Compulsive methamphetamine taking in the presence of punishment is associated with increased oxytocin expression in the nucleus accumbens of rats

Irina N Krasnova,Jean Lud Cadet,Michael T Mccoy,Donna Walther,Bruce Ladenheim,Maria Carla Gerra,Christie Brannock,Subramaniam Jayanthi

doi:10.1038/s41598-017-08898-8

Irina N Krasnova, Jean Lud Cadet + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-08898-8

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Abstract

Methamphetamine addiction is mimicked in rats that self-administer the drug. However, these self-administration (SA) models do not include adverse consequences that are necessary to reach a diagnosis of addiction in humans. Herein, we measured genome-wide transcriptional consequences of methamphetamine SA and footshocks in the rat brain. We trained rats to self-administer methamphetamine for 20 days. Thereafter, lever-presses for methamphetamine were punished by mild footshocks for 5 days. Response-contingent punishment significantly reduced methamphetamine taking in some rats (shock-sensitive, SS) but not in others (shock-resistant, SR). Rats also underwent extinction test at one day and 30 days after the last shock session. Rats were euthanized one day after the second extinction test and the nucleus accumbens (NAc) and dorsal striatum were collected to measure gene expression with microarray analysis. In the NAc, there were changes in the expression of 13 genes in the SRvsControl and 9 genes in the SRvsSS comparison. In the striatum, there were 9 (6 up, 3 down) affected genes in the SRvsSS comparison. Among the upregulated genes was oxytocin in the NAc and CARTpt in the striatum of SR rats. These observations support a regional role of neuropeptides in the brain after a long withdrawal interval when animals show incubation of methamphetamine craving.

Highlights

Methamphetamine (METH) addiction is a biopsychosocial disorder with a very high prevalence throughout the world[1]
The analysis showed a significant effect of training day x reward type [F(19,456) = 25.31, p < 0.0001]
We found significant increases in CARTpt mRNA levels in the dorsal striatum but not in the nucleus accumbens (NAc) of compulsive METH takers, suggesting that different neurotransmitter systems may be activated in different brain regions during protracted forced abstinence from METH self-administration

Summary

Introduction

Methamphetamine (METH) addiction is a biopsychosocial disorder with a very high prevalence throughout the world[1]. These statements suggest that addiction may occur as the result of repeated exposure to drugs that lead to neuropathological changes in distributed networks of potentially dissociable reward and non-reward pathways in the mammalian brain[4, 8] This conclusion is supported by accumulated evidence from epigenetic, transcriptional, neuroimaging, and neuropsychological studies that have provided support for a role of various brain regions in the development and maintenance of addicted states[7, 10, 12,13,14]. A better understanding of how individual drugs differentially impact specific brain regions within these distributed networks will require more in-depth knowledge of the specific biochemical and molecular consequences of each addictive drug on different brain regions[4] This statement hints to the need to decipher molecular changes that may be predictive of resilience to and/or of risk to develop an addictive state[9]. We have used this model to investigate transcriptional changes in the nucleus accumbens (NAc) and dorsal striatum after a month of forced abstinence

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