- Email: [email protected]
Amantadine: evaluation of reinforcing properties and effect on cocaine self-injection in baboons
Drug and Alcohol Dependence, 21(19881195- 202 Elsevier Scientific Publishers Ireland Ltd.
Amanta~ine: evaluation of reinforcing properties and effect on cocaine self-injection in baboons Christine
A. Sanneruda and Roland R. Griffithsasb
“Department of Psychiatry and Behavioml Sciences and 9epartment of Neuroscience, The Johns Hopkins University School of Medicine, 720 Rutland Ave., 62.9 Traylor, Baltimore, MD 21205 I7LJ.S.A.J (Received November 10th. 19871
The ability of amantadine to maintain self-injection behavior and to alter self-administration of cocaine was examined in baboons using a standard intravenous cocaine self-injection procedure. Responding was maintained under a FR 80- or 160response schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h timeout allowing a maximum of 8 injections/day. Vehicle or amantadine doses were substituted for cocaine for a period of 15 or more days. Evaluation of a wide range of amantadine doses (0.32-32 mgkg per injection1 showed that this compound did not maintain self-administration behavior above vehicle control levels. In another experiment using the cocaine self-injection baseline, amantadine (10 or 32 mg/hg per day1 was administered via a chronic intravenous infusion. Cocaine self-injection behavior was maintained and reinitiated during chronic amantadine exposure, suggesting that the reinforcing efficacy of cocaine was not modified by chronic amantadine administration. Key words: amantadine; cocaine: self-administration; baboon
Introduction Cocaine abuse in the U.S.A. has increased dramatically in the past decade and has become a major medical and public health concern [l]. The resulting priority for research on cocaine has led to increased exploration of the pharmacological mechanisms of cocaine’s reinforcing and behavioral effects as well as to increased interest in developing pharmacological approaches to treatment intervention. A large body of data exists that provides evidence for the hypothesis that the reinforcing properties of cocaine are mediated through central monoaminergic systems [2,3]. Since cocaine produces a variety of CNS disruptions (cf. Refs. 3-51, it has been further suggested that related pharmacological changes may be the basis of a withdrawal syndrome that has been reported by abstinent cocaine abusers (e.g. the craving experienced by cocaine abu-
sers may result from the over stimulation and subsequent depletion of dopamine [3,6]). Pharmacological interventions to treat withdrawal have attempted to cocaine counteract this dopamine hypofunetion and alleviate withdrawal symptoms by using a variety of agents that increase dopamine’s actions (see review, Ref. 3). Because of the appearance of major side effects, some of these compounds have been used with limited success [7,8]. Recently, there have been preliminary clinical reports that amantadine (100 mg, b.i.d.1, an agent with indirect dopamine agonist properties and without some of the side effects reported for dopamine agonist treatments, has been used with some success to treat cocaine dependence f7]. Amantadine is an anti-Parkinsonianiantiviral agent that may have anti-cholinergic effects [9] and is thought to act by augmenting the release of dopamine and other catecholamines from
0376~8716/38/$03.50 0 1988 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland.
196
neuronal storage sites and by delaying the reuptake of these neurotransmitters into synaptic vesicles [9,10]. The pharmacological properties of amantadine have been exploited in an effort to control a variety of clinical problems including dementia [ll], the side effects of neuroleptic treatment [12], and, most recently, cocaine dependence [7]. The present set of two experiments was undertaken to characterize the possible reinforcing properties of amantadine and to evaluate its potential use as a pharmacotherapeutic agent for reducing cocaine self-administration. Both experiments utilized intravenous drug self-injection procedures in baboons which have been previously used to evaluate the effects of pharmacological adjuncts of drug self-injection [13] and to characterize the reinforcing effects of compounds from a wide variety of pharmacological classes, including psychomotor stimulant [14- 161, sedativelanxiolytic [17], opioids [18] and dissociative anesthetics [19]. Methods Subjects Six male baboons Cpapio anubiss) weighing between 23 and 26 kg were used as subjects; 3 baboons were used in the study of amantadine self-injection, 4 baboons were used in the study of amantadine’s effect on cocaine self-injection, and 1 baboon was used in both studies of amantadine. Baboons were surgically prepared with chronically indwelling silastic catheters implanted in either femoral, jugular or auxillary veins under pentobarbital or halothane anesthesia using methods described by Lukas et al. [20]. Two animals were drug naive (Baboons CL and GUI and the 4 other baboons had served in studies of intravenous self-administration with a variety of drugs. Animals had continuous access to water via a drinking tube and to food pellets (as described below). Animals received 2 pieces of fresh fruit and a multivitamin (Goldline Fruity Chews) daily. Apparatus Baboons were housed in standard
