressing the lever (shock-sensitive) despite the shocks. We trained male Sprague-Dawley rats to self-administer methamphetamine (0.1 mg/kg/infusion) for 9 hours daily for 20 days. Control group self-administered saline. Subsequently, methamphetamine self-administration rats were punished by mild electric footshocks for 10 days with gradual increases in shock intensity. Two hours after stopping behavioral experiments, we euthanized rats and isolated nucleus accumbens (NAc) samples. Affymetrix Array experiments revealed 24 differentially expressed genes between the shock-resistant and shock-sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis showed that these transcripts belong to classes of genes involved in nervous system function, behavior, and disorders of the basal ganglia. These genes included prodynorphin (PDYN) and proenkephalin (PENK), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms, which impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats.

Highlights

Methamphetamine is a highly addictive psychostimulant whose abuse is characterized by repeated use of the drug despite adverse medicolegal ramifications[1]
We showed that compulsive methamphetamine self-administration triggered increases in the expression of PDYN and PENK mRNA levels in the nucleus accumbens (NAc) of rats euthanized 2 hours after the last self-administration session
We used this time interval because molecular events that occur after repeated drug exposure might potentially offer a window to molecular substrates of methamphetamine addiction and its adverse sequelae

Summary

Introduction

Methamphetamine is a highly addictive psychostimulant whose abuse is characterized by repeated use of the drug despite adverse medicolegal ramifications[1]. Methamphetamine self-administering rats, given extended access to the drug, escalate their use over time[8] This approach has helped to discover the potential role of various neurotransmitter systems, the involvement of gene regulation, and epigenetic mechanisms in the modulation of methamphetamine-taking behaviors[9,10,11,12]. These studies have used all animals that self-administered methamphetamine, whereas many human substance users reduce or stop their drug use in the presence of potential adverse consequences and do not develop addiction[13,14]. These results further implicate these neuropeptides in the manifestation of methamphetamine addiction

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