Abstract
Sigma1 receptors (σ1Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ1R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ1R agonist. In contrast, after subjects self-administered cocaine σ1R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ1R agonists, extinguished when injections were discontinued, and reconditioned when σ1R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ1R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ1R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ1R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Aydar E, Palmer CP, Klyachko VA, Jackson MB (2002). The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron 34: 399–410.
Barrett AC, Miller JR, Dohrmann JM, Caine SB (2004). Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats. Neuropharmacology 47 (Suppl 1): 256–273.
Barrett JE (1977). Behavioral history as a determinant of the effects of d-amphetamine on punished behavior. Science 198: 67–69.
Collins GT, Woods JH (2007). Drug and reinforcement history as determinants of the response-maintaining effects of quinpirole in the rat. J Pharmacol Exp Ther 323: 599–605.
Collins GT, Woods JH (2009). Influence of conditioned reinforcement on the response-maintaining effects of quinpirole in rats. Behav Pharmacol 20: 492–504.
Cormaci G, Mori T, Hayashi T, Su TP (2007). Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: implication for neuroplasticity. J Pharmacol Exp Ther 320: 202–210.
Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE (2009). The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323: 934–937.
Garcés-Ramírez L, Green J, Hiranita T, Kopajtic T, Mereu M, Thomas A et al (2011). Sigma receptor agonists: receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis in rats. Biol Psychiatry 69: 208–217.
Glowa JR, Barrett JE (1983). Drug history modifies the behavioral effects of pentobarbital. Science 220: 333–335.
Gorelick DA, Gardner EL, Xi ZX (2004). Agents in development for the management of cocaine abuse. Drugs 64: 1547–1573.
Gudelsky GA (1995). Effects of sigma receptor ligands on the extracellular concentration of dopamine in the striatum and prefrontal cortex of the rat. Eur J Pharmacol 286: 223–228.
Hayashi T, Justinova Z, Hayashi E, Cormaci G, Mori T, Tsai SY et al (2010). Regulation of sigma-1 receptors and endoplasmic reticulum chaperones in the brain of methamphetamine self-administering rats. J Pharmacol Exp Ther 332: 1054–1063.
Hayashi T, Su TP (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131: 596–610.
Heikkila RE, Orlansky H, Cohen G (1975). Studies on the distinction between uptake inhibition and release of [3H]dopamine in rat brain tissue slices. Biochem Pharmacol 24: 847–852.
Hemby SE, Smith JE, Dworkin SI (1996). The effects of eticlopride and naltrexone on responding maintained by food, cocaine, heroin and cocaine/heroin combinations in rats. J Pharmacol Exp Ther 277: 1247–1258.
Hill RT (1970). Facilitation of conditioned reinforcement as a mechanism of psychomotor stimulation. In: Costa E,, Garattini S, (eds). Amphetamines and Related Compounds. Raven Press: New York. pp 781–795.
Hiranita T, Soto P, Tanda G, Katz J (2011a). Lack of cocaine-like discriminative-stimulus effects of σ receptor agonists in rats. Behav Pharmacol 22: 525–530.
Hiranita T, Soto PL, Kohut SJ, Kopajtic T, Cao J, Newman AH et al (2011b). Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and {σ} receptors. J Pharmacol Exp Ther 339: 662–677.
Hiranita T, Soto PL, Newman AH, Katz JL (2009). Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors. J Pharmacol Exp Ther 329: 677–686.
Hiranita T, Soto PL, Tanda G, Katz JL (2010). Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine. J Pharmacol Exp Ther 332: 515–524.
Katz JL, Su TP, Hiranita T, Hayashi T, Tanda G, Kopajtic T et al (2011). A role for sigma receptors in stimulant self administration and addiction. Pharmaceuticals 4: 880–914.
Li SM, Campbell BL, Katz JL (2006). Interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine. J Pharmacol Exp Ther 317: 1088–1096.
Liu Y, Chen GD, Lerner MR, Brackett DJ, Matsumoto RR (2005). Cocaine up-regulates Fra-2 and sigma-1 receptor gene and protein expression in brain regions involved in addiction and reward. J Pharmacol Exp Ther 314: 770–779.
Liu Y, Matsumoto RR (2008). Alterations in fos-related antigen 2 and sigma1 receptor gene and protein expression are associated with the development of cocaine-induced behavioral sensitization: time course and regional distribution studies. J Pharmacol Exp Ther 327: 187–195.
Maj J, Rogoz Z, Skuza G (1996). Some behavioral effects of 1,3-di-o-tolylguanidine, opipramol and sertraline, the sigma site ligands. Polish J Pharmacol 48: 379–395.
Martin-Fardon R, Maurice T, Aujla H, Bowen WD, Weiss F (2007). Differential effects of sigma1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs natural reward. Neuropsychopharmacology 32: 1967–1973.
Matsumoto RR (2009). Targeting sigma receptors: novel medication development for drug abuse and addiction. Expert Rev Clin Pharmacol 2: 351–358.
Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, De Costa BR, Bowen WD (2001). Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice. Eur J Pharmacol 419: 163–174.
