Identification of Gene Expression Changes in Relation to a Sensitized Motor Response or Signs of Tolerance Due to Chronic D-Amphetamine Exposure
Abstract
Drug addiction is a disorder in which people continue to escalate drug use despite the presence of negative consequences. The repeated use of drugs of abuse is a major risk factor in drug addiction. There is a compulsive component of drug addiction that may stem from the effects of drugs of abuse on the dorsal striatum. The dorsal striatum is known to be a brain region that is critical for habit formation. Varying patterns of gene induction in the dorsal striatum are correlated with the intensity of drug-induced repetitive behaviors known as stereotypies. It is challenging to disrupt these repetitive behaviors once initiated and they resemble extreme habits. We compared stereotypy and mRNA sequence changes in the striatum of mice injected repeatedly with D-amphetamine, a habit-forming drug that induces long-lasting changes in behavior.With the administration of D-amphetamine, the transcriptome response presented a parallel to the behavioral response. On the first day of D-amphetamine administration, there was high variability in the locomotor and gene induction responses when comparing drug-injected mice against the vehicle treated control mice. Following one week of daily D-amphetamine treatment, all of the mice presented highly similar behavioral responses consisting of immediate hyperlocomotion followed by strong stereotypy. In a parallel treatment group that was being used for RNA sequencing, it was shown that the genes that were significantly changed were consistently and strongly upregulated among all of the mice. However, by treatment day 21 most of the significantly changed genes at earlier time points showed downregulation compared to vehicle treated controls. Furthermore, mice treated for 21 days with D-amphetamine presented significantly shorter periods of stereotypy compared to mice that were treated for seven days. This behavioral observation is in line with the development of tolerance to the stereotypy inducing effects of D-amphetamine. Mice treated with D-amphetamine for 7 days to induce the most severe stereotypy showed the most upregulation of immediate-early genes, relative to mice treated for 1 or 21 days.
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