Differential Expression of mRNAs Coding for Histone Deacetylases (HDACs) in the Nucleus Accumbens of Compulsive Methamphetamine Takers and Abstinent Rats

Abstract

Methamphetamine (METH) addiction is a common neuropsychiatric disorder that is associated with loss of control over drug use. The long-term manifestations of METH addiction may be related to epigenetic neuroadaptations in the brain. To test this idea, we used rats of divergent phenotypes triggered by footshocks that helped to distinguish rats that continue to take METH compulsively (shock-resistant, SR) from those that become abstinent (shock-sensitive, SS). Male Sprague-Dawley rats were trained to self- administer METH (0.1 mg/kg/injection, IV) or saline during twenty 9-hour sessions. During training, all rats escalated their intake of METH. Following the training phase, rats were subjected to progressive increases in footshock intensity. This approach led to a split of the rats into the SR and SS phenotypes. Two hours after the last shock sessions the nucleus accumbens (NAc) was dissected and processed to measure mRNA levels. We found significant differences in the expression of HDAC1, HDAC3, HDAC6, and HDAC8 between the SR and SS rats. There was also increased expression of HDAC11 in the SS group in comparison to the SR and control groups. There were also significant differences in the mRNA expression of Sirt1, Sirt2, Sirt3, Sirt5, Sirt6, and Sirt7, with Sirt2 showing the greatest increase in the SS phenotype. Because these HDACs are differentially located in the cytoplasm, mitochondria, and the nucleus, these results suggest that METH self-administration may have impacted signaling pathways in various cellular compartments. Further dissection of these pathways should help us to elucidate molecular events that are involved in the maintenance of abstinence.