Abstract
Rationale
Synthetic cathinones constitute a class of abused drugs that can act at dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Intracranial self-stimulation (ICSS) is a preclinical procedure that can be used to evaluate abuse potential of drugs, and prior studies have indicated that abuse-related ICSS effects of monoamine-transporter substrates, including some synthetic cathinones, are positively correlated with drug selectivity for DAT vs. SERT. Abuse potential of drugs can also be influenced by regimens of repeated drug exposure, but the role of repeated exposure on abuse-related ICSS effects of synthetic cathinones has not been examined.
Objectives
This study used ICSS to evaluate effects of repeated treatment with the DAT>SERT substrate methcathinone, the DAT<SERT substrate fenfluramine, and the DAT≈SERT substrate mephedrone.
Methods
Male Sprague-Dawley rats were trained in a frequency-rate ICSS procedure, and different groups were used to evaluate effects of methcathinone, mephedrone, and fenfluramine before, during, and after regimens of repeated treatment with the designated drug.
Results
Before repeated treatment, methcathinone produced dose-dependent and abuse-related ICSS facilitation, fenfluramine produced dose-dependent ICSS depression, and mephedrone produced mixed effects that included both facilitation and depression. Chronic treatment produced no change in effects of methcathinone, but complete tolerance to effects of fenfluramine. For mephedrone, chronic treatment produced partial tolerance to ICSS depression and enhanced expression of ICSS facilitation.
Conclusions
Repeated exposure to mixed-action DAT≈SERT substrates such as mephedrone can result in increased abuse potential due to sustained expression of DAT-mediated abuse-related effects and tolerance to SERT-mediated abuse-limiting effects.
Similar content being viewed by others
References
Altarifi AA, Negus SS (2011) Some determinants of morphine effects on intracranial self-stimulation in rats: dose, pretreatment time, repeated treatment, and rate dependence. Behav Pharmacol 22:663–673
Altarifi AA, Miller LL, Negus SS (2012) Role of micro-opioid receptor reserve and micro-agonist efficacy as determinants of the effects of micro-agonists on intracranial self-stimulation in rats. Behav Pharmacol 23:678–692
Altarifi AA, Rice KC, Negus SS (2013) Abuse-related effects of micro-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure. Behav Pharmacol 24:459–470
Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168:850–862
Bauer CT, Banks ML, Negus SS (2014) The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats. Psychopharmacology 231:2461–2470
Bauer CT, Banks ML, Blough BE, Negus SS (2015) Role of 5-HT(2)C receptors in effects of monoamine releasers on intracranial self-stimulation in rats. Psychopharmacology 232:3249–3258
Baumann MH, Solis E Jr, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL (2014) Baths salts, spice, and related designer drugs: the science behind the headlines. J Neurosci 34:15150–15158
Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology 231:199–207
Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS (2015) Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172:2433–2444
Bradbury S, Bird J, Colussi-Mas J, Mueller M, Ricaurte G, Schenk S (2014) Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release. Addict Biol 19:874–884
Carlezon WA Jr, Chartoff EH (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995
Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58
Dahl CB, Gotestam KG (1989) Lack of self-administration of different fenfluramine isomers in rats. Addict Behav 14:239–247
De Felice LJ, Glennon RA, Negus SS (2014) Synthetic cathinones: chemical phylogeny, physiology, and neuropharmacology. Life Sci 97:20–26
Do J, Schenk S (2013) Self-administered MDMA produces dose- and time-dependent serotonin deficits in the rat brain. Addict Biol 18:441–447
Freitas K, Carroll FI, Negus SS (2016) Comparison of effects produced by nicotine and the alpha4beta2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats. Exp Clin Psychopharmacol 24:65–75
Grim TW, Wiebelhaus JM, Morales AJ, Negus SS, Lichtman AH (2015) Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice. Drug Alcohol Depend 150:31–37
Hillhouse TM, Porter JH, Negus SS (2014) Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats. Psychopharmacology 231:2705–2716
John WS, Martin TJ, Nader MA (2017) Behavioral determinants of cannabinoid self-administration in Old World Monkeys. Neuropsychopharmacology 42:1522–1530
Johnson AR, Banks ML, Selley DE, Negus SS (2018) Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats. Neuropsychopharmacology 43:1753–1762
Kintz P, Mangin P (1992) Toxicological findings after fatal fenfluramine self-poisoning. Hum Exp Toxicol 11:51–52
Kleven MS, Schuster CR, Seiden LS (1988) Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine. J Pharmacol Exp Ther 246:822–828
Kornetsky C, Esposito RU (1979) Euphorigenic drugs: effects on the reward pathways of the brain. Fed Proc 38:2473–2476
Kwilasz AJ, Negus SS (2012) Dissociable effects of the cannabinoid receptor agonists Delta9-tetrahydrocannabinol and CP55940 on pain-stimulated versus pain-depressed behavior in rats. J Pharmacol Exp Ther 343:389–400
Lazenka MF, Blough BE, Negus SS (2016) Preclinical abuse potential assessment of flibanserin: effects on intracranial self-stimulation in female and male rats. J Sex Med 13:338–349
Legakis LP, Negus SS (2018) Repeated morphine produces sensitization to reward and tolerance to antiallodynia in male and female rats with chemotherapy-induced neuropathy. J Pharmacol Exp Ther 365:9–19
Miller LL, Altarifi AA, Negus SS (2015a) Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus. Exp Clin Psychopharmacol 23:405–414
Miller LL, Leitl MD, Banks ML, Blough BE, Negus SS (2015b) Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats. Pain 156:175–184
National Research Council (2011) Guide for the Care and Use of Laboratory Animals, 8th ed. The National Academies Press, Washington D.C.
