Psychopharmacology (1999) 145:227–233

© Springer-Verlag 1999

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

Karen K. Szumlinski · Isabelle M. Maisonneuve Stanley D. Glick

Pretreatment with the putative anti-addictive drug, ibogaine, increases the potency of cocaine to elicit locomotor responding: a study with acute and chronic cocaine-treated rats Received: 19 December 1998 / Final version: 2 March 1999

Abstract Rationale: Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. Objectives: To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. Methods: Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). Results: Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. Conclusions: These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal. Key words Ibogaine · Cocaine · Dose-response · Locomotor activity · Sensitization · Rat

Introduction The naturally occurring indole alkaloid, ibogaine, is being investigated currently for its anti-addictive properties K.K. Szumlinski (✉) · I.M. Maisonneuve · S.D. Glick Department of Pharmacology and Neuroscience (A-136), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA e-mail: [email protected] Fax: +1-518-262-5799

(Cappendijk and Dzoljic 1993; Glick et al. 1994; Rezvani et al. 1995). Both human anecdotal reports and preclinical studies indicate that a single dose of ibogaine can produce prolonged decreases in the self-administration of a wide variety of drugs of abuse, including cocaine, morphine, nicotine and alcohol (Glick et al. 1991, 1994; Cappendijk and Dzoljic 1993; Sheppard 1994; Rezvani et al. 1995). Receptor binding studies demonstrate that ibogaine binds with moderate affinity to kappa opioid receptors (Pearl et al. 1995a), the NMDA subtype of glutamate receptor (Popik et al. 1995) and the serotonin transporter (Mash et al. 1995). Noribogaine (12-hydroxyibogamine), the only known metabolite of ibogaine (Hearn et al. 1995), also appears to have affinity for these same receptors (cf. Glick and Maisonneuve 1998). Given the complex receptor binding profile for ibogaine and its metabolite, the precise neural mechanism(s) underlying ibogaine’s putative anti-addictive effects are unclear. However, in vivo microdialysis studies have demonstrated that ibogaine affects the dopaminergic responses in the nucleus accumbens to many drugs of abuse (Maisonneuve and Glick 1992; Maisonneuve et al. 1992a,b; Glick et al. 1993, 1994), actions which may mediate ibogaine’s effects on the rewarding properties of abused drugs (e.g., Fibiger and Phillips 1986; Wise and Bozarth 1987; Koob 1992). Consistent with the many implications for accumbal dopamine transmission in expression of drug-induced locomotion (e.g., Pijnenburg et al. 1975; Broderick 1991; Kuczenski et al. 1991; Camp et al. 1994; Heidbreder and Feldon 1998), ibogaine also alters drug-induced locomotor behavior in both mice (Sershen et al. 1992) and rats (Maisonneuve and Glick 1992; Maisonneuve et al. 1992a,b, 1997; Pearl et al. 1995b; Blackburn and Szumlinski 1997; Szumlinski et al. 1998). The effects of ibogaine on locomotion appear to depend on a number of factors, including the type and dose of drug administered (e.g., Maisonneuve and Glick 1992; Pearl et al. 1995b, 1997), the species studied (e.g., Sershen et al. 1994; Blackburn and Szumlinski 1997; Szumlinski et al. 1999), the sex of the animal (Pearl et al. 1997), the time after

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ibogaine injection (Maisonneuve and Glick 1992; Broderick et al. 1994; Maisonneuve et al. 1997) and the previous drug history of the animal (Pearl et al. 1995b; Blackburn and Szumlinski 1997; Szumlinski et al. 1999). With respect to the latter factor, evidence suggests that prior drug experience may enhance an animal’s sensitivity to the effects of ibogaine on drug-induced behavior. For example, ibogaine produces a greater decrease in morphine-induced locomotion in rats chronically treated with morphine, compared to acutely treated controls (Pearl et al. 1995b). In addition, recent studies using cocaine have demonstrated that ibogaine enhances locomotor responding to a low dose of cocaine (7.5 mg/kg) in rats treated chronically, but not acutely, with this stimulant (Szumlinski et al. 1999). To extend these recent findings, the present study assessed the effect of ibogaine pretreatment (19 h earlier) on the dose-response function for cocaine-induced locomotion in chronic and acute cocaine-treated rats.

