Abstract
Rationale
Sigma1 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 We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D2 autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that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.
Objectives
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 D2 autoreceptors.
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References
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
Defagot MC, Malchiodi EL, Villar MJ, Antonelli MC (1997) Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. Mol Brain Res 45:1–12
De La Garza R, Madras BK (2000) [3H]PNU-101958, a D4 dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non-human primate brain. Synapse 37:232–244
Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320
Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW (1999) Associative processes in addiction and reward. The role of amygdala-ventral striatal substems. Ann N Y Acad Sci 877:412–438
Hayashi T, Su TP (2001) Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci USA 98:491–496
Hayashi T, Su TP (2003a) σ-1 Receptors (σ-1 binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther 306:718–725
Hayashi T, Su TP (2003b) Intracellular dynamics of σ-1 receptors (σ-1 binding sites) in NG-108-15 cells. J Pharmacol Exp Ther 306:726–733
Itzhak Y (1993) Repeated methamphetamine-treatment alters brain σ receptors. Eur J Pharmacol 230:243–244
Itzhak Y (1994) Modulation of the PCP/NMDA receptor complex and sigma binding sites by psychostimulants. Neurotoxicol Teratol 16:363–368
Ljungberg T, Apicella P, Schultz W (1992) Responses of monkey dopamine neurons during learning of behavioural reactions. J Neurophysiol 67:145–163
Matsumoto RR, McCracken KA, Pouw B, Zhang Y, Bowen WD (2002) Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. Neuropharmacology 42:1043–1055
Maurice T, Martin-Fardon R, Romieu P, Matsumoto RR (2002) Sigma1 receptor antagonists represent a new strategy against cocaine addiction and toxicity. Neurosci Biobehav Rev 26:499–527
Munzar P, Baumann MH, Shoaib M, Goldberg SR (1999) Effects of dopamine and serotonin-releasing agents on methamphetamine discrimination and self-administration in rats. Psychopharmacology 141:287–296
Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su T-P, Tam SW, Taylor DP (1992) A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13:85–86
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291
Romieu P, Martin-Fardon R, Maurice T (2000) Involvement of the sigma-1 receptor in the cocaine-induced conditioned place preference. Neuroreport 11:2885–2888
Romieu P, Phan VL, Martin-Fardon R, Maurice T (2002) Involvement of the sigma1 receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. Neuropsychopharmacology 26:444–455
Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–41
Sharkey J, Glen KA, Wolfe S, Kuhar MJ (1988) Cocaine binding at sigma receptors. Eur J Pharmacol 149:171–174
Shoaib M, Schindler CW, Goldberg SR (1997) Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology 129:35–43
Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135
Su TP, Hayashi T (2001) Cocaine affects the dynamics of cytoskeletal proteins via σ-1 receptors. Trends Pharmacol Sci 22:456–458
Takebayashi M, Hayashi T, Su T-P (2002) Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: Implications for antidepressants. J Pharmacol Exp Ther 303:1227–1237
Tropea D, Capsoni S, Tongiogi E, Giannotta S, Cattaneo A, Domenici L (2001) Mismatch between BDNF mRNA and protein expression in the developing visual cortex: the role of visual experience. Eur J Neurosci 13:709–721
Ujike H, Kuroda S, Otsuki S (1996) Sigma receptor antagonists block the development of sensitization to cocaine. Eur J Pharmacol 296:123–128
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587
White FJ (1996) Synaptic regulation of mesocorticolimbic dopamine neurons. Annu Rev Neurosci 19:405–436
White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51:141–153
Acknowledgements
This study was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS.
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R.S., Z.J., T.H. and M.T. contributed equally to this work
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Stefanski, R., Justinova, Z., Hayashi, T. et al. Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls. Psychopharmacology 175, 68–75 (2004). https://doi.org/10.1007/s00213-004-1779-9
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DOI: https://doi.org/10.1007/s00213-004-1779-9