stainless
steel primate cages with a bench running the length of one wall of the cage. Each cage, which served as the experimental chamber, was surrounded by a sound attenuating double walled plywood external enclosure which was continuously illuminated with a 20-W frosted bulb. The catheter was protected by a harness/vest system that allowed the baboons virtually unrestricted movement within the cage [20]. The infusion system is similar to that described by Findley et al. [21]. The catheter was attached to a valve system that allowed slow continuous administration (approx. 55- 60 ml/24 h) of heparinized saline (5 units/ml) via a peristaltic pump to maintain catheter patency. Drug was injected into the valve system by means of a second pump and then flushed into the animal with 5 ml of saline from a third pump. This system necessitated a delay of approximately 20 s between the onset of drug delivery and actual injection into the vein. Drugs were delivered within a 2-min period. An aluminum ‘intelligence panel’ (0.7 x 1.0 m) containing levers and associated stimulus lights (approx. 1 cm dia.) was mounted on the rear wall of the cage. A Lindsley lever (Ralph Gerbrands Co., No. G6310) (lower left of panel), a leaf lever (lower right of panel), and a food hopper with stimulus light (lower left of panel) were mounted on the panel. A 5 x 5-cm translucent Plexiglas panel that could be transilluminated was mounted on the aluminum panel in the upper left corner. A speaker for delivery of white noise and tones was mounted behind the panel. A feeder (BRS/LVE PDC 050 or Ralph Gerbrands Co. G5210) for delivering food pellets into the food pellet tray was mounted on the top of the wooden enclosure. Procedure for examining amantadine selfinjec t&w2 Animals were trained to self-inject cocaine (0.32 mg/kg per injection) under a fixed ratio 80 or 160 (FR 80 or FR 160) response schedule on the Lindsley lever. Drug injections were available every 3 h and were signaled by a 5-s tone followed by the illumination of the jewel light over the Lindsley lever. When the jewel light was illuminated, each response on the Lindsley
197
lever produced a brief feedback tone. Upon completion of the fixed ratio requirement, the jewel light was extinguished and the 5 ml drug injection was begun, followed by a 5ml flush injection. Following the completion of the injections, the 5 x 5 cm translucent panel was illuminated for a l-h period and the 3-h time-out period was begun. There was no time limit for the completion of the response requirement. There was an exception to this general procedure - the fixed-ratio response requirement for Baboon GI was 80. When criterion cocaine self-injection performance (6 or more injections per day for 3 consecutive days) was obtained, a dose of amantadine or vehicle was substituted for 0.32 mg/kg cocaine for 15 or more days. Occasional equipment malfunction necessitated extending the period of substitution beyond 15 days. Cocaine self-injection performance was reestablished, and when criterion performance was obtained (typically in 3- 5 days), another dose of amantadine was substituted. This procedure of replacing cocaine with amantadine was continued through the study of a range of amantadine doses and its vehicle. The order of exposure to different doses was usually an ascending sequence. There were, however, occasions on which lower doses were examined after higher doses. The drug vehicle was generally examined immediately before or after the series of doses. Food was available 24 h/day under a fixed ratio 30 (FR 301 response schedule on the leaf lever; i.e. every thirtieth response delivered a l-g banana flavored food pellet (either P.J. Noyes or Bio-Serv, Inc.1 and produced a brief flash of the hopper light. fOT eVah5ting the effeC’h Of chronic amantadine administration on cocaine selfinjection A study to assess the ability of amantadine to block or otherwise affect cocaine selfinjection was also conducted. Using the standard cocaine self-injection baseline described above (0.32 mg/kg per injection), 4 baboons were evaluated before and during chronic administration of amantadine (10 or 32 mg/kg
PTOCedUTe
per day). Following the establishment of 0.32 mg/kg cocaine self-injection performance, 10 mg/kg or 32.0 mg/kg amantadine HCl was administered in a slow intravenous infusion of 50 ml/day via the continuously infusing peristaltic pump. During the study, sequential phases of cocaine and vehicle substitution for 15 days or more were examined before and during chronic amantadine infusion to assess the maintenance and re-establishment cocaine selfinjection behavior. The chronic amantadine phase of the study varied between 21 and 60 days across individual animals.
Drugs and control equipment Cocaine HCl and amantadine HCl were dissolved in physiological saline (0.9% sodium chloride) and then filter sterilized (Milliporel. Amantadine HCl was generously provided by DuPont Pharmaceuticals, Inc. (Wilmington, DE). Experimental control and data collection were accomplished by using a PDP8A computer (Digital Equipment Corp.1 programmed in SUPERSKEDe. Temporal patterning of responses was also recorded using cumulative recorders (Ralph Gerbrands, Co.). Data were recorded between 08:OO and 09:OO h daily and drug changes were performed at this time, if appropriate. Results
Amantadine self-injection Figure 1 presents the self-injection data for amantadine in 3 baboons using the cocaine substitution procedure. The standard dose of 0.32 mg/kg cocaine maintained high daily rates of self-injection behavior (mean daily rates ranged between 7.2 and 7.6 injections/day). Vehicle substitution resulted in low levels of selfinjection behavior (mean daily rates ranged between 0.4 and 2.0 injections/day). Evaluation of a wide range of doses of amantadine (0.32-32 mg/kg per injection1 showed that this compound maintained only low rates of selfinjection behavior that were not consistently above vehicle control levels.
198
AMANTADINE
SELF-INJECTION
0 6-
TA
Oa L
5 . 4-
A G' - mean
3 . 21 . O-
-r C
lV
1 0.32
I I .o
I 3.2
AMANTADINE
I 10
I 32
(mg/kg/inj)
Fig. 1. Mean number of injections per day for days 11- 15 of amantadine or amantadine vehicle (saline) substitution under a FR 80- or 16Oresponse T.O. 3-h schedule of intravenous injection. Individual data for 3 baboons (TA, GA, Gil and the group means are presented. The vertical axis represents the number of injections per day. The horizontal axis represents doses of amantadine HCl (log scale). The points above ‘V’ represent the data obtained during vehicle (saline) substitution. The points above ‘C’ represent the grand mean of the 3 days of cocaine HCI (0.32 mg/lcg per injection) availability that preceded each amantadine dose or saline substitution.
Evaluation of the effects of chronic amantadine administration on cocaine self-injection
Figures 2 and 3 present the number of cocaine injections self-administered across sequential experimental days in all 4 baboons. As shown in these figures, cocaine alone (Phase A1 maintained high daily rates of self-injection behavior in all 4 baboons: mean rates were 7.2 - 7.8 injections/day. Subsequent vehicle (saline) substitution (Phase Bl resulted in a progressive reduction in self-injection behavior over 2-5 days; at the end of this phase mean daily rates were about 2 injections/day. After cocaine was re-introduced (Phase Cl, high rates of self-injection behavior were re-established within 1- 7 days.
In the next phase (Phase Dl, the addition of the chronic amantadine infusion produced no changes in the terminal rates of cocaine selfinjection in 3 of the 4 animals: at the end of this phase self-injection behavior was maintained at high stable daily rates of 6-8 injections/day in Baboons CL, GU and TA. However, 2 animals exposed to the high dose of amantadine (32 mgl kg per day) showed a disrupted pattern of cocaine self-injection accompanied by signs suggesting psychomotor stimulant toxicity. More specificially, throughout Phase D Baboon FA showed an erratic pattern of cocaine selfinjection behavior which was accompanied by suppression of food intake and behavioral agitation (psychomotor agitation; hypersensitivity to noise; stereotypic movements; appearing to track nonexistent visual objects, suggesting hallucinations). Similarly, a dramatic suppression of food intake and disruption of cocaine self-injection behavior was observed in Baboon GU during initial administration of 32 mg/kg per day amantadine for 5 days in Phase D. The daily dose of amantadine was subsequently reduced to 10 mg/kg per day to avoid the psychomotor stimulant toxicity observed in Baboon FA. Cocaine self-injection behavior returned to high rates within 3 days and food intake returned to normal levels within 7 days of the amantadine dose reduction in Baboon GU. Although the high dose of amantadine (32 mg/kg per day) in combination with cocaine did not produce psychomotor stimulant toxicity in Baboon CL in Phase D, these effects (i.e., suppressed food intake, behavioral agitation, erratic and cocaine self-injection) were observed in a follow-up experiment under these same conditions (data not shown). In the next experimental condition (Phase El, which was conducted in the three baboons without evidence of psychomotor stimulant toxicity (Baboons CL, GU and TAl, saline was substituted for cocaine in the presence of the chronic amantadine infusion. In all three self-injection baboons performance was observed to decrease to relatively low rates similar to those maintained by saline alone in Phase B.
COCAINE + AMANfADlNE SALINE + AMANTADINE
(32.0 m(y(cg) (32.0 [email protected])
Daily number of self-injections of 0.32 mgkg cocaine or saline alone or in combination with a continuous intravenous infusion of amantadine in Baboons Fig. 2. FA and CL. Vertical axes represent the number of injections per day; horizontal axes represent consecutive days. Baboon FA was administered 32 mg/kg per day amantadine for 21 days in Phase D. Baboon CL was administered 32 mg&g per day amantadine for 32 days in Phases D and E up to day 68 and 10 mg/kg amantadine for 28 days in Phases E and F starting at day X19 (missing data between days 59 and li8 and between days X36 and 141 were due to equipment problems).
Q
EFFECTS OF AMANTADtNE ON COCAtNE SELF-INJECTtON
lr,*~.,‘r,,‘Ir,~..r’rr,.~
0
20
40
‘ 60
DAYS
80
100
120
COCAINE + AMAMADINE COCAINE + AMAMADINE SALINE + AMANTAOINE
+ a 0
(0.32 mglkg)
fOC;NE
2
(32.0 rqfkg) (10.0 ~Q&J) (10.0 ma/kg)
Fig. 3. Daily number of self-injections of 0.32 mg/kg cocaine or saline alone or in combination with a continuous intravenous infusion of amantadine in Baboons GU and TA. Baboon GU was administered 32 mg/kg per day for 5 days (first 5 days of Phase D1and 10 m&g per day amantadine for 48 days bfter day 5 in Phase D and throughout Phases E and FL Baboon TA was administered 10 mg/kg per day amantadine for 47 days in Phases D, E and F.
Baboon TA
OA
2-
4-
6-
8-
Baboon GU
EFFECTS OF AMANTAOINE ON COCAINE SELF-INJECTION
201
When cocaine was subsequently reintroduced in the presence of chronic amantadine (Phase Fl, high rates of cocaine self-injection behavior were reestablished within 6 days in all 3 animals. After chronic amantadine was discontinued (Phase Gl, cocaine self-injection behavior was maintained at high rates in all 3 baboons: there was no disruption of cocaine self-injection behavior when amantadine administration was terminated. Discussion These studies indicate that intravenous amantadine over a wide range of doses does not serve as an effective reinforcer in the baboon under conditions that support self-injection behavior with some commonly abused CNS stimulants such as amphetamine and cocaine [15]. The results of the present self-injection study showing that amantadine does not have reinforcing efficacy similar to amphetamine or cocaine are interesting in light of evidence that amantadine shares a prominent pharmacological mechanism of action (delays dopamine reuptakel with amphetamine and cocaine (i.e., acts as an indirect dopamine agonist). Although the reinforcing properties of cocaine are thought to be mediated through the dopamine systems in the brain (cf. Ref. 31, these data suggest that a functionally similar pharmacological profile of action in the dopamine system may not be sufficient to maintain self-injection behavior. It should be recognized, however, that both cocaine and amantadine produce a variety of effects at neurotransmitter systems other than dopamine. It is possible that these unshared effects may contribute to the differences in the reinforcing efficacy between amantadine and cocaine. Several groups of investigators have suggested that during chronic cocaine use the dopamine systems are depleted and that this dopamine deficiency may be a driving force in cocaine dependence and abuse [3]. Based on this hypothesis, treatment with drugs that have direct or indirect dopamine agonist properties
has been tried in an attempt to prevent ‘cocaine craving’ during cocaine withdrawal [3,6 - 81. Specifically, in human cocaine abusers, low oral doses of bromocriptine and amantadine during 2 weeks of cocaine withdrawal have been reported to reduce or alleviate complaints of cocaine craving [7,8] and reduce self-administration of cocaine [7]. The present study shows that chronic amantadine administration did not alter cocaine self-injection in the baboon. Cocaine self-injection behavior was both maintained and re-initiated during periods of chronic amantadine exposure. These results provide no evidence to support the promising, but preliminary, clinical observations that amantadine may be useful in treating cocaine abuse [7]. It should be noted, however, that the failure to block the reinitiation of cocaine selfinjection is not necessarily incompatible with the observation that amantadine can reduce complaints of cocaine craving in cocaine abstinent abusers. The present study did reveal some potential toxicity of amantadine in combination with cocaine. Evidence of psychomotor stimulant toxicity was apparent in 3 baboons exposed to the highest dose of amantadine (32 mg/kg per day) in combination with an intermediate cocaine dose (0.32 mg/kg per injection). Such toxicity has not been previously observed in baboons self-injecting these intermediate doses of cocaine alone, although the profile of behavioral effects and toxicity is similar to that previously observed during chronic high dose exposure to cocaine (Griffiths, unpublished observations1 and other psychomotor stimultants such as d-amphetamine [15]. A mechanism for this effect may be that amantadine may potentiate cocaine effects via its ability to augment release and delay reuptake of dopamine and other catecholamines. If amantadine does potentiate actions of cocaine, patients so treated may be at increased risk of experiencing overdose reactions or other drug related toxicity. It is also possible that amantadine-treated patients may be able to use relatively less cocaine in order to achieve a desired subjective or behavioral effect.