Materials and methods Subjects Female (200–225 g) Sprague-Dawley rats (Taconic, Germantown, N.Y., USA) were housed in groups of four and allowed food and water ad lib. The animals were maintained on a 12-h light cycle (lights on at 0700 hours) in a room carefully controlled for heat and humidity. All testing began at approximately 1000 hours. Apparatus Locomotion was studied in cylindrical (60 cm) photocell activity cages with three intersecting light beams. The photocells were located equidistantly from each other around the circumference of the cage, 3 cm above the floor. Each time a light beam was broken a single activity count was recorded by a 386 PC computer with Med Associates software. To reduce the probability of misinterpreting repetitive or movements in front of a photocell as locomotion, single activity counts were only recorded by the computer if two light beams were broken in succession. Drugs Cocaine hydrochloride (Sigma Chemical Co., St Louis, Mo., USA) was dissolved in 0.9% saline and injected IP at a volume of 1.0 ml/kg. Cocaine was administered at a dose of 15 mg/kg for the chronic treatment phase of the study and doses of 0, 5, 10, 20 and 40 mg/kg for the dose-response tests for sensitization. Ibogaine hydrochloride (40 mg/kg; Sigma Chemical Co.) was dissolved in MilliQ water and injected IP at a volume of 2.0 ml/kg. Design and procedure Based on their initial locomotor response to a saline challenge (1 ml/kg; 2-h session, conducted 1–2 days prior to chronic treatment), rats were randomly assigned to chronic treatment groups such that the groups had equivalent baseline activity levels prior to any drug administration. For chronic treatment, rats received five daily injections of either cocaine (15 mg/kg) or saline and locomotor behavior was monitored for 2 h. Prior to each chronic treatment injection, animals were habituated to the activity cages for 30 min following an injection of saline. Following the fifth chron-

ic treatment injection, animals were withdrawn from treatment for 2 weeks. On the last day of withdrawal, rats were randomly assigned to receive a pretreatment injection of either ibogaine (40 mg/kg) or vehicle. Nineteen hours later, the first dose-response test for sensitization was conducted. On this test, rats received one of five cocaine doses (0, 5, 10, 20 or 40 mg/kg) and locomotor behavior was monitored for 2 h. Again, a 30-min habituation period preceded the cocaine injection. Assignment to the test dose was random, except that groups had equivalent mean locomotor performances on injection 5 of chronic treatment. Twentyfour hours following the first dose-response test, rats originally receiving ibogaine pretreatment were pretreated with vehicle and vice versa. Nineteen hours following the second pretreatment, a second, identical dose-response test was conducted (i.e., rats were habituated and then received the same dose of cocaine as on the first test). The order of ibogaine/vehicle pretreatment was counterbalanced across both chronic treatment groups and cocaine test doses. For each injection day, rats were transported from their colony room to an experimental room where they were weighed and then injected with saline. Rats were immediately placed in activity cages after each injection. After 30 min, animals were removed from the activity cages, injected with the appropriate dose of saline or cocaine and then returned to the activity cage where they remained for 2 h. The only exception to this injection protocol was the ibogaine pretreatment injections, when animals were weighed and injected in the colony room. Statistical analysis For chronic treatment, data were examined for main effects by analysis of variance (ANOVA) for Chronic treatment (cocaine versus saline) and Injection number (1–10). For the dose-response tests, data were examined for main effects by ANOVA for Chronic treatment, Dose (0, 5, 10, 20, 40 mg/kg cocaine) and Pretreatment (ibogaine versus vehicle). If there were significant effects, the data were decomposed and least significant difference (LSD) post hoc tests were performed (Statistica).

