Abstract
BackgroundMethamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving). We previously demonstrated a role of anterior intralaminar nucleus of thalamus (AIT) to dorsomedial striatum (DMS) projections in this incubation. Here, we examined molecular alterations in DMS and AIT neurons activated (identified by neuronal activity marker Fos) during “incubated” Meth‐seeking relapse test after prolonged withdrawal.MethodsWe trained male rats to self‐administer Meth or saline (control condition) for 10 days (6 hr/day). Using fluorescence‐activated cell sorting, we examined gene expression in Fos‐positive (activated during a 2‐hr relapse test) and Fos‐negative (nonactivated) DMS and AIT neurons.ResultsIn DMS, we found increased mRNA expressions of immediate early genes (IEGs) (Arc, Egr1, Npas4, Fosb), Trkb, glutamate receptors subunits (Gria3, Grin1, Grin2b, Grm1), and epigenetic enzymes (Hdac3, Hdac5, Crebbp) in Fos‐positive neurons, compared with Fos‐negative neurons. In AIT, we found that fewer genes (Egr1, Fosb, TrkB, Grin1, and Hdac5) exhibited increased mRNA expression in Fos‐positive neurons. Unexpectedly, in both brain regions, gene alterations described above also occurred in drug‐naïve saline self‐administration control rats.ConclusionsThese results demonstrated that transcriptional regulations in Fos‐positive neurons activated during the relapse tests are brain region‐specific but are not uniquely associated with drug exposure during the self‐administration training.
Highlights
A key challenge for treating methamphetamine (Meth) addiction is relapse during abstinence (Elkashef et al, 2008)
We found that dorsomedial striatum (DMS) activa‐ tion is asso‐ ciated with this incubation and that DMS injections of SCH23390, a D1‐family receptor (D1R) antagonist that decreases striatal Fos expression (Valjent et al, 2000), decreased incubated Meth seeking after 30 withdrawal days (Li, Rubio, et al, 2015)
To determine whether the gene expression pattern in DMS and anterior intralaminar nucleus of thalamus (AIT) Fos‐positive neurons generally occurs in response to other Fos‐in‐ ducing stimuli, we examined mRNA expression of the same genes in DMS and AIT neurons activated by acute novel context exposure, a condition known to induce strong Fos expression in cortical and sub‐ cortical regions (Badiani et al, 1998; Uslaner et al, 2001)
Summary
A key challenge for treating methamphetamine (Meth) addiction is relapse during abstinence (Elkashef et al, 2008). Reversible inactiva‐ tion of the lateral AIT (AIT‐L; but not medial AIT [AIT‐M]) and revers‐ ible asymmetric inactivation (Bossert et al, 2012) of AIT‐L‐to‐DMS glutamatergic projections and local D1R signaling in DMS decreased incubated Meth seeking (Li, Witonsky, et al, 2018) These studies demonstrate that activation of DMS, AIT‐L, and AIT‐L‐to‐DMS pro‐ jections is critical to incubation of meth craving. In AIT, we found that fewer genes (Egr, Fosb, TrkB, Grin, and Hdac5) exhibited increased mRNA expression in Fos‐positive neurons In both brain regions, gene alterations described above occurred in drug‐naïve saline self‐administration control rats. Conclusions: These results demonstrated that transcriptional regulations in Fos‐posi‐ tive neurons activated during the relapse tests are brain region‐specific but are not uniquely associated with drug exposure during the self‐administration training
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