Maurice T, Su TP (2009). The pharmacology of sigma-1 receptors. Pharmacol Ther 124: 195–206.
McCracken KA, Bowen WD, de Costa BR, Matsumoto RR (1999). Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity. Eur J Pharmacol 370: 225–232.
Meunier J, Demeilliers B, Celerier A, Maurice T (2006). Compensatory effect by sigma1 (σ1) receptor stimulation during alcohol withdrawal in mice performing an object recognition task. Behav Brain Res 166: 166–176.
Navarro G, Moreno E, Aymerich M, Marcellino D, McCormick PJ, Mallol J et al (2010). Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine. Proc Nat Acad Sci USA 107: 18676–18681.
Nuwayhid SJ, Werling LL (2003). Sigma1 receptor agonist-mediated regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release is dependent upon protein kinase C. J Pharmacol Exp Ther 304: 364–369.
O′Connell AW, Earley B, Leonard BE (1996). The sigma ligand JO 1784 prevents trimethyltin-induced behavioural and sigma-receptor dysfunction in the rat. Pharmacol Toxicol 78: 296–302.
Patrick SL, Walker JM, Perkel JM, Lockwood M, Patrick RL (1993). Increases in rat striatal extracellular dopamine and vacuous chewing produced by two sigma receptor ligands. Eur J Pharmacol 231: 243–249.
Paxinos G, Watson C (1998). The Rat Brain in Stereotaxic Coordinates. Sidney, Australia: Academic Press.
Pontieri FE, Tanda G, Di Chiara G (1995). Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the "shell" as compared with the "core" of the rat nucleus accumbens. Proc Nat Acad Sci USA 92: 12304–12308.
Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996). Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382: 255–257.
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987). Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219–1223.
Romieu P, Martin-Fardon R, Maurice T (2000). Involvement of the sigma1 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 sigma(1) receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. Neuropsychopharmacology 26: 444–455.
Sharkey J, Glen KA, Wolfe S, Kuhar MJ (1988). Cocaine binding at sigma receptors. Eur J Pharmacol 149: 171–174.
Stefanski R, Justinova Z, Hayashi T, Takebayashi M, Goldberg SR, Su TP (2004). Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls. Psychopharmacology 175: 68–75.
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.
Tanda G, Ebbs A, Newman AH, Katz JL (2005). Effects of 4′-chloro-3 alpha-(diphenylmethoxy)-tropane on mesostriatal, mesocortical, and mesolimbic dopamine transmission: comparison with effects of cocaine. J Pharmacol Exp Ther 313: 613–620.
Tanda G, Kopajtic TA, Katz JL (2008). Cocaine-like neurochemical effects of antihistaminic medications. J Neurochem 106: 147–157.
Tanda G, Pontieri FE, Di Chiara G (1997). Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276: 2048–2050.
van Rossum JM, Hurkmans JAThM (1964). Mechanism of action of psychomotor stimulant drugs: significance of dopamine in locomotor stimulant action. Int J Neuropharmacol 3: 227–239.
Vocci FJ, Acri J, Elkashef A (2005a). Medication development for addictive disorders: the state of the science. Am J Psychiatry 162: 1432–1440.
Vocci FJ, Elkashef A (2005b). Pharmacotherapy and other treatments for cocaine abuse and dependence. Curr Opin Psychiatry 18: 265–270.
Witkin JM, Nichols DE, Terry P, Katz JL (1991). Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections. J Pharmacol Exp Ther 257: 706–713.
Young AM, Woods JH (1981). Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218: 720–727.
Zhang D, Zhang L, Tang Y, Zhang Q, Lou D, Sharp FR et al (2005). Repeated cocaine administration induces gene expression changes through the dopamine D1 receptors. Neuropsychopharmacology 30: 1443–1454.
Acknowledgements
We thank Patty Ballerstadt for administrative assistance and Drs Tsung-Ping Su, Teruo Hayashi, James H. Woods, and James E. Barrett for advice on these studies and the preparation of the manuscript. The work reported herein was supported by the Intramural Research Program of the National Institute on Drug Abuse.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Portions of this manuscript were presented at the annual meeting of International Study Group Investigating Drugs as Reinforcers (Scottsdale, AZ; June 2010), the annual meeting of Experimental Biology (Washington, DC; April 2011), and the Early Career Investigators Poster Session (cosponsored by NIDA/NIAAA/APA, and APA Divisions 28 and 50), American Psychological Association, 119th Annual Meeting (Washington, DC; August 2011). An abstract describing these results was included in the program materials of the canceled annual meeting of the Japanese Pharmacological Society(Yokohama, Japan; March 2011)
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Rights and permissions
About this article
Cite this article
Hiranita, T., Mereu, M., Soto, P. et al. Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists. Neuropsychopharmacol 38, 605–615 (2013). https://doi.org/10.1038/npp.2012.224
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2012.224
Keywords
This article is cited by
-
Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism
Neuropsychopharmacology (2022)
-
Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens
Molecular Psychiatry (2020)