Results Chronic treatment Chronic cocaine administration (15 mg/kg, daily for 5 days) induced high levels of locomotor responding on all injections, compared to animals repeatedly injected with saline [main effect of Chronic treatment, F(1,4)= 245.14, P<0.0001]. However, the locomotion expressed after cocaine did not change as a function of the number of injections [no main effect of, or interaction with, Injection number, P>0.05] (Fig. 1, main figure), indicating a lack of locomotor sensitization by injection 5 of chronic cocaine treatment. The locomotor response to saline of both chronic treatment groups during the 30-min habituation sessions habituated across injections [main effect of Injection number, F(4,312)=18.54, P<0.0001; no Chronic treatment by Injection number interaction, P>0.05]. As can be observed in Fig. 1 (insert), chronic cocaine animals displayed augmented responses to saline on injections 2–5 [main effect of Chronic treatment, F(1,78)=15.01, P<0.0002; LSD post-hoc tests]. This phenomenon was observed in the absence of any difference in the locomotor responses between the two chronic treatment groups

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Fig. 1 Main figure: total locomotor response in 2 h of animals treated daily with either saline (circles) or 15 mg/kg cocaine IP (squares). Insert: total locomotor response of chronic treatment groups during the 30-min saline habituation sessions which preceded each daily treatment injection. Each point represents the mean number of beam breaks (±SEM) of 40 rats for the times indicated. *P<0.05, compared to chronic saline animals, +P<0.05, compared to the first injection (LSD post-hoc tests)

on either the 2-h saline session prior to the commencement of chronic treatment [no main effect of Chronic treatment, P>0.05; data not shown] or the 30-min habituation session prior to injection 1 of chronic treatment (LSD post-hoc tests).

Fig. 2 Main figure: Composite of the effects of ibogaine (40 mg/kg IP, 19 h earlier; closed symbols) or vehicle (open symbols) pretreatment on the dose-response curve for total locomotion induced by cocaine (0, 5, 10, 20, 40 mg/kg IP) in animals treated chronically with either saline (circles) or cocaine (5×15 mg/kg IP, daily; squares). Error bars were omitted for clarity. Data represent the mean number of beam breaks of eight rats in 2 h. Insert: effects of ibogaine (40 mg/kg IP, 18.5 h earlier) on the locomotor response to saline during the pre-test habituation sessions. Each bar represents the mean number of beam breaks in 30 min (±SEM) of 20 animals. Clear bar, Sal-Veh, hatched bar, Sal-Ibo, crosshatched bar, Coc-Veh, gray bar, Coc-Ibo. *P<0.05, compared to respective vehicle-pretreated controls, +P<0.05, compared to saline-vehicle animals (LSD post-hoc tests)

Cocaine (0, 5, 10, 20 and 40 mg/kg) induced dosedependent effects on locomotion in all treatment groups on the test for sensitization conducted 2 weeks following the cessation of chronic treatment [main effect of dose, F(4,70)=28.63, P<0.0001] (Fig. 2, main). As can be observed in Fig. 2 (main; for clarity see also Table 1), a comparison of the dose-response functions for cocaineinduced locomotor responding between the two vehiclepretreated groups demonstrated that chronic cocaine

treatment produced an overall shift to the left in the cocaine dose-locomotor response function in chronic cocaine-treated rats, compared to rats chronically treated with saline [main effect of Chronic treatment, F(4,70)= 4.22, P=0.044], indicating the presence of sensitization on the test day. Inspection of Fig. 2 (main) reveals that the cocaine dose-locomotor response relationship was influenced by ibogaine pretreatment; ibogaine pretreatment significantly augmented that locomotor response to cocaine in rats treated chronically with either cocaine or saline [Dose by Pretreatment interaction, F(4,70)=3.18, P<0.02]. The effect of ibogaine pretreatment on the cocaine dose-locomotor response relationship dissipated between 19 and 43 h after ibogaine administration as revealed by no significant main effects or interaction with pretreatment or-

