Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls.
BACKGROUND
Sigma(1) receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D(2) autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Involvement of Sig-1R in the self-administration of psychostimulants, however, has never been reported.


OBJECTIVE
This study examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine.


METHODS
Three groups of rats were tested simultaneously 5 days per week, for 5 weeks (25 daily sessions). Two groups served as yoked controls and passively received an injection of either 0.1 mg/kg methamphetamine or saline (not contingent on responding) each time a response-contingent injection of 0.1 mg/kg methamphetamine was actively self-administered by the first group of rats. Protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively.


RESULTS
There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats.


CONCLUSIONS
Neuroadaptive increases in Sig-1R seen in this study may contribute to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be mediated by increased protein kinase A activity due to downregulation of dopamine D(2) autoreceptors.
Stefanski
Roman
R
Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, NIDA-IRP, NIH, DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Justinova
Zuzana
Z
Hayashi
Teruo
T
Takebayashi
Minoru
M
Goldberg
Steven R
SR
Su
Tsung-Ping
TP
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004789:Enzyme Activation; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis; D017480:Receptors, sigma / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012646:Self Administration; D015854:Up-Regulation; D000097605:Sigma-1 Receptor
D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D008694:Methamphetamine; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor