Methamphetamine-lnduced Changes in AP-1 Binding and Dynorphin in the Striatum: Correlated, Not Causally Related Events?

Abstract

Activation of D₁ dopamine (DA) receptors in the striatum increases the expression of the opioid neuropeptide, dynorphin (DYN). While cAMP is generally accepted as a second messenger in this signal transduction pathway, the role of Fos/FRA proteins and AP-1 binding in mediating D₁ receptor-induced changes in DYN expression remains uncertain. In this study, DYN peptide and mRNA levels, as well as Fos/FRA proteins and AP-1 DNA binding activity, were measured in individual animals following acute challenge with the psychostimulant drug methamphetamine (METH). METH caused an initial decrease in striatal levels of DYN A, reflecting increased peptide release. Six hours postinjection, DYN mRNA levels were significantly elevated by METH as compared to vehicle-injected controls. At the same time, these drugs increased the expression of Fos/FRA-ir proteins, in particular the 35- and 40-kDa molecular weight species, and increased binding to the AP-1 DNA element. Analyses of the time course of METH''s effects revealed that DYN mRNA levels, Fos/FRA proteins and AP-1 binding activity showed variable increases by 3 h but all were significantly elevated above control levels by 6 h post-treatment. The D₁-specific antagonist, SCH 23390, completely blocked the METH-induced changes in DYN peptide and mRNA levels while a D₂ receptor antagonist (sulpiride) had little or no effect. These data indicate that stimulant drugs such as METH increase the expression of DYN and AP-1 factors in the striatum via a D₁ receptor-mediated mechanism. However, the finding that AP-1 binding merely paralleled but did not precede, the increase in DYN expression, as would be expected if it were mediating increased gene transcription, suggests these may be correlative, not causally related events.

Chronic methamphetamine exposure suppresses the striatal expression of members of multiple families of immediate early genes (IEGs) in the rat: normalization by an acute methamphetamine injection

“…We had predicted that both Tac1 and Pdyn would show similar changes in expression after chronic METH exposure because they are localized in the same striatal neurons (Angulo et al, 1995) and because previous data suggested that they are both induced by METH (Bannon et al, 1987; Wang et al, 1995). Our present findings, although unexpected, thus, point to the possible existence of factors, other than AP1 transcription factors (Bronstein et al, 1996), which might play more essential roles in regulating Pdyn expression. Some of these factors might include differential chromatin modifications and/or accumulation of repressors and co-repressors (Ballas and Mandel, 2005; Rojo, 2001; Wolffe et al, 2000) on Tac1 and Pdyn promoters during chronic METH exposure.…”

Exposure to Extremely Low Frequency Magnetic Fields Induces Fos-Related Antigen-Immunoreactivity Via Activation of Dopaminergic D1 Receptor

“…These results are in line with previous findings showing that direct stimulation of D1 receptor with specific agonist (Wirtshafter, 2007) or indirect stimulation of D1 receptor with psychostimulants (Young et al, 1991; Bronstein et al, 1996; Zhang et al, 2002) augments FRA expression in the striatal complex. Especially, it has been suggested that dopaminergic D1 receptor-mediated adenylate cyclase signaling pathway, but not phospholipace C pathway, is necessary for inducing FRA in the striatum (Wirtshafter, 2007).…”

“…AP-1 binding sites are located in the promoter regions of various genes, including tyrosine hydroxylase, proenkephalin, prodynorphin, and glial fibrillary acidic protein (Pennypacker et al, 1994; Nakashima et al, 2003). Among these genes, proenkephalin- and prodynorphin-gene expressions have shown temporal correlation with long-lasting expressions of 35-kDa FRA induced by psychostimulants (Bronstein et al, 1996; Shin et al, 2005) or kainate (Bing et al, 1997b; Kim et al, 1998). Enkephalin and dynorphin, which are derived from proenkephalin precursor and prodynorphin precursor, respectively, have been suggested to play an important role in the neuroadaptive responses related to behavioral sensitization, drug reward, drug withdrawal, or recovery of motor function via modulating post-synaptic dopaminergic receptor sensitivity or pre-synaptic dopamine release (Steiner and Gerfen, 1998; Bruijnzeel, 2009).…”

Epigenetic Effects Induced by Methamphetamine and Methamphetamine‐Dependent Oxidative Stress

“…AP-1 DNA-binding complex is in fact a dimer composed of IEGs, which are members of Jun (c-Jun, Jun B, and Jun D) and Fos (c-Fos, Fos B, Fra-1, and Fra-2) TF families [ 222 ]. Several studies demonstrate that METH causes an early increase in IEG expression belonging to Jun and Fos families [ 91 , 123 , 197 – 199 , 205 – 207 , 209 , 212 , 218 , 219 , 223 – 227 ]. Among these genes, a special emphasis is given to ΔFosB, which consists of a stable splice variant of FosB.…”