Table 1 Individual comparisons between ibogaine pretreatment groups on the dose-response test for sensitization conducted following chronic treatment with either cocaine or saline. Each

data entry represents the mean number of beam breaks (± SEM) of 8 rats in 2 h. *P<0.05, compared to respective vehicle-pretreated controls, +P<0.05, compared to saline-vehicle animals

Effects of ibogaine pretreatment on the dose-response curve for cocaine-induced locomotion in acute and chronic cocaine-treated rats

Treatment group Sal-Veh Sal-Ibo Coc-Veh Coc-Ibo

Test dose of cocaine (mg/kg) 0

5

10

20

40

133.63±16.65 135.63±19.26 395.50±162.00 559.50±298.61

338.00±61.31 967.13±291.73 958.13±204.07 1252.63±350.43+

1392.38±152.64 1926.13±330.98 1911.25±392.29 2337.75±345.39+

2194.78±281.85 3256.33±526.30* 3350.88±414.04 3434.25±467.67+

2532.00±464.94 2278.29±466.50 2525.63±568.70 1601.63±350.85*+

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der on locomotor responding to the test doses for either chronic treatment group (P>0.05). For chronic saline rats, post-hoc analysis demonstrated that the only significant difference between the two groups occurred at the 20 mg/kg test dose of cocaine (LSD post-hoc tests). Inspection of Fig. 2 (main) reveals that the dose-response functions for chronic salineibogaine pretreated (closed circles) and chronic cocainevehicle pretreated (open squares) animals are virtually identical, demonstrating that ibogaine pretreatment alone can produce a similar enhancement of cocaine-induced locomotion as that produced by chronic cocaine treatment. Overall, the effect of ibogaine pretreatment on the cocaine dose-locomotor response relationship did not differ as a function of prior cocaine experience [no Chronic treatment by Pretreatment interaction; no Dose by Chronic treatment by Pretreatment interaction, P>0.05]. In contrast to chronic saline-treated rats, the locomotor response to 20 mg/kg cocaine in chronic cocaine-treated animals was virtually identical between the two pretreatment groups (Table 1). However, ibogaine-pretreated chronic cocaine rats displayed less locomotor activation to the 40 mg/kg test dose, compared to their vehicle-pretreated controls (LSD post-hoc tests) (Table 1). As can be observed from Fig. 2 (main), ibogaine pretreatment enhanced the expression of locomotor sensitization to cocaine in chronically treated rats. Comparing the locomotor responses of the chronic saline-vehicle-pretreated group (open circles) with those of the chronic cocaineibogaine-pretreated group (closed squares) revealed that locomotor sensitization was expressed at 5, 10 and 20 mg/kg cocaine. In addition, chronic cocaine ibogainepretreated animals displayed less locomotion in response to 40 mg/kg cocaine (LSD post-hoc tests), indicating that ibogaine can also potentiate the locomotor attenuating effects of higher doses of cocaine in chronic cocainetreated rats. In contrast to ibogaine’s potentiating effects on cocaine-induced behavior observed on the dose-response tests for sensitization, ibogaine pretreatment decreased the amount of locomotion expressed during the 30-min pre-test habituation sessions by both chronic treatment groups [main effect of Pretreatment, F(2,78)=20.52, P<0.0001]. As depicted in Fig. 2 (insert), vehicle-pretreated chronic cocaine animals still displayed an augmented response to saline; their locomotor activity was greater than that of the other groups tested [main effect of Chronic treatment, F(1,78)=9.03, P=0.004; LSD posthoc tests]. However, ibogaine pretreatment reversed this effect, bringing the level of locomotor responding to saline down to the level of the chronic saline groups (LSD post-hoc tests).