Negus SS, Banks ML (2017) Decoding the structure of abuse potential for new psychoactive substances: structure-activity relationships for abuse-related effects of 4-substituted methcathinone analogs. Curr Top Behav Neurosci 32:119–131
Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869–917
Negus SS, Gatch MB, Mello NK, Zhang X, Rice K (1998) Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys. J Pharmacol Exp Ther 286:362–375
Negus SS, Rosenberg MB, Altarifi AA, O'Connell RH, Folk JE, Rice KC (2012) Effects of the delta opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats. J Pain 13:317–327
Olds ME, Yuwiler A (1992) Effects of acute and chronic fenfluramine on self-stimulation and its facilitation by amphetamine. Eur J Pharmacol 216:363–372
Potter DN, Damez-Werno D, Carlezon WA Jr, Cohen BM, Chartoff EH (2011) Repeated exposure to the kappa-opioid receptor agonist salvinorin A modulates extracellular signal-regulated kinase and reward sensitivity. Biol Psychiatry 70:744–753
Reid LD (1987) Tests involving pressing for intracranial stimulation as an early procedure for screening the likelihood of addiction of opioids and other drugs. In: Bozarth MJ (ed) Methods of assessing the reinforcing properties of abused drugs. Springer-Verlag, Berlin, pp 391–420
Riday TT, Kosofsky BE, Malanga CJ (2012) The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice. Neuropharmacology 62:1858–1866
Robinson JE, Agoglia AE, Fish EW, Krouse MC, Malanga CJ (2012) Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: comparison to cocaine. Behav Brain Res 234:76–81
Rosenberg MB, Carroll FI, Negus SS (2013) Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J Pain 14:246–259
Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41
Rowland N, Carlton J (1983) Different behavioral mechanisms underlie tolerance to the anorectic effects of fenfluramine and quipazine. Psychopharmacology 81:155–157
Rowland NE, Carlton J (1986) Tolerance to fenfluramine anorexia: fact or fiction? Appetite 7(7 Suppl):71–83
Schenk S (2009) MDMA self-administration in laboratory animals: a summary of the literature and proposal for future research. Neuropsychobiology 60:130–136
Schenk S, Hely L, Lake B, Daniela E, Gittings D, Mash DC (2007) MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding. Eur J Neurosci 26:3229–3236
Schulteis G, Markou A, Gold LH, Stinus L, Koob GF (1994) Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. J Pharmacol Exp Ther 271:1391–1398
Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS, Banks ML (2016) Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: microdialysis studies of nucleus accumbens dopamine and serotonin. J Pharmacol Exp Ther 356:182–190
van de Wetering R, Schenk S (2017) Repeated MDMA administration increases MDMA-produced locomotor activity and facilitates the acquisition of MDMA self-administration: role of dopamine D2 receptor mechanisms. Psychopharmacology 234:1155–1164
Vivero LE, Anderson PO, Clark RF (1998) A close look at fenfluramine and dexfenfluramine. J Emerg Med 16:197–205
Wang Y, Joharchi N, Fletcher PJ, Sellers EM, Higgins GA (1995) Further studies to examine the nature of dexfenfluramine-induced suppression of heroin self-administration. Psychopharmacology 120:134–141
Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, Wegner S, Blough BE, Marusich JA, Olive MF (2012) The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in “bath salts”. J Addict Res Ther Suppl 9
Watterson LR, Kufahl PR, Nemirovsky NE, Sewalia K, Grabenauer M, Thomas BF, Marusich JA, Wegner S, Olive MF (2014) Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Addict Biol 19:165–174
Wee S, Woolverton WL (2006) Self-administration of mixtures of fenfluramine and amphetamine by rhesus monkeys. Pharmacol Biochem Behav 84:337–343
Wiebelhaus JM, Walentiny DM, Beardsley PM (2016) Effects of acute and repeated administration of oxycodone and naloxone-precipitated withdrawal on intracranial self-stimulation in rats. J Pharmacol Exp Ther 356:43–52
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
Young AM, Herling S, Woods JH (1981) History of drug exposure as a determinant of drug self-administration. NIDA Res Monogr 37:75–88
Funding
This work was supported by grants R01 DA033930 and F30 DA037649.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics statement
All animal use protocols were approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee.
Additional information
This article belongs to a Special Issue on Bath Salts
Rights and permissions
About this article
Cite this article
Suyama, J.A., Banks, M.L. & Negus, S.S. Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats. Psychopharmacology 236, 1057–1066 (2019). https://doi.org/10.1007/s00213-018-5029-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-018-5029-y