Psychopharmacology (2000) 151:85–90 Digital Object Identifier (DOI) 10.1007/s002130000476

O R I G I N A L I N V E S T I G AT I O N

Susan Schenk · Brian Partridge · Toni S. Shippenberg

Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593

Received: 10 February 2000 / Accepted: 26 April 2000 / Published online: 17 June 2000 © Springer-Verlag 2000

Abstract Rationale: Results of a previous study indicated that prior administration of the kappa-opioid receptor agonist, U69593, blocked the ability of cocaine to reinstate extinguished cocaine-taking behavior. Objectives: In order to determine whether the effect of U69593 was specific to cocaine or was common to cocaine seeking produced by other dopamine uptake inhibitors, the effects of U69593 on cocaine seeking produced by experimenter-administered injections of cocaine, the dopamine uptake inhibitor, GBR 12909, or the cocaine analogs, WIN 35,428 and RTI-55, were compared. Methods: Reinstatement of extinguished cocaine-taking behavior was measured for rats that received injections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 15 min prior to injections of cocaine- (0.0– 20.0 mg/kg, IP), GBR 12909- (0.0–30.0 mg/kg, IP), WIN 35,428- (0.0–3.0 mg/kg, IP) or RTI-55 (0.0– 0.50 mg/kg, IP). Results: All of the drugs produced a dose-dependent reinstatement of extinguished cocainetaking behavior. However, only the effects of cocaine and RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC). The U69593-produced attenuation of cocaine-produced cocaine seeking was reversed by prior administration of the kappa-opioid antagonist, norbinaltorphimine (30.0 µg, ICV), indicating that the effect was mediated by central kappa-opioid receptors. Conclusions: The failure of U69593 to attenuate GBR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55-produced cocaine seeking raises the posS. Schenk (✉) · B. Partridge Texas A&M University, Department of Psychology, College Station, TX 77843, USA e-mail: [email protected] Fax: +1-409-845-4727 T. S. Shippenberg National Institute on Drug Abuse, Integrative Neuroscience Unit, Behavioral Neuroscience Laboratory, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA

sibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter. Key words U69593 · Cocaine · WIN 35,428 · RTI-55 · Relapse · Kappa-opioid

Introduction Relapse to cocaine abuse occurs in a high percentage of subjects (Washton 1988) and recent investigations have focused on determining factors that contribute to recidivism. Both clinical and preclinical studies have indicated that exposure to small amounts of cocaine (DeWit and Stewart 1981; Jaffe et al. 1989; Worley et al. 1994; Self et al. 1996), other drugs (Slikker et al. 1984; Wise et al. 1990; Rush et al. 1995; Schenk et al. 1996; Schenk and Partridge 1999) or cocaine-related cues (Rohsenow et al. 1990; Grant et al. 1996; Childress et al. 1999; Renshaw et al. 1999; Wang et al. 1999) produced craving in addicts and reinstatement of extinguished drug-taking behavior in rats. Some studies of cocaine seeking by laboratory animals (Self et al. 1996; Pilla et al. 1999; Spealman et al. 1999) have suggested that manipulations of dopaminergic systems might be an effective means of decreasing drug seeking and relapse. A number of neurochemical systems modulate dopaminergic activity. Among these, kappa-opioid agonists are effective in decreasing cocaine-produced behaviors. For example, the ability of a cocaine-paired environment to acquire a preference was blocked by prior treatment with the kappa-opioid agonist, U-50,488H (Crawford et al. 1995). Several studies have indicated that pretreatment with kappa-opioid receptor agonists decreased cocaine self-administration (Glick et al. 1995; Negus et al. 1997; Mello and Negus 1998; Schenk et al. 1999) and decreased the discriminative stimulus properties of low doses of cocaine (Spealman and Bergman 1992; 1994; Riberdy et al. 1995). Further, pretreatment with kappaopioid receptor agonists decreased cocaine-evoked dopamine overflow in the nucleus accumbens (Heidbreder