Discussion Present findings show that pretreatment (19 h earlier) with the putative anti-addictive compound, ibogaine

(40 mg/kg), augments cocaine-induced locomotion in animals treated chronically with either cocaine (five injections of 15 mg/kg) or saline. Ibogaine pretreatment produced virtually identical effects on the acute dose-response curve as that produced by chronic cocaine administration. This indicates that a single ibogaine pretreatment can potentiate the level of locomotor responding of cocaine-naive animals to that of animals with chronic cocaine experience. As predicted, given that the doseresponse function for cocaine-induced locomotion is inverted U-shaped (e.g., Kalivas et al. 1988; O’Dell et al. 1996; Browman et al. 1998), ibogaine pretreatment did not alter the locomotor response of chronic cocainetreated animals to 20 mg/kg and ibogaine-pretreated chronic cocaine rats displayed less locomotor stimulation in response to 40 mg/kg, compared to vehicle-pretreated chronic cocaine controls. The latter finding is consistent with previous studies using amphetamine in rats (Blackburn and Szumlinski 1997), which also demonstrated that ibogaine pretreatment decreased stimulant-induced locomotion in chronically treated animals. Consistent with the results of single dose studies (Szumlinski et al. 1999), chronic cocaine animals pretreated with ibogaine displayed locomotor sensitization to cocaine doses which did not elicit sensitized levels of locomotor responding in vehicle-pretreated controls (e.g., 5 and 10 mg/kg). This finding indicates that ibogaine pretreatment enhances the expression of cocaineinduced locomotor sensitization in chronic cocaine-treated animals. This effect does not appear to depend either on a selective effect of ibogaine on undrugged locomotion in chronic cocaine treated animals or on an ibogaine-induced potentiation of the conditioned locomotor effects of cocaine. This statement is supported by the observations that, during the pre-test habituation sessions, ibogaine pretreatment: 1) decreased the locomotor response to saline in both chronic treatment groups; and 2) lowered the augmented response to saline observed in the chronic cocaine rats to that of the chronic saline controls. Combined, present findings demonstrate that although ibogaine pretreatment attenuates the expression of undrugged locomotion, and perhaps, conditioned locomotion, it definitively increases an animal’s sensitivity to the locomotor effects of cocaine. Based on the observation that ibogaine pretreatment attenuated amphetamine-induced locomotion in animals treated chronically, but not acutely, with this stimulant, Blackburn and Szumlinski (1997) proposed that ibogaine’s anti-addictive efficacy may be related to this compound’s ability to reverse the neuroadaptations produced by chronic amphetamine administration (e.g., Robinson and Becker 1986; Kalivas and Stewart 1991; Robinson and Berridge 1993; Stewart and Badiani 1993). However, previous (Szumlinski et al. 1999) and present results demonstrate that ibogaine potentiates, rather than attenuates, the locomotor-sensitizing effects of cocaine. The repeated administration of amphetamine and/or cocaine also sensitizes the expression of stereotypic behaviors (e.g., Downs and Eddy 1932; Hitzemann et