202
Acknowledgements We thank S. Womack, S. Knipp, E. Koehler and S. James for their technical assistance in conducting this study. This study was supported by National Institute on Drug Abuse Grant DA 01147 and National Institute on Drug Abuse Contract No. 271-86-8113. During this project, C.A. Sannerud was supported by National Institute on Drug Abuse National Research Service Award DA 05233. References
6
6 7 8 9 10 11 12 13 14
N.J. Kozel and E.H. Adams fEdsI, In: Cocaine Use in America: Epidemiological and Clinical Perspectives, National Institute of Drug Abuse Monograph No. 61. U.S. Government Printing Office, Washington, D.C., 1935. R.A. Wise, Neural mechanisms of the reinforcing actions of cocaine, in: J. Grabowski (Ed.), Cocaine: Pharmacology Effects and Treatment of Abuse, National Institute of Drug Abuse Monograph No. 50. U.S. Government Printing Office, Washington, D.C., 1984, pp. 15-33. C.A. Da&s and M.S. Gold, Neurosci. Biobehav. Rev., 9 (1985) 469. R. Kuczenski, Biochemical actions of amphetamine and
15 16 17 18 19 20 21
other stimulants, in: I. Creese (Ed.), Stimulants: Neurochemical, Behavioral and Clinical Perspectives, Raven Press, New York, 1983, pp. 31-62. D.K. Pitt and J. Marwah, Pharmacol. B&hem. Behav., 26 (1987) 463. C.A. Da&is, M.S. Gold and D.R. Sweeney, Arch. Gen. Psychiatry, 44 (1987) 298. F.S. Tennant and A.A. Sagherian, Arch. Int. Med., 147 (198’7)109. C.A. Dackis et al., Psychiat, Res., 20 (1987) 261. A.E. Lang, Can. J. Neurol. Sci., 110984) 210. R.M. Allen, Clin. Neuropharmacol., 6 (1983) S64. J.P. McEnvoy et al., Am. J. Psychiatry, 144 (1987) 573. N. Correa et al., J. Ciin. Psychopharmacol., 7 (1987) 91. R.M. Wurster et al., Pharmacol. Biochem. Behav., 7 (1977) 519. R.R. Griffiths et al., Psychopharmacologia, 50 (1976) 251. R.R. Griffiths, J.V. Brady and L.D. Bradford, Adv. Behav. Pharmacol., 2 (1979) 163. R.J. Lamb and R.R. Griffiths, Psychopharmacologia, 91(1987) 268. R.R. Griffiths et al., Psychopharmacologia, 75 (1981) 101. S.E. Lukas, J.V. Brady and R.R. Griffiths et al., J. Pharmacol. Exp. Ther., 238 (1986) 924. S.E. Lukas, Psychopharmacologia, 83 (1984) 316. S.E. Lukas et al., Pharmacol. Biochem. Behav., 17 (1982) 823. J.D. Findley. W.W. Robinson and L. Peregrine, Psychopharmacologia. 26 (1972) 93.
Amanta~ine: evaluation of reinforcing properties and effect on cocaine self-injection in baboons Christine
A. Sanneruda and Roland R. Griffithsasb
“Department of Psychiatry and Behavioml Sciences and 9epartment of Neuroscience, The Johns Hopkins University School of Medicine, 720 Rutland Ave., 62.9 Traylor, Baltimore, MD 21205 I7LJ.S.A.J (Received November 10th. 19871
The ability of amantadine to maintain self-injection behavior and to alter self-administration of cocaine was examined in baboons using a standard intravenous cocaine self-injection procedure. Responding was maintained under a FR 80- or 160response schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h timeout allowing a maximum of 8 injections/day. Vehicle or amantadine doses were substituted for cocaine for a period of 15 or more days. Evaluation of a wide range of amantadine doses (0.32-32 mgkg per injection1 showed that this compound did not maintain self-administration behavior above vehicle control levels. In another experiment using the cocaine self-injection baseline, amantadine (10 or 32 mg/hg per day1 was administered via a chronic intravenous infusion. Cocaine self-injection behavior was maintained and reinitiated during chronic amantadine exposure, suggesting that the reinforcing efficacy of cocaine was not modified by chronic amantadine administration. Key words: amantadine; cocaine: self-administration; baboon
Introduction Cocaine abuse in the U.S.A. has increased dramatically in the past decade and has become a major medical and public health concern [l]. The resulting priority for research on cocaine has led to increased exploration of the pharmacological mechanisms of cocaine’s reinforcing and behavioral effects as well as to increased interest in developing pharmacological approaches to treatment intervention. A large body of data exists that provides evidence for the hypothesis that the reinforcing properties of cocaine are mediated through central monoaminergic systems [2,3]. Since cocaine produces a variety of CNS disruptions (cf. Refs. 3-51, it has been further suggested that related pharmacological changes may be the basis of a withdrawal syndrome that has been reported by abstinent cocaine abusers (e.g. the craving experienced by cocaine abu-
sers may result from the over stimulation and subsequent depletion of dopamine [3,6]). Pharmacological interventions to treat withdrawal have attempted to cocaine counteract this dopamine hypofunetion and alleviate withdrawal symptoms by using a variety of agents that increase dopamine’s actions (see review, Ref. 3). Because of the appearance of major side effects, some of these compounds have been used with limited success [7,8]. Recently, there have been preliminary clinical reports that amantadine (100 mg, b.i.d.1, an agent with indirect dopamine agonist properties and without some of the side effects reported for dopamine agonist treatments, has been used with some success to treat cocaine dependence f7]. Amantadine is an anti-Parkinsonianiantiviral agent that may have anti-cholinergic effects [9] and is thought to act by augmenting the release of dopamine and other catecholamines from
0376~8716/38/$03.50 0 1988 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland.
