Compulsive methamphetamine taking under punishment increases the expression of AP1 family of transcription factors in the rat nucleus accumbens

Authors

• MT McCoy
• B Ladenheim
• L Contu
• M Job
• B Campbell
• CA Blackwood
• S Jayanthi
• JL Cadet

Abstract

Methamphetamine is an illicit psychostimulant whose abuse is accompanied by severe neurological and psychiatric complications. So far, however, there is no pharmacological treatment for this patient population. The lack of comprehensive pharmacological approaches may be related to insufficient understanding of cellular and molecular substrates of methamphetamine addiction. As a first step towards identifying the molecular bases of compulsive methamphetamine taking, our laboratory has started to use footshocks as adverse consequences during methamphetamine self-administration (SA) because the psychiatric definition of addiction includes the presence of adverse consequences. Herein we use this model to measure potential changes in immediate early gene (IEG) expression in the nucleus accumbens of rats after short withdrawal times from methamphetamine SA. Rats were trained to self-administer METH or saline for 4 weeks. Then, contingent footshocks were administered in increasing intensity over 8 days of METH SA. Footshocks dichotomized rats into two distinct methamphetamine SA groups: (1) shock-resistant (SR) rats that continued to press the lever for methamphetamine despite punishment and (2) shock-sensitive (SS) rats that significantly reduced their lever pressing. We then extracted RNA from the nucleus accumbens and ran RT-qPCR to measure the expression of IEGs from the fos and jun families. SR rats showed significant increases in cfos, fosB, Fra2, and junB mRNA levels in the nucleus accumbens. Animals yoked to the SR rats showed no changes in the expression of these IEGs. Our model of drug self-administration in the presence of adverse consequences may provide greater insight into the neurobiology of methamphetamine addiction.

Scientific Focus Area: Neuroscience

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