Long‐term changes in dopamine‐stimulated gene expression after single‐day methamphetamine exposure

Abstract

Methamphetamine (mAMPH) is a highly addictive psychostimulant drug that injures monoaminergic neurons and results in behavioral impairments in humans and animals. Although evidence exists for changes in cortical volume, metabolism, and blood oxygenation levels in human mAMPH abusers, animal models have instead emphasized this drug's long-lasting influence on ascending monoaminergic (dopamine, serotonin) projections. The aim of this study was to investigate cortical and subcortical function in rats long after administration of a single-day mAMPH regimen known to damage monoaminergic systems, at a time point when behavioral impairments are still evident. Rats were given either saline or a neurotoxic (4 x 4 mg/kg, sc) mAMPH regimen. Five weeks later, they were given pharmacological treatments that stimulate cortical gene expression: either the dopaminergic agonist apomorphine (3 mg/kg, sc) or the muscarinic acetylcholine agonist pilocarpine (25 mg/kg, ip). Cortical and subcortical immediate early gene (IEG) responses were measured by immunocytochemical analysis of Fos or JunB, protein products of the IEGs, c-fos and junB. Compared with saline-pretreated controls, mAMPH-pretreated animals had about 50-70% fewer Fos- and JunB-immunoreactive cells in anterior cingulate, infralimbic, orbital, somatosensory, and rhinal cortices as well as caudate-putamen and nucleus accumbens, 90 min after apomorphine challenge. By contrast, mAMPH-pretreated rats had no reductions in the numbers of Fos or JunB-positive cells following pilocarpine challenge. This study demonstrates the profound and enduring effects of mAMPH administration on dopamine-stimulated cortical function in animals.

Work aversion and associated changes in dopamine and serotonin transporter after methamphetamine exposure in rats

“…A single-day of binge mAMPH has been reported to result in cortical changes, affecting metabolism and gene expression in several cortical areas (Pontieri et al 1990; Belcher et al 2009). Such functional 5-HT changes can occur secondarily to changes in DA transmission (Marshall et al 2007; Belcher et al 2009) and might predispose the organism to work and/or delay aversion. Serotonin in the frontal cortex is also altered after mAMPH (Hotchkiss and Gibb 1980).…”

Reversal-Specific Learning Impairments After a Binge Regimen of Methamphetamine in Rats: Possible Involvement of Striatal Dopamine

“…However, at the doses used here, single-day binge mAMPH administration produces no loss of serotonin transporter in the cortical areas sampled (Belcher et al, 2008), while even higher binge mAMPH doses—sufficient to produce greater than 50% reductions in striatal dopamine—result in no significant depletion of frontal cortex dopamine (Ohmori et al, 1993). Several groups have reported that a single-day binge mAMPH administration leads to altered functioning of cerebral cortex, affecting metabolism and immediate early gene expression of several cortical areas (including OFC; Pontieri et al, 1990; Belcher et al, 2009). Elsewhere we have hypothesized that these functional changes in cerebral cortex of binge mAMPH-treated rats occur secondarily to the decreases in striatal dopamine, achieved through alterations in striato-nigro-thalamo-cortical loops (Marshall et al, 2007; Belcher et al, 2009).…”

“…Several groups have reported that a single-day binge mAMPH administration leads to altered functioning of cerebral cortex, affecting metabolism and immediate early gene expression of several cortical areas (including OFC; Pontieri et al, 1990; Belcher et al, 2009). Elsewhere we have hypothesized that these functional changes in cerebral cortex of binge mAMPH-treated rats occur secondarily to the decreases in striatal dopamine, achieved through alterations in striato-nigro-thalamo-cortical loops (Marshall et al, 2007; Belcher et al, 2009). The basal ganglia-cortical loop hypothesis also provides a useful framework for interpreting the above-mentioned reports of the correspondence between diminished OFC activity and level of D2 receptors found in the brains of stimulant addicts (Volkow et al, 2001b).…”

Disruption of subcellular Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss induced by methamphetamine

“…Additionally, cortical immediate‐early gene induction by DA receptor agonists is blunted in rats with METH‐induced neurotoxicity (Belcher et al . ). Furthermore, novelty‐induced c‐ fos mRNA expression in striatopallidal neurons is dependent on corticostriatal transmission (Ferguson and Robinson ), sensitive to decreases in D1‐DA receptor activation (Ferguson et al .…”

“…Disruption of striatal D1-DA receptor activation decreases cortical excitability (Steiner and Kitai 2000;Yano et al 2006;Gross and Marshall 2009). Additionally, cortical immediate-early gene induction by DA receptor agonists is blunted in rats with METH-induced neurotoxicity (Belcher et al 2009). Furthermore, noveltyinduced c-fos mRNA expression in striatopallidal neurons is dependent on corticostriatal transmission (Ferguson and Robinson 2004), sensitive to decreases in D1-DA receptor activation (Ferguson et al 2003), and sensitive to blockade of NMDA receptors or ERK1/2 signaling (Ferguson et al 2003;Ferguson and Robinson 2004).…”