Differential regulation of prodynophin, c‐fos, and serotonin transporter mRNA following withdrawal from a chronic, escalating dose regimen of D‐amphetamine

Abstract

Several lines of evidence suggest that D-amphetamine (D-AMPH) withdrawal induces a syndrome with symptoms similar to major depressive disorder (MDD). Upregulation of dynorphin (DYN) may underlie the symptoms of MDD and contribute to the negative emotional symptoms associated with psychostimulant withdrawal. Changes in the serotonin transporter (SERT) have also been reported in MDD, and changes in the immediate early gene c-fos have been observed in the context of psychostimulant withdrawal. This study examined the effects of chronic, escalating doses of D-AMPH followed by 24 h of withdrawal on the expression of prodynorphin (PD) and c-fos mRNA in limbic regions of the brain, caudate putamen (CPu), and brainstem and SERT mRNA expression in the dorsal raphe nucleus (DRN). Male Sprague-Dawley rats were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg) and sacrificed 24 h after the last injection. Following 24 h of withdrawal, there was an increase in PD and c-fos mRNA expression in the CPu and nucleus accumbens (NAc), and a decrease in PD and c-fos expression in hippocampus and amygdala. SERT mRNA expression was decreased in the DRN, and PD mRNA expression was increased in the adjacent ventrolateral periaqueductal gray (VLPAG) following D-AMPH withdrawal. These data indicate that region-specific changes in PD and c-fos expression occur after withdrawal, while SERT mRNA expression is suppressed, similar to what has been reported in MDD. Alterations in PD, c-fos, and SERT expression could contribute to the depression-like syndrome associated with psychostimulant withdrawal. Synapse 63:257-268,

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

“…In the current study, amphetamine injection was not paired to a specific context, suggesting different changes in synaptic properties in structures such as the hippocampus that do not involve BDNF, which may limit the effect of ketamine on passivity in the FST in the present study. Although the present study highlighted the key role of the DA system after acute amphetamine withdrawal, other systems, such as the serotoninergic (Horner et al, 2009) and norepinephrine (Koob, 2009) systems, could also be involved in the negative state during withdrawal. Indeed, serotonin systems, particularly those involving serotonin 5-HT1B receptor activation in the nucleus accumbens, also have been implicated in the acute reinforcing effects of psychostimulant drugs.…”

Dynorphins Regulate Fear Memory: from Mice to Men

“…However, the inverse relation between c-fos and dynorphin expression is probably specific to cocaine-induced expression changes. Neither methylphenidate treatment (Yano and Steiner, 2005), withdrawal from chronic amphetamine (Horner et al, 2009) nor postoperative pain (Campillo et al, 2010) induced opposite change in Pdyn and c-fos expression. Moreover, the expression of c-fos after mild stress was reduced in limbic areas of Pdyn Ϫ/Ϫ mice (Bilkei-Gorzo et al, 2008), similar to its expression in the present study.…”

Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: The role of mu opioid receptor activation

“…For the detection of PD mRNA, an oligonucleotide probe (GeneDetect, Bradenton, FL, USA) that was complementary to bases 762-809 of the PD mRNA (Civelli et al, 1985) was end-labeled with [ 35 S]-dATP (Perkin Elmer NEN, Wellesley, MA, USA), as previously described (Adams et al, 2003; Horner et al, 2005; Horner and Keefe, 2006; Horner et al, 2009). Briefly, the probe was diluted in hybridization buffer (0.6 M sodium chloride, 80 mM Tris, 4 mM EDTA, 0.1% w/v sodium pyrophosphate, 10% w/v dextran, 0.2% w/v lauryl sulfate, 0.5 mg/ml heparin, 50% formamide) and 90 μl of the probe in hybridization buffer was applied to each slide and covered with glass coverslips.…”

“…Immunohistochemistry for mu opioid receptors was performed as previously described (Adams et al, 2003; Horner et al, 2005; Horner and Keefe, 2006; Horner et al, 2009), using serial, 12-μm sections through the CPu that were adjacent to those used for in situ hybridization. Sections were post-fixed in 4% paraformaldehyde/0.9% NaCl and then rinsed three times in 0.1 M phosphate-buffered saline (PBS).…”