Gene Expression Related to Synaptogenesis, Neuritogenesis, and MAP Kinase in Behavioral Sensitization to Psychostimulants

Abstract

The most important characteristic of behavioral sensitization to psychostimulants, such as amphetamine and cocaine, is the very long‐lasting hypersensitivity to the drug after cessation of exposure. Rearrangement and structural modification of neural networks in CNS must be involved in behavioral sensitization. Previous microscopic studies have shown that the length of dendrites and density of dendritic spines increased in the nucleus accumbens and frontal cortex after repeated exposure to amphetamine and cocaine, but the molecular mechanisms responsible are not well understood. We investigated a set of genes related to synaptogenesis, neuritogenesis, and mitogen‐activated protein (MAP) kinase after exposure to methamphetamine. Synaptophysin mRNA, but not VAMP2 (synaptobrevin 2) mRNA, which are considered as synaptogenesis markers, increased in the accumbens, striatum, hippocampus, and several cortices, including the medial frontal cortex, after a single dose of 4 mg/kg methamphetamine. Stathmin mRNA, but not neuritin or narp mRNA, which are markers for neuritic sprouting, increased in the striatum, hippocampus, and cortices after a single dose of methamphetamine. The mRNA of arc, an activity‐regulated protein associated with cytoskeleton, but not of alpha‐tubulin, as markers for neuritic elongation, showed robust increases in the striatum, hippocampus, and cortices after a single dose of methamphetamine. The mRNAs of MAP kinase phosphatase‐1 (MKP‐1), MKP‐3, and rheb, a ras homologue abundant in brain, were investigated to assess the MAP kinase cascades. MKP‐1 and MKP‐3 mRNAs, but not rheb mRNA, increased in the striatum, thalamus, and cortices, and in the striatum, hippocampus, and cortices, respectively, after a single methamphetamine. Synaptophysin and stathmin mRNAs did not increase again after chronic methamphetamine administration, whereas the increases in arc, MKP‐1, and MKP‐3 mRNAs persisted in the brain regions after chronic methamphetamine administration. These findings indicate that the earlier induction process in behavioral sensitization may require various plastic modifications, such as synaptogenesis, neuritic sprouting, neuritic elongation, and activation of MAP kinase cascades, throughout almost the entire brain. In contrast, later maintenance process of sensitization may require only limited plastic modification in restricted regions.

Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase‐1, C/EBP‐β and ILAD‐1, a novel gene with homology to arrestins

“…Its expression within the brain is localized to discrete areas that include high expression in specific regions of the cortex and thalamus (Kwak et al 1994). Interestingly, the MKP-1 transcript is rapidly increased after both a single dose of methamphetamine and behavioral sensitization to methamphetamine in the rat prefrontal cortex (Ujike et al 2002). Its expression peaked very rapidly, at 30 min and then declined rapidly after acute administration of methamphetamine (Ujike et al 2002) similarly to what was observed with LSD in the present experiments.…”

“…Interestingly, the MKP-1 transcript is rapidly increased after both a single dose of methamphetamine and behavioral sensitization to methamphetamine in the rat prefrontal cortex (Ujike et al 2002). Its expression peaked very rapidly, at 30 min and then declined rapidly after acute administration of methamphetamine (Ujike et al 2002) similarly to what was observed with LSD in the present experiments. The sensitivity of MKP-1 to methamphetamine suggests that its LSD-influenced expression may be partially increased through LSD interactions at dopamine receptors, in addition to its partial effects at 5-HT 2A receptors as shown in this work (Figs 4 and 5).…”

One-Year Follow-Up After Bone Marrow Stromal Cell Treatment in Middle-Aged Female Rats With Stroke

“…Synaptophysin is an indicator of presynaptic plasticity and synaptogenesis. 13 As shown in Figures 4J through 4L, BMSC treatment significantly increased synaptophysin expression (PϽ0.05) compared with control rats.…”

Effects of Methamphetamine Dependence and HIV Infection on Cerebral Morphology

“…Similar effects were observed in the prefrontal cortex. In previous studies (28,29) the effects of methamphetamine exposure on plasticity-related genes in the rat brain were examined. Such exposure resulted in increases by 20%-40% in the expression of synaptophysin mRNA in the nucleus accumbens and in prefrontal and temporal cortices within 1 day of administration.…”