Compulsive methamphetamine taking and abstinence in the presence of adverse consequences: Epigenetic and transcriptional consequences in the rat brain

Abstract

Methamphetamine addiction is characterized by compulsive binges of drug intake despite adverse life consequences. A model of methamphetamine self-administration that includes contingent footshocks to constitute adverse consequences has helped to segregate rats that reduce or stop lever pressing for methamphetamine (sensitive) from those that continue to lever press for the drug (resistant) in the presence of negative outcomes. We have observed differential DNA hydroxymethylation and increased expression of potassium channel mRNAs in the nucleus accumbens of sensitive compared to resistant rats, suggesting a role of these channels in suppressing methamphetamine intake. There were also significant increases in nerve growth factor (NGF) expression and activation of its downstream signaling pathway (NGF-TrkA and p75NTR/MAPK signaling) in only the dorsal striatum of sensitive rats after a month of abstinence. In contrast, oxytocin mRNA expression was increased in only the nucleus accumbens of resistant rats compared to sensitive rats euthanized after that time. These results indicate that footshocks can differentiate two behavioral phenotypes with differential biochemical and epigenetic consequences in the ventral and dorsal striatum.

Keywords: Addiction; DNA hydroxymethylation; Fear conditioning; Footshocks; HDACs; Incubation of drug seeking; Methamphetamine; Punishment; Stress.