Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls

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 We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D(2) autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that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.

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

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.

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.

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.