196
neuronal storage sites and by delaying the reuptake of these neurotransmitters into synaptic vesicles [9,10]. The pharmacological properties of amantadine have been exploited in an effort to control a variety of clinical problems including dementia [ll], the side effects of neuroleptic treatment [12], and, most recently, cocaine dependence [7]. The present set of two experiments was undertaken to characterize the possible reinforcing properties of amantadine and to evaluate its potential use as a pharmacotherapeutic agent for reducing cocaine self-administration. Both experiments utilized intravenous drug self-injection procedures in baboons which have been previously used to evaluate the effects of pharmacological adjuncts of drug self-injection [13] and to characterize the reinforcing effects of compounds from a wide variety of pharmacological classes, including psychomotor stimulant [14- 161, sedativelanxiolytic [17], opioids [18] and dissociative anesthetics [19]. Methods Subjects Six male baboons Cpapio anubiss) weighing between 23 and 26 kg were used as subjects; 3 baboons were used in the study of amantadine self-injection, 4 baboons were used in the study of amantadine’s effect on cocaine self-injection, and 1 baboon was used in both studies of amantadine. Baboons were surgically prepared with chronically indwelling silastic catheters implanted in either femoral, jugular or auxillary veins under pentobarbital or halothane anesthesia using methods described by Lukas et al. [20]. Two animals were drug naive (Baboons CL and GUI and the 4 other baboons had served in studies of intravenous self-administration with a variety of drugs. Animals had continuous access to water via a drinking tube and to food pellets (as described below). Animals received 2 pieces of fresh fruit and a multivitamin (Goldline Fruity Chews) daily. Apparatus Baboons were housed in standard
stainless
steel primate cages with a bench running the length of one wall of the cage. Each cage, which served as the experimental chamber, was surrounded by a sound attenuating double walled plywood external enclosure which was continuously illuminated with a 20-W frosted bulb. The catheter was protected by a harness/vest system that allowed the baboons virtually unrestricted movement within the cage [20]. The infusion system is similar to that described by Findley et al. [21]. The catheter was attached to a valve system that allowed slow continuous administration (approx. 55- 60 ml/24 h) of heparinized saline (5 units/ml) via a peristaltic pump to maintain catheter patency. Drug was injected into the valve system by means of a second pump and then flushed into the animal with 5 ml of saline from a third pump. This system necessitated a delay of approximately 20 s between the onset of drug delivery and actual injection into the vein. Drugs were delivered within a 2-min period. An aluminum ‘intelligence panel’ (0.7 x 1.0 m) containing levers and associated stimulus lights (approx. 1 cm dia.) was mounted on the rear wall of the cage. A Lindsley lever (Ralph Gerbrands Co., No. G6310) (lower left of panel), a leaf lever (lower right of panel), and a food hopper with stimulus light (lower left of panel) were mounted on the panel. A 5 x 5-cm translucent Plexiglas panel that could be transilluminated was mounted on the aluminum panel in the upper left corner. A speaker for delivery of white noise and tones was mounted behind the panel. A feeder (BRS/LVE PDC 050 or Ralph Gerbrands Co. G5210) for delivering food pellets into the food pellet tray was mounted on the top of the wooden enclosure. Procedure for examining amantadine selfinjec t&w2 Animals were trained to self-inject cocaine (0.32 mg/kg per injection) under a fixed ratio 80 or 160 (FR 80 or FR 160) response schedule on the Lindsley lever. Drug injections were available every 3 h and were signaled by a 5-s tone followed by the illumination of the jewel light over the Lindsley lever. When the jewel light was illuminated, each response on the Lindsley
197