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and Shippenberg 1994; Maisonneuve et al. 1994), providing a potential dopaminergic mechanism underlying the behavioral interactions between cocaine and kappaopioid agonists. Recently, we demonstrated that cocaine-produced cocaine seeking was blocked by pretreatment with the kappa-opioid agonist, U69593 (Schenk et al. 1999). The effect of U69593 was specific since amphetamine-produced cocaine seeking was unaltered by pretreatment with this kappa-agonist (Schenk et al. 1999). Amphetamine stimulates the release of dopamine via reverse transport (Kuczenski 1983) which is impulse-independent (Westerink et al. 1987) whereas the increase in synaptic dopamine produced by cocaine is via reuptake blockade and is therefore impulse dependent. One possibility for the failure of U69593 to attenuate drug seeking produced by amphetamine is that kappa-opioid receptor agonists interact with the presynaptic site that is specific to cocaine. In order to test this hypothesis, the effects of U69593 on cocaine seeking produced by the dopamine transporter inhibitor GBR 12909 (Anderson 1989; Baldo and Kelley 1991), or the cocaine analogs, WIN 35,428 (Boja et al. 1990; Izenwasser et al. 1993) and RTI-55 (Carroll et al. 1991; Little et al. 1993) and cocaine were compared.

Materials and methods

Apparatus Self-administration tests were conducted in experimental chambers (Med Associates, ENV-001) equipped with two levers. Depression of one lever (the “active” lever) resulted in a 12.0-s IV infusion (0.1 ml). Depression of the other lever (the “inactive” lever) was without programmed consequence. Coincident with drug infusions was the illumination of a stimulus light located above the active lever. Rats were maintained in their home cages in the animal facility until testing. Immediately prior to each daily test session, the catheters were flushed with 0.1 ml of the heparin-penicillin-streptokinase solution and the exposed stainless steel tubing was attached to a length of microbore tubing that was connected through a swivel apparatus to a 20 ml syringe housed in a mechanical pump (Razel, Model A with 1 rpm motor) which delivered the drug. Drug delivery and data acquisition were controlled by an interfaced microcomputer using the OPN software package (Spencer and Emmett-Oglesby 1985). Training Acquisition of cocaine self-administration was conducted during daily 2-h sessions. Every session began with an experimenter-delivered infusion of drug. Thereafter, each depression of the active lever (FR1 reinforcement schedule) resulted in an automatic infusion of cocaine (0.5 mg/kg per infusion) paired with a stimulus light located directly above the active lever. The criterion for acquisition of drug self-administration consisted of at least (1) 30 reinforced responses during the 2-h session (15 mg/kg cocaine) and (2) a 2:1 ratio of active:inactive lever responses for a minimum of 3 days. Following acquisition, the response requirements were increased to FR5. Daily 2-h sessions were conducted until there was less than 20% variation in active lever responses on 3 consecutive days.

Subjects Adult male Sprague-Dawley rats (Harlan, Tex., USA) weighing 325–350 g were used. Rats were housed individually in standard hanging polycarbonate cages in a temperature and humidity controlled animal housing facility at Texas A&M University. The colony is accredited by the American Association for the Accreditation of Laboratory Animal Care (AALAC) and was maintained on a 12-h light/dark cycle (lights on at 0800 hours). All tests were conducted during the light portion of the cycle (beginning at 0900 hours). Food and water were available ad libitum except during testing. Principles of laboratory animal care were followed (NIH publication NO. 85-23, rev. 1996). Surgery Rats were implanted with a Silastic catheter in the external jugular vein under deep anesthesia produced by separate IP injections of ketamine (60.0 mg/kg) and pentobarbital (20.0 mg/kg). The external jugular vein was isolated and the tubing was inserted and fixed in place. The distal end of the tubing was passed subcutaneously to an exposed portion of the skull and fitted onto a 2 cm length of 22 ga stainless steel tubing which was then attached to the skull using jeweler’s screws embedded in acrylic dental cement. Some rats also received an intracerebroventricular cannula (22 ga outer diameter, Plastics One, Roanoke, Va., USA). These cannulae were implanted stereotaxically at the same time as the IV catheters. They were plugged with an obturator that extended 1.0 mm below the tip. Testing began 5–7 days following surgery. Each day following surgery the catheters were infused with 0.1 ml of a sterile saline solution containing heparin (1.25 IU/ml), penicillin G potassium (250 000 IU/ml), and streptokinase (8000 IU/ml) to maintain catheter patency and to prevent infection and the formation of clots and fibroids.

