Abstract
Rationale
To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.
Objective
The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.
Materials and methods
Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.
Results
Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.
Conclusions
These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.
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References
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
Ettenberg A (2004) Opponent process properties of self-administered cocaine. Neurosci Biobehav Rev 27:721–728
Fiore MC (2000) US public health service clinical practice guideline: treating tobacco use and dependence. Respir Care 45:1200–1262
Foltin RW, Evans SM (1999) The effects of d-amphetamine on intake of food and a sweet fluid containing cocaine. Pharmacol Biochem Behav 62:457–464
Glowa JR, Wojnicki FHE, Matecka D, Rice KC, Rothman RB (1995) Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: II. Comparisons with other drugs and repeated administrations. Exp Clin Psychopharmacol 3:232–239
Grabowski J, Rhoades H, Schmitz J, Stotts A, Daruzska LA, Creson D, Moeller FG (2001) Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J Clin Psychopharmacol 21:522–526
Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C, Dougherty A, Moeller FG, Hassan S, Schmitz J (2004a) Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 29:969–981
Grabowski J, Shearer J, Merrill J, Negus SS (2004b) Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29:1439–1464
Jayanthi LD, Ramamoorthy S (2005) Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. AAPS J 7:E728–738
Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 16:223–244
Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, Blecha L, Lowenstein W, Martinot JL, Reynaud M, Lepine JP (2008) New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 11:425–438
Kreek MJ, Vocci FJ (2002) History and current status of opioid maintenance treatments: blending conference session. J Subst Abuse Treat 23:93–105
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
Lorrain DS, Arnold GM, Vezina P (2000) Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule. Behav Brain Res 107:9–19
Lynch WJ, Heaser WA, Carroll ME (1998) Effects of amphetamine, butorphanol, and morphine pretreatment on the maintenance and reinstatement of cocaine-reinforced responding. Exp Clin Psychopharmacol 6:255–263
Mansbach RS, Balster RL (1993) Effects of mazindol on behavior maintained or occasioned by cocaine. Drug Alcohol Depend 31:183–191
Negus SS (2003) Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. Neuropsychopharmacology 28:919–931
Negus SS, Mello NK (2003a) Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. Psychopharmacology 167:324–332
Negus SS, Mello NK (2003b) Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys. Drug Alcohol Depend 70:39–52
O’Brien CP (2005) Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiat 162:1423–1431
Peltier RL, Li DH, Lytle D, Taylor CM, Emmett-Oglesby MW (1996) Chronic d-amphetamine or methamphetamine produces cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine. J Pharmacol Exp Ther 277:212–218
Preti A (2007) New developments in the pharmacotherapy of cocaine abuse. Addict Biol 12:133–151
Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11
Roberts DC, Andrews MM, Vickers GJ (1996) Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology 15:417–423
Roberts DCS, Bennett SA, Vickers GJ (1989a) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98:408–411
Roberts DCS, Loh EA, Vickers GJ (1989b) Self-administration of cocaine on a progressive ratio schedule in rats: dose–response relationship and effect of haloperidol pretreatment. Psychopharmacology 97:535–538
Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114
Scarponi M, Bernardi G, Mercuri NB (1999) Electrophysiological evidence for a reciprocal interaction between amphetamine and cocaine-related drugs on rat midbrain dopaminergic neurons. Eur J Neurosci 11:593–598
Schenk S, Partridge B (1999) Cocaine-seeking produced by experimenter-administered drug injections: dose–effect relationships in rats. Psychopharmacology 147:285–290
Shearer J (2008) The principles of agonist pharmacotherapy for psychostimulant dependence. Drug Alcohol Rev 27:301–308
Shearer J, Wodak A, van BI, Mattick RP, Lewis J (2003) Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction 98:1137–1141
Theeuwes F, Yum SI (1976) Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann Biomed Eng 4(4):343–353
Ukairo OT, Ramanujapuram S, Surratt CK (2007) Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, at mammalian cells expressing the dopamine transporter. Brain Res 1131:68–76
Vezina P, Lorrain DS, Arnold GM, Austin JD, Suto N (2002) Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine. J Neurosci 22:4654–4662
Vocci FJ, Acri J, Elkashef A (2005) Medication development for addictive disorders: the state of the science. Am J Psychiatry 162:1432–1440
Vocci FJ, Elkashef A (2005) Pharmacotherapy and other treatments for cocaine abuse and dependence. Curr Opin Psychiatry 18:265–270
Ward SJ, Morgan D, Roberts DC (2005) Comparison of the reinforcing effects of cocaine and cocaine/heroin combinations under progressive ratio and choice schedules in rats. Neuropsychopharmacology 30:286–295
Wheeler RA, Twining RC, Jones JL, Slater JM, Grigson PS, Carelli RM (2008) Behavioral and electrophysiological indices of negative affect predict cocaine self-administration. Neuron 57:774–785
Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492
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Funding provided by Grants F30DA18014 (CML), R01DA14030 (DCSR), and P50DA06634-14 (DCSR).
Keri A. Chiodo* and Christopher M. Läck* contributed equally to this project and should be considered co-first authors.
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Chiodo, K.A., Läck, C.M. & Roberts, D.C.S. Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous d-amphetamine treatment in rats. Psychopharmacology 200, 465–473 (2008). https://doi.org/10.1007/s00213-008-1222-8
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DOI: https://doi.org/10.1007/s00213-008-1222-8