lever produced a brief feedback tone. Upon completion of the fixed ratio requirement, the jewel light was extinguished and the 5 ml drug injection was begun, followed by a 5ml flush injection. Following the completion of the injections, the 5 x 5 cm translucent panel was illuminated for a l-h period and the 3-h time-out period was begun. There was no time limit for the completion of the response requirement. There was an exception to this general procedure - the fixed-ratio response requirement for Baboon GI was 80. When criterion cocaine self-injection performance (6 or more injections per day for 3 consecutive days) was obtained, a dose of amantadine or vehicle was substituted for 0.32 mg/kg cocaine for 15 or more days. Occasional equipment malfunction necessitated extending the period of substitution beyond 15 days. Cocaine self-injection performance was reestablished, and when criterion performance was obtained (typically in 3- 5 days), another dose of amantadine was substituted. This procedure of replacing cocaine with amantadine was continued through the study of a range of amantadine doses and its vehicle. The order of exposure to different doses was usually an ascending sequence. There were, however, occasions on which lower doses were examined after higher doses. The drug vehicle was generally examined immediately before or after the series of doses. Food was available 24 h/day under a fixed ratio 30 (FR 301 response schedule on the leaf lever; i.e. every thirtieth response delivered a l-g banana flavored food pellet (either P.J. Noyes or Bio-Serv, Inc.1 and produced a brief flash of the hopper light. fOT eVah5ting the effeC’h Of chronic amantadine administration on cocaine selfinjection A study to assess the ability of amantadine to block or otherwise affect cocaine selfinjection was also conducted. Using the standard cocaine self-injection baseline described above (0.32 mg/kg per injection), 4 baboons were evaluated before and during chronic administration of amantadine (10 or 32 mg/kg
PTOCedUTe
per day). Following the establishment of 0.32 mg/kg cocaine self-injection performance, 10 mg/kg or 32.0 mg/kg amantadine HCl was administered in a slow intravenous infusion of 50 ml/day via the continuously infusing peristaltic pump. During the study, sequential phases of cocaine and vehicle substitution for 15 days or more were examined before and during chronic amantadine infusion to assess the maintenance and re-establishment cocaine selfinjection behavior. The chronic amantadine phase of the study varied between 21 and 60 days across individual animals.
Drugs and control equipment Cocaine HCl and amantadine HCl were dissolved in physiological saline (0.9% sodium chloride) and then filter sterilized (Milliporel. Amantadine HCl was generously provided by DuPont Pharmaceuticals, Inc. (Wilmington, DE). Experimental control and data collection were accomplished by using a PDP8A computer (Digital Equipment Corp.1 programmed in SUPERSKEDe. Temporal patterning of responses was also recorded using cumulative recorders (Ralph Gerbrands, Co.). Data were recorded between 08:OO and 09:OO h daily and drug changes were performed at this time, if appropriate. Results
Amantadine self-injection Figure 1 presents the self-injection data for amantadine in 3 baboons using the cocaine substitution procedure. The standard dose of 0.32 mg/kg cocaine maintained high daily rates of self-injection behavior (mean daily rates ranged between 7.2 and 7.6 injections/day). Vehicle substitution resulted in low levels of selfinjection behavior (mean daily rates ranged between 0.4 and 2.0 injections/day). Evaluation of a wide range of doses of amantadine (0.32-32 mg/kg per injection1 showed that this compound maintained only low rates of selfinjection behavior that were not consistently above vehicle control levels.
198
AMANTADINE
SELF-INJECTION
0 6-
TA
Oa L
5 . 4-
A G' - mean
3 . 21 . O-
-r C
lV
1 0.32
I I .o
I 3.2
AMANTADINE
I 10
I 32
(mg/kg/inj)
Fig. 1. Mean number of injections per day for days 11- 15 of amantadine or amantadine vehicle (saline) substitution under a FR 80- or 16Oresponse T.O. 3-h schedule of intravenous injection. Individual data for 3 baboons (TA, GA, Gil and the group means are presented. The vertical axis represents the number of injections per day. The horizontal axis represents doses of amantadine HCl (log scale). The points above ‘V’ represent the data obtained during vehicle (saline) substitution. The points above ‘C’ represent the grand mean of the 3 days of cocaine HCI (0.32 mg/lcg per injection) availability that preceded each amantadine dose or saline substitution.
Evaluation of the effects of chronic amantadine administration on cocaine self-injection
Figures 2 and 3 present the number of cocaine injections self-administered across sequential experimental days in all 4 baboons. As shown in these figures, cocaine alone (Phase A1 maintained high daily rates of self-injection behavior in all 4 baboons: mean rates were 7.2 - 7.8 injections/day. Subsequent vehicle (saline) substitution (Phase Bl resulted in a progressive reduction in self-injection behavior over 2-5 days; at the end of this phase mean daily rates were about 2 injections/day. After cocaine was re-introduced (Phase Cl, high rates of self-injection behavior were re-established within 1- 7 days.