Effect of U69593 on cocaine-, GBR 12909-, WIN 35,428and RTI-55-produced cocaine seeking Once responding on the FR5 schedule was stable, the influence of experimenter-administered drug primes upon drug seeking was measured. The test was conducted in a single day and consisted of three phases. The first phase, drug self-administration, consisted of a 1-h period of cocaine self-administration (0.5 mg/kg per infusion, FR5). During the next phase, the extinction phase, the drug syringe was replaced with one containing saline and responding was measured for 3 h. During this phase the stimulus light continued to illuminate under an FR5 schedule, but only saline was infused. At the start of the third phase, the reinstatement phase, separate groups of rats (n=4–8 per group) received an injection of U69593 (0.0 or 0.32 mg/kg, SC) 15 min prior to an injection of cocaine (5.0, 10.0, 20.0 or 40.0 mg/kg, IP), the dopamine uptake inhibitor, GBR 12909 (0.0, 3.0, 10.0 or 30.0 mg/kg, IP), or the cocaine analogs, WIN 35,428 (0.1, 0.3, 1.0 or 3.0 mg/kg, IP) or RTI-55 (0.0, 0.05, 0.1 or 0.5 mg/kg, IP). This dose of U69593 was chosen based on our previous study that indicated an attenuation of cocaine seeking following pretreatment with this dose as well as with a lower dose of 0.16 mg/kg (Schenk et al. 1999). Higher doses of U69593 were not tested since there was concern about loss of specificity of this compound for the kappa-opioid receptor (Spanagel et al. 1990). During this phase, active lever responses continued to produce an infusion of saline and the light stimulus according to an FR5 schedule of reinforcement. The number of responses on the lever that had previously been associated with cocaine self-administration was measured during 3 (cocaine, GBR 12909 and WIN35428) or 6 (RTI-55) hours. The extended period of testing was conducted following administration of RTI-55, since our preliminary tests had indicated a delayed onset of action of this drug. Each rat was tested only once. A high percentage of rats that were treated with the 40.0 mg/kg dose of cocaine, in combination with

87 either the vehicle or 0.32 mg/kg dose of U69593, died following treatment. Therefore, data from the surviving rats were not used in any analyses. Additional groups (n=4–6) received an infusion of the kappa-opioid antagonist, nor-binaltorphimine (nor-BNI, 0.0 or 30.0 µg, ICV) 24 h prior to the start of reinstatement test (Portoghese et al. 1987). For these infusions, the dummy cannula was removed and an inner cannula (27 ga, Plastics One) that extended 1.0 mm below the tip of the 22 ga outer cannula was inserted. The drug was infused through a 10.0 µl Hamilton syringe via a Harvard Apparatus PA 22 microinfu-