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al. 1977; Post and Contel 1983; Kuczenski et al. 1991; Wolgin 1995) and the expression of many stereotypic behaviors is physically incompatible with the expression of locomotion (e.g., Glick 1972). That ibogaine-pretreated chronic cocaine rats displayed lower levels of locomotor activation, compared to vehicle-pretreated animals, at the highest cocaine dose tested suggests that, at higher cocaine doses, ibogaine might also potentiate the expression of cocaine-induced stereotypy. Numerous theories of drug addiction implicate a role for associations between drug effects and environmental cues in the mediation of drug self-administration, drug craving and relapse during drug abstinence (e.g., Robinson and Berridge 1993; Berridge and Robinson 1998; Kalivas et al. 1998). Although the effects of ibogaine on conditioned locomotion were not systematically investigated in this study, present evidence does indicate that the chronic cocaine treatment regimen used in this study produced conditioned locomotion during chronic cocaine administration (as reflected by augmented responding to saline during the habituation sessions prior to injections 2–5 and prior to the dose-response test for sensitization) and that ibogaine pretreatment reversed this effect. This finding is particularly interesting given that anecdotal reports suggest that this compound is remarkably effective at blocking drug craving and relapse for several months up to years in humans (e.g., Sheppard 1994). That the observed effect of ibogaine on conditioned locomotor sensitization reflects a general disruption of associative processes does not appear likely given that ibogaine pretreatment (40 mg/kg, 24 h prior) does not interfere with the expression of a conditioned taste-preference in rats (Blackburn and Szumlinski 1997). Several findings are relevant to an understanding of the increase in ibogaine’s efficacy on cocaine-induced locomotor behavior produced by chronic cocaine administration. Chronic cocaine treatment typically causes an enduring increase in extracellular levels of dopamine in the nucleus accumbens and the striatum (e.g., Pettit et al. 1990; Weiss et al. 1992; Kalivas et al. 1993; Heidbereder et al. 1996), an effect which presumably mediates the locomotor sensitizing effects of cocaine, and other stimulant drugs (for reviews, see Kalivas and Stewart 1991; Kalivas et al. 1993). Ibogaine potentiates the dopaminergic response to acute injections of both cocaine (Maisonneuve and Glick 1992) and amphetamine (Maisonneuve et al. 1992) in these two regions. Thus, it is possible that the effects of ibogaine on the dose-response function for cocaine-induced locomotion in chronic cocaine-treated animals reflects the additive effects of an ibogaine-induced potentiation of the dopaminergic response to cocaine and increased extracellular levels of dopamine produced by chronic cocaine administration. Alternatively, chronic cocaine administration is known to up- or down-regulate several receptors for which ibogaine and its active metabolite, noribogaine, show moderate binding affinity (Mash et al. 1995; Pearl et al. 1995a; Popik et al. 1995; Glick et al. 1997). For example, chronic cocaine administration has been demon-

strated to produce either up- (Staley et al. 1997) or down-regulations (Spangler et al. 1996, 1997) of kappa opioid receptors and/or kappa opioid receptor mRNA. Additionally, some evidence suggests that both NMDA receptors (Itzak 1994) and serotonin transporters (Belej et al 1996; Burchett and Banon 1997) can be up-regulated by chronic cocaine administration. It is possible that such changes were produced by the chronic cocaine treatment regimen used in the present study, thereby enhancing ibogaine’s efficacy in chronic cocaine-treated animals. Lastly, differences in ibogaine’s ability to potentiate responding to cocaine between acute and chronic cocaine-treated animals may reflect differences in pharmacokinetic interactions between these two compounds in cocaine-experienced and naive animals. Although it is not known whether ibogaine decreases cocaine metabolism, as it does amphetamine metabolism (Glick et al. 1992), Szumlinski et al. (1999) demonstrated that ibogaine pretreatment alters the time-course of cocaine-induced in chronic, but not acute, cocaine-treated rats, in a manner consistent with a slowing of cocaine metabolism. That chronic cocaine administration is known to decrease cocaine metabolism (Nayak et al. 1976; Estevez et al. 1977; Reith et al. 1987) may account, in part, for the differential effects of ibogaine on cocaine-induced locomotion in animals treated chronically versus acutely with cocaine. In conclusion, the present results demonstrate that ibogaine augments cocaine-induced locomotion in both acute and chronic cocaine-treated rats. In cocaine-naive animals, ibogaine pretreatment increases the level of cocaine-induced locomotor responding to that of cocaine sensitized controls; in cocaine-experienced animals, this same pretreatment further enhances sensitivity to cocaine. Given that the psychomotor stimulant effect of high doses of cocaine can be aversive (Cohen 1975), it is proposed that ibogaine’s putative anti-addictive property may be related to an ability to increase the aversiveness of cocaine in chronic cocaine users. Acknowledgement This study was supported by NIDA grant DA 03817.

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