In the next phase (Phase Dl, the addition of the chronic amantadine infusion produced no changes in the terminal rates of cocaine selfinjection in 3 of the 4 animals: at the end of this phase self-injection behavior was maintained at high stable daily rates of 6-8 injections/day in Baboons CL, GU and TA. However, 2 animals exposed to the high dose of amantadine (32 mgl kg per day) showed a disrupted pattern of cocaine self-injection accompanied by signs suggesting psychomotor stimulant toxicity. More specificially, throughout Phase D Baboon FA showed an erratic pattern of cocaine selfinjection behavior which was accompanied by suppression of food intake and behavioral agitation (psychomotor agitation; hypersensitivity to noise; stereotypic movements; appearing to track nonexistent visual objects, suggesting hallucinations). Similarly, a dramatic suppression of food intake and disruption of cocaine self-injection behavior was observed in Baboon GU during initial administration of 32 mg/kg per day amantadine for 5 days in Phase D. The daily dose of amantadine was subsequently reduced to 10 mg/kg per day to avoid the psychomotor stimulant toxicity observed in Baboon FA. Cocaine self-injection behavior returned to high rates within 3 days and food intake returned to normal levels within 7 days of the amantadine dose reduction in Baboon GU. Although the high dose of amantadine (32 mg/kg per day) in combination with cocaine did not produce psychomotor stimulant toxicity in Baboon CL in Phase D, these effects (i.e., suppressed food intake, behavioral agitation, erratic and cocaine self-injection) were observed in a follow-up experiment under these same conditions (data not shown). In the next experimental condition (Phase El, which was conducted in the three baboons without evidence of psychomotor stimulant toxicity (Baboons CL, GU and TAl, saline was substituted for cocaine in the presence of the chronic amantadine infusion. In all three self-injection baboons performance was observed to decrease to relatively low rates similar to those maintained by saline alone in Phase B.
COCAINE + AMANfADlNE SALINE + AMANTADINE
(32.0 m(y(cg) (32.0 [email protected])
Daily number of self-injections of 0.32 mgkg cocaine or saline alone or in combination with a continuous intravenous infusion of amantadine in Baboons Fig. 2. FA and CL. Vertical axes represent the number of injections per day; horizontal axes represent consecutive days. Baboon FA was administered 32 mg/kg per day amantadine for 21 days in Phase D. Baboon CL was administered 32 mg&g per day amantadine for 32 days in Phases D and E up to day 68 and 10 mg/kg amantadine for 28 days in Phases E and F starting at day X19 (missing data between days 59 and li8 and between days X36 and 141 were due to equipment problems).
Q
EFFECTS OF AMANTADtNE ON COCAtNE SELF-INJECTtON
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0
20
40
‘ 60
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80
100
120
COCAINE + AMAMADINE COCAINE + AMAMADINE SALINE + AMANTAOINE
+ a 0
(0.32 mglkg)
fOC;NE
2
(32.0 rqfkg) (10.0 ~Q&J) (10.0 ma/kg)
Fig. 3. Daily number of self-injections of 0.32 mg/kg cocaine or saline alone or in combination with a continuous intravenous infusion of amantadine in Baboons GU and TA. Baboon GU was administered 32 mg/kg per day for 5 days (first 5 days of Phase D1and 10 m&g per day amantadine for 48 days bfter day 5 in Phase D and throughout Phases E and FL Baboon TA was administered 10 mg/kg per day amantadine for 47 days in Phases D, E and F.
Baboon TA
OA
2-
4-
6-
8-
Baboon GU
EFFECTS OF AMANTAOINE ON COCAINE SELF-INJECTION
201
When cocaine was subsequently reintroduced in the presence of chronic amantadine (Phase Fl, high rates of cocaine self-injection behavior were reestablished within 6 days in all 3 animals. After chronic amantadine was discontinued (Phase Gl, cocaine self-injection behavior was maintained at high rates in all 3 baboons: there was no disruption of cocaine self-injection behavior when amantadine administration was terminated. Discussion These studies indicate that intravenous amantadine over a wide range of doses does not serve as an effective reinforcer in the baboon under conditions that support self-injection behavior with some commonly abused CNS stimulants such as amphetamine and cocaine [15]. The results of the present self-injection study showing that amantadine does not have reinforcing efficacy similar to amphetamine or cocaine are interesting in light of evidence that amantadine shares a prominent pharmacological mechanism of action (delays dopamine reuptakel with amphetamine and cocaine (i.e., acts as an indirect dopamine agonist). Although the reinforcing properties of cocaine are thought to be mediated through the dopamine systems in the brain (cf. Ref. 31, these data suggest that a functionally similar pharmacological profile of action in the dopamine system may not be sufficient to maintain self-injection behavior. It