sion pump. Infusions were delivered over a period of 3.0 min and the cannula remained in place for an additional minute to allow diffusion of the drug. On the test day, rats received an injection of U69593 (0.0 or 0.32 mg/kg, SC) 15 min prior to an injection of cocaine (0.0 or 20.0 mg/kg, IP) at the start of phase 3. As above, responding was measured for 3 h following the cocaine injection. Drugs Cocaine-HCl and nor-BNI (NIDA) were dissolved in a sterile saline vehicle. GBR 12909 (MDD, NIDA), WIN 35,428 (NIDA) and RTI-55 (NIDA) were dissolved in sterile distilled water. U69593 (NIDA) was dissolved in an aqueous solution of 25% propylene glycol. Intravenous infusions were in a volume of 100 µl, IP and SC injections were given in a 1.0 ml/kg volume and ICV injections were delivered as described above. All drug doses were calculated based on salt weights. Data analyses Responses on the lever that had previously resulted in an infusion of drug were recorded for each hour of phase 3. The total number of responses and/or the number of responses produced during each hour of phase 3 were analyzed separately using analysis of variance (ANOVA; Dose U69593×Dose test drug) followed by the Tukey-HSD post hoc analysis where appropriate. Data are expressed as the average number of responses+SEM.

Results

Fig. 1 Mean (+SEM) number of responses during phases 1 and 2 for a representative group of rats (n=6). Responding during phase 1 was reinforced on an FR5 schedule by an infusion of cocaine. During phase 2, the cocaine solution was replaced with saline and extinction responding was monitored for 3 h Fig. 2 Mean (+SEM) number of responses per hour following injections of cocaine (top panels), GBR12909 (middle panels), or WIN 35,428 (bottom panels) for rats that were trained to self-administer cocaine and were pretreated with U69593. During the first hour of testing, cocaine-produced reinstatement was attenuated by pretreatment with U69593 (P<0.05). No other significant effects of U69593 were produced

All groups demonstrated high responding during the initial hour of drug self-administration and responding extinguished so that fewer than 20 responses were produced during the last hour of the second phase. Data from phases 1 and 2 for a representative group of rats from the present study are shown in Fig. 1.

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Fig. 4 Mean (+SEM) number of responses in the first hour following injection of cocaine. Pretreatment with U69593 (0.32 mg/kg) 15 min prior to cocaine attenuated cocaine-produced reinstatement and this attenuation was reversed in groups that received nor-BNI (30 µg, ICV) 24 h prior to injections of U69593. *P<0.05 Fig. 3 Mean (+SEM) number of responses per hour following an injection of RTI-55 for rats that were trained to self-administer cocaine and were pretreated with U69593. During hours 5 and 6 of testing, RTI-55-produced reinstatement was attenuated by pretreatment with U69593 (P<0.05)

Effects of U69593 on cocaine seeking Figure 2 presents the number of responses following injections of cocaine (top panels), GBR 12909 (middle panels) and WIN 35,428 (bottom panels) as a function of time during the 3-h period that comprised phase 3. The ability of cocaine to reinstate extinguished cocaine-taking behavior was restricted primarily to hour 1 of the test (top panels). The time course for the effects of GBR 12909 and WIN 35,428 was longer. The cocaine-produced effects were attenuated by pretreatment with U69593 during hour 1 [F(1,18)=9.802, P=0.006]. However, U69593 failed significantly to attenuate effects of any doses of GBR 12909 or WIN 35,428 at any of the three time periods (P>0.05). Figure 3 shows the number of responses produced during each of the 6 h following the injection of RTI-55 to rats that had received pretreatment with either vehicle or U69593. There were minimal effects of RTI-55 during the first 2 h following its administration. However, during hours 3–6, there was an increase in responding by control rats administered 0.1 mg/kg (hours 3 and 4) or 0.5 mg/kg (hours 4, 5 and 6). Individual ANOVAs (Dose U69593×Dose RTI-55) on the data from each hour of the test revealed a significant reduction of responding produced by U69593 during hours 5 [F(1,34)=7.744, P=0.009] and 6 [F(1,34)=7.692, P=0.024].

Figure 4 presents the mean “active” lever responses of rats that received combinations of nor-BNI, U69593 and cocaine prior to the start of phase 3. Because the number of responses produced by cocaine peaked at the first hour and then returned to baseline levels, data are presented only for the first hour following the injection of cocaine. Cocaine produced an increase in responding [F(1,10)=9.346, P<0.05] that was attenuated by prior administration of U69593 [F(1,15)=4.794, P<0.05]. The U69593-produced attenuation of cocaine seeking was reversed by prior administration of nor-BNI [F(1,35)= 4.835, P<0.05].

