Models of Neurological Disease (Substance Abuse): Self‐Administration in Monkeys

Donna M. Platt1, Galen Carey2, Roger D. Spealman1

1 New England Primate Research Center/Harvard Medical School, Southborough, Massachusetts, 2 Ironwood Pharmaceuticals, Cambridge, Massachusetts
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 10.5
DOI:  10.1002/0471141755.ph1005s56
Online Posting Date:  March, 2012
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Drug self‐administration is a procedure in which a subject performs a specified response that results in the delivery of a drug injection. This procedure is viewed as a relevant model for the study of human drug‐taking behavior. Drug self‐administration in primates has several characteristics that resemble drug‐taking behavior in humans, and agents commonly abused by humans also generally maintain self‐administration behavior in monkeys. Self‐administration procedures allow for the study of a variety of drug properties. For instance, they can be used to investigate the abuse potential of new compounds and to study the effects of candidate medications for the treatment of drug addiction. These procedures can also be employed for examining drug reinforcement mechanisms. Described in this unit are procedures for studying intravenous drug self‐administration in large primates, such as rhesus macaques, and smaller primates, such as squirrel monkeys. Curr. Protoc. Pharmacol. 56:10.5.1‐10.5.17. © 2012 by John Wiley & Sons, Inc.

Keywords: self‐administration; monkey; intravenous

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Table of Contents

  • Introduction
  • Strategic Planning
  • Basic Protocol 1: Self‐Administration Training and Testing
  • Support Protocol 1: Catheter Implantation
  • Support Protocol 2: Determination of Catheter Patency Using the Ketamine Test
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1: Self‐Administration Training and Testing

  • Monkeys: male/female ≥4‐kg rhesus macaques (e.g., Covance Research Products) or ≥0.75‐kg squirrel monkeys (e.g., Worldwide Primates)
  • Raisins or peanuts (optional)
  • Short length of metal chain (optional)
  • 100 to 200 IU/ml heparinized saline, sterile
  • Sterile saline
  • Training compound and vehicle, filter‐sterilized
  • Remote‐chamber or home‐cage self‐administration apparatus (see Strategic Planning) with schedule control apparatus (e.g., Med Associates; Lafayette Instrument Company)
  • Tether system: custom‐fitted jacket connected to a flexible stainless steel cable by a fluid swivel (e.g., Lomir Biomedical; Alice King Chatham Medical Arts)
  • Restraining chair (for remote chamber only: Plas‐Labs; Crist Instruments Company; Primate Products for macaques; Med Associates for squirrel monkeys)
  • Huber needle (i.e., right angled, noncoring needle)
  • Additional reagents and equipment for implanting and testing patency of catheter (see Support Protocols protocol 21 and protocol 32)

Support Protocol 1: Catheter Implantation

  • Habituated monkeys (see protocol 1, steps 1a and 1b)
  • Ketamine, veterinary grade (e.g., Butler Schein Animal Health)
  • Normal saline
  • Atropine, veterinary grade (e.g., Butler Schein Animal Health)
  • 1% to 1.5% (v/v) isoflurane in oxygen
  • Propofol, veterinary grade (e.g., Butler Schein Animal Health)
  • Povidone iodine (e.g., Butler Schein Animal Health)
  • 70% (v/v) ethanol
  • Intravenous catheter line (angiocatheter; 22‐G for macaques, 24‐G for squirrel monkeys; Terumo Medical)
  • Tracheal tube (2.5‐ to 5.5‐mm diameter for macaques, 2‐ to 3‐mm for squirrel monkeys; Rusch Medical/Teleflex Medical)
  • Electric razor (Oster;
  • Sterile surgical instruments
  • Surgical table (Paragon Medical)
  • 4‐0 Ethibond Excel polyester suture (e.g., Ethicon)
  • Vascular clips
  • Vannas scissors (Miltex, Inc., York, PA; Roboz Surgical Instrument)
  • Catheter (see Table 10.5.1)
  • Sterile stainless steel obturator (optional; Vita Needle Company)
  • Access port (optional; Access Technologies)
  • 4‐0 Surgical gut suture (e.g., Ethicon)
  • 3‐0 Ethilon monofilament nylon suture (e.g., Ethicon)
NOTE: Perform catheter implantations under aseptic conditions in a fully equipped veterinary operating room.

Support Protocol 2: Determination of Catheter Patency Using the Ketamine Test

  • Catheterized monkey (see protocol 2)
  • Ketamine, veterinary grade (Butler Schein Animal Health)
  • Sterile saline
  • 1‐ to 3‐ml syringes
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Literature Cited

   Banks, M.L. and Negus, S.S. 2010. Effects of extended access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys. Neuropsychopharmacology 35:493‐504.
   Caine, S.B., Lintz, R., and Koob, G.F. 1993. Intravenous drug self‐administration techniques in animals. In Behavioral Neuroscience: A Practical Approach (A. Seghal, ed.) pp. 117‐139. Oxford University Press, New York.
   Czoty, P.W., Martelle, J.L., Carroll, F.I., and Nader, M.A. 2010. Lower reinforcing strength of the phenyltropane cocaine analogs RTI‐336 and RTI‐177 compared to cocaine in nonhuman primates. Pharmacol. Biochem. Behav. 96:274‐278.
   Fantegrossi, W.E., Ullrich, T., Rice, K.C., Woods, J.H., and Winger, G. 2002. 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) and its stereoisomers as reinforcers in rhesus monkeys: Serotonergic involvement. Psychopharmacology 161:356‐364.
   Gerak, L.R., Galici, R., and France, C.P. 2008. Self administration of heroin and cocaine in morphine‐dependent and morphine‐withdrawn rhesus monkeys. Psychopharmacology 204:403‐411.
   Gerak, L.R., Galici, R., and France, C.P. 2009. Self administration of cocaine in monkeys receiving LAAM acutely or chronically. Physiol. Behav. 93:20‐26.
   Goldberg, S.R. 1975. Stimuli associated with drug injections as events that control behavior. Pharmacol. Rev. 27:325‐340.
   Griffiths, R.R., Bradford, L.D., and Brady, J.V. 1979. Progressive ratio and fixed ratio schedules of cocaine‐maintained responding in baboons. Psychopharmacology 65:125‐136.
   Johanson, C.E. 1976. Pharmacological and environmental variables affecting drug preference in rhesus monkeys. Pharmacol. Rev. 27:343‐355.
   Kelleher, R.T. 1975. Characteristics of behavior controlled by scheduled injections of drugs. Pharmacol. Rev. 27:307‐324.
   Kimmel, H.L., Negus, S.S., Wilcox, K.M., Ewing, S.B., Stehouwer, J., Goodman, M.M., Votaw, J.R., Mello, N.K., Carroll, F.I., and Howell, L.L. 2008. Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys. Pharmacol. Biochem. Behav. 90:453‐462.
   Mello, N.K. and Negus, S.S. 1998. The effects of buprenorphine on self‐administration of cocaine and heroin “speedball” combinations and heroin alone by rhesus monkeys. J. Pharmacol. Exp. Ther. 285:444‐456.
   Nader, M.A. and Mach, R.H. 1996. Self‐administration of the dopamine D3 agonist 7‐OH‐DPAT in rhesus monkeys is modified by prior cocaine exposure. Psychopharmacology Ser. 125:13‐22.
   Negus, S.S. 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, S.S. 2006. Choice between heroin and food in nondependent and heroin‐dependent rhesus monkeys: Effects of naloxone, buprenorphine, and methadone. J. Pharmacol. Exp. Ther. 317:711‐723.
   Negus, S.S. and Mello, N.K. 2004. Effects of chronic methadone treatment on cocaine‐ and food‐maintained responding under second‐order, progressive‐ratio and concurrent‐choice schedules in rhesus monkeys. Drug Alcohol Depend. 74:297‐309.
   Rowlett, J.K., Platt, D.M., Yao, W.D., and Spealman, R.D. 2007. Modulation of heroin and cocaine self‐administration by dopamine D1‐ and D2‐like receptor agonists in rhesus monkeys. J. Pharmacol. Exp. Ther. 321:1135‐1143.
   Schuster, C.R. and Johanson, C.E. 1974. The use of animal models for the study of drug abuse. In Research Advances in Alcohol and Drug Problems (R.J. Gibbins, Y. Israel, H. Kalant, R.E. Popham, W. Schmidt and R.G. Smart, eds.) pp 1‐31. John Wiley & Sons, New York.
   Spealman, R.D. and Goldberg, S.R. 1978. Drug self‐administration by laboratory animals: Controls by schedules of reinforcement. Ann. Rev. Pharmacol. Toxicol. 18:313‐339.
   Weeks, J.R. 1972. Long‐term intravenous infusion. In Methods in Psychobiology, Vol. 2 (R.D. Meyers, ed.) pp. 155‐168. Academic Press, New York.
Key References
   Kelleher, 1975. See above.
  Description of characteristic performance under different schedules of drug self‐administration.
   Schuster and Johanson, 1974. See above.
  Description of use of drug self‐administration procedures to assess the abuse potential of drugs.
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