Abstract
BackgroundThe repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (“sensitization”) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix.Methodology/Principal FindingsIn the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens.Conclusions/SignificanceThese data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine.
Highlights
Repeated intermittent exposure to drugs of abuse produces long lasting changes in behavior, which are believed to be due to alterations in patterns of neural activity within relevant brain circuits [1,2]
Exposure to amphetamine can produce behavior dominated by stereotyped actions; locomotor distance is sometimes not the most sensitive measure of sensitization [24]
Repetitive head movements were analyzed immediately following methamphetamine and saline administration for 30 min, a time period where stereotyped behaviors are more apparent than locomotor activity
Summary
Repeated intermittent exposure to drugs of abuse produces long lasting changes in behavior, which are believed to be due to alterations in patterns of neural activity within relevant brain circuits [1,2]. Alterations in Fos expression might help to identify neural circuits in the brain related to the long-term changes in behavior produced by repeated drug treatment. One area of the brain that shows changes in Fos expression following repeated treatment with cocaine and amphetamine is the striatum. There have been conflicting reports in the literature of tolerance, sensitization, or no effect on striatal Fos expression following repeated drug treatment [6,7,8] These discrepant findings may be due to a number of factors, such as differences in the environment in which drugs were administered, or the neuroanatomical heterogeneity of the striatum [9,10]. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix
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