Discussion Following extinction of cocaine self-administration, experimenter-administered injections of either cocaine, the dopamine transporter inhibitor, GBR 12909 or the cocaine analogs, WIN 35,428 and RTI-55, produced a dose-dependent reinstatement of extinguished cocainetaking behavior. Pretreatment with the kappa-opioid receptor agonist, U69593 (Lahti et al. 1985), attenuated cocaine- and RTI-55-produced reinstatement of responding but failed to attenuate the effects of GBR 12909 or WIN 35,428. The attenuation of cocaine-produced cocaine seeking produced by prior administration of U69593 was blocked when rats were pretreated with the specific kappa-opioid antagonist, nor-BNI (Portoghese et al. 1987), suggesting that the effect is mediated by an action of U69593 at central kappa-opioid receptors. We previously reported a specific effect of U69593 on cocaine-produced reinstatement of responding (Schenk

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et al. 1999); amphetamine-produced reinstatement was not altered by pretreatment with the kappa-opioid receptor agonist. Other studies have also suggested that U69593 produced effects specific to cocaine. For example, rats that received pretreatment with either morphine or cocaine were subsequently sensitized to the ability of these drugs to produce a conditioned place preference (Shippenberg and Heidbreder 1995; Shippenberg et al. 1996). When U69593 was co-administered with either cocaine or morphine during pretreatment, a blockade of cocaine- but not morphine-induced sensitization was produced (Shippenberg et al. 1998). We reasoned that the specificity of the effect of U69593 on cocaine-produced reinstatement might reflect specific interactions at the dopamine transporter. If so, U69593 should have also attenuated the effects of WIN 35,428 which binds with high affinity to the transporter (Carroll et al. 1992; Deutsch et al. 1999) and displaces cocaine in in vitro studies (Cline et al. 1992; Stathis et al. 1995). However, in the present experiment a dose of U69593 that attenuated cocaine-produced cocaine seeking failed to reduce the ability of WIN 35,428 to reinstate extinguished cocaine-taking behavior. This dose of U69593 also failed to affect GBR 12909-produced reinstatement strengthening the hypothesis that U69593’s effects are not mediated to a significant degree by direct interactions with the dopamine transporter. Interestingly, U69593 attenuated cocaine seeking produced by administration of RTI-55. These data are important for at least two reasons. First, drug seeking produced by RTI-55 was delayed to 4–6 h following administration. In spite of the delayed onset of action, U69593 attenuated the reinstating effects of RTI-55 produced during hours 5 and 6. These data argue against the possibility that the failure to observe effects of U69593 on GBR 12909- or WIN 35,428-produced cocaine seeking was due to inadequate dosing or a limited duration of action of U69593. Second, since RTI-55 and cocaine share the ability to inhibit uptake at serotonergic transporters with greater affinity than the ability to inhibit uptake at dopaminergic transporters (Boja et al. 1992), the data raise the possibility that U69593 may attenuate drug seeking produced by low doses of experimenter-administered drugs via interactions with serotonergic mechanisms. Recent data have suggested that serotonergic mechanisms may be critical to cocaine seeking. For example, depletions produced by either 5,7-DHT lesions or p-CPA (Tran-Nguyen et al. 1999a, 1999b) altered cocaine-produced cocaine seeking. An interaction between kappaopioid agonists and serotonergic mechanisms has been proposed in kappa-opioid produced analgesia (Vonvoigtlander et al. 1984; Ho and Takemori 1990) and kappaopioid receptors are localized on serotonergic neurons (Kalyuzhny and Wessendorf 1999). Tests are underway to determine whether these kappa-opioid/serotonin interactions underlie the ability of U69593 to attenuate cocaine seeking. Acknowledgement This research was supported by DA 10084.

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