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Discriminative Stimulus Effects of Acute Morphine Followed by Naltrexone in the Squirrel Monkey

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Discriminative Stimulus Effects of Acute Morphine Followed by Naltrexone in the Squirrel Monkey Psychopharmacology (2003) 167:203–210 DOI 10.1007/s00213-002-1367-9 ORIGINAL INVESTIGATION David A. White · Stephen G. Holtzman Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey Received: 8 September 2002 / Accepted: 27 November 2002 / Published online: 18 March 2003 Springer-Verlag 2003 Abstract Rationale The discriminative stimulus effects Keywords Acute dependence · Conditioned behavior · of a combination of acute morphine followed by naltrex- Dextrorphan · Drug discrimination · Levorphanol · one have been described in rats. Objective: The purpose Naloxone · Non-human primate · Opioid · U69,593 of this study was to extend observations to a non-human primate. Methods: Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discrimi- Introduction nate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR!NTX) versus In physically dependent subjects, abstinence or opioid- saline (1.0 ml/kg, IM, 4 h) followed by naltrexone antagonist administration following chronic treatment (0.1 mg/kg, IM, 0.25 h) (SAL!NTX). Results: Seven with morphine-like drugs results in a number of promi- subjects acquired the discrimination in an average of nent physiological and behavioral changes in addition to 108€14 sessions. MOR!NTX-appropriate responding subjective symptoms (e.g. negative mood states) associ- increased as an orderly function of increasing dose of ated with the syndrome of withdrawal from drug treat- morphine (0.56–1.7 mg/kg) and of naltrexone (0.01– ment (Martin 1983). Single doses of a morphine-like 10 mg/kg). The discrimination was also dependent upon agonist followed by the administration of an opioid interval between morphine and naltrexone administration. antagonist result in many of the same changes comprising The MOR!NTX cue was fully generalized to the the withdrawal syndrome, suggesting a common mecha- combination of levorphanol (0.3 mg/kg) followed by nism. For example, in humans a single dose of morphine naltrexone, but not to the non-opioid stereoisomer of followed by the antagonist naloxone elicits physical signs levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the that are qualitatively similar to those experienced after kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/ withdrawal from chronic morphine treatment (Bickel et kg) followed by naltrexone. Naltrexone administered al. 1988; Heishman et al. 1989; June et al. 1995). 15 min before morphine dose-dependently blocked Similarities in antagonist-precipitated changes after MOR!NTX-appropriate responding. Conclusions: This chronic and acute administration of morphine also have is the first non-rodent study of the discriminative effects been observed for a variety of dependent measures in of MOR!NTX. MOR!NTX produces a unique intero- several animal models (Kosersky et al. 1974; Eisenberg ceptive stimulus that is pharmacologically selective, 1982; Krystal and Redmond Jr 1983; Ramabadran 1983; requires occupation of opioid receptors, presumably mu, Schnur 1991; Easterling and Holtzman 1997). Addition- for some minimum period of time, and is reversible. This ally, naloxone after a single dose of morphine induces discrimination procedure might provide new insights into subjective symptoms that are identified as withdrawal by the early drug-receptor interactions that underlie the subjects with a history of opiate use (Bickel et al. 1988; development of physical dependence upon morphine-like Heishman et al. 1989; June et al. 1995). These studies drugs. indicate that even a single dose of a morphine-like agonist can induce a state of physical dependence, which is revealed following challenge with an opioid antagonist. D. A. White ()) · S. G. Holtzman Drug discrimination affords a useful animal model for Department of Pharmacology, studying subjective drug effects, including those associ- Emory University School of Medicine, Rollins Research Center, ated with morphine withdrawal (Holtzman 1990). Rats 1510 Clifton Road NE, Suite 5074, Atlanta, GA 30322, USA treated chronically with morphine can be trained to e-mail: [email protected] discriminate saline from 0.1 mg/kg of the opioid antag- Tel.: +1-404-7270356 onist naltrexone (Gellert and Holtzman 1979; Holtzman Fax: +1-404-7270365 204 1985), which is significantly less than the discriminable Materials and methods dose in non-morphine dependent animals (Valentino et al. 1983). This interoceptive stimulus is generalized to other Subjects opioid antagonists but not to opioid agonists or to non- Eight male squirrel monkeys (Saimiri sciureus), weighing between opioid drugs. Additionally, rats abruptly withdrawn from 550 and 700 g at the beginning of experimentation, were pair- chronic morphine treatment respond as though they have housed with unlimited access to food and water. Monkeys were received naltrexone, suggesting similarities in the inter- provided with fresh fruit, peanuts, or a vitamin supplement mixture oceptive states elicited by naltrexone-precipitated and each day in the home cage. All of the monkeys were experimentally naive at the beginning of this study. Animals were maintained spontaneous withdrawal. according to the “Guide for the Care and Use of Laboratory The discriminative effects of antagonist-precipitated Animals” (National Academy of Sciences, 1996), and all proce- withdrawal from acute opioid dependence have also been dures were approved by the Institutional Animal Care and Use characterized in rats (Easterling and Holtzman 1999). Committee of Emory University. Subjects were trained to discriminate a combination of 10 mg/kg morphine and 0.3 mg/kg naltrexone adminis- Apparatus tered (SC) 4 and 0.25 h before a session, respectively (MOR!NTX), from a combination of saline followed by During experimental sessions, monkeys were seated in small 0.3 mg/kg naltrexone (SAL!NTX) at the same pretreat- primate chairs housed in ventilated and sound-attenuated chambers (BRS/LVE Inc., Laurel, Md., USA). The chairs were equipped with ment times. MOR!NTX-appropriate responding was an a small stock and two brass electrodes through which electric orderly function of the doses of naltrexone and morphine, current was delivered to a shaved portion of the monkey’s tail. Two with increased responding generally occurring with response levers were mounted 9.5 cm apart on the front panel and increased dose of drug. Additionally, MOR!NTX- 3 cm from the sidewalls. A Plexiglas partition extended from the ceiling to the waist-plate of the chair, creating a wall 6 cm out from appropriate responding was a function of the interval of the front panel. Two slots approximately 10 cm apart, measuring time between the administration of morphine and nal- 45 cm each, were cut out of this partition just in front of each lever trexone, with peak responding occurring at an interval of with approximately 10 cm between the slots to prevent the monkey 3.75 h. Rats trained with MOR!NTX also generalized to from reaching and pressing both levers simultaneously. A red morphine followed by naloxone. Finally, when training stimulus light was mounted at eye level and centered between the two response levers on the front panel. A white house light was was suspended and morphine was administered to the positioned above the red stimulus light or on the rear wall of the subjects continuously via osmotic pumps (20 or 40 mg/kg chamber, depending on the chamber used. The chambers were per day), subsequent injections of naltrexone occasioned equipped with white noise to mask extraneous sounds. dose-dependent increases in MOR!NTX-appropriate responding and complete generalization with the Drug discrimination procedure MOR!NTX training state. This further suggests that the interoceptive stimuli produced by an opioid antagonist Experimental sessions were conducted daily Monday through following either acute or prolonged pretreatment with an Friday and consisted of 25 trials. Monkeys were trained to press the response levers under a fixed-ratio 1 (FR1) schedule of stimulus opioid agonist are qualitatively similar. termination/avoidance. At the beginning of each trial, the house The purpose of this study was to extend observations on light was illuminated and the monkey had 5 s to press the lever interoceptive stimuli associated with antagonist-precipitat- appropriate for the injection combination received before the ed withdrawal from acute morphine dependence to a non- session in order to avoid a 2–4 mA electrical stimulus to the tail. If human primate: the squirrel monkey. Compared to rats, the monkey failed to press the correct lever within 5 s, the electrical stimulus was delivered in 1-s pulses every 2 s until the monkey monkeys show differences in the relative ratios and responded on the correct lever or until 15 stimuli were delivered. At distribution of opioid receptor subtypes (Mansour et al. the end of the trial, the house light was turned off and the red 1988). Species-related behavioral differences exist as well. stimulus light was turned on for a 30-s time-out period. Each For example, pretreatment with a single dose of morphine response on the incorrect lever resulted in an electrical stimulus and a 3-s changeover delay, during which responses on the correct lever markedly potentiates the response-rate-decreasing effect of did not end the trial. Each response during the 30-s time-out period opioid antagonists in rats (Young 1986; Adams and also resulted in the delivery of an electrical stimulus to the tail in Holtzman 1990; Oliveto et al. 1991; Easterling and order to discourage responding between trials. Holtzman 1997), an effect not observed in monkeys Monkeys received an IM injection of either saline or 1.7 mg/kg morphine 4 h before each daily session, followed by 0.1 mg/kg (France and Morse 1989). Therefore, we first determined if naltrexone 3.75 h later (SAL!NTX and MOR!NTX, respective- stimulus control of behavior could be established in the ly). These training doses were selected on the basis of the results of absence of those marked effects on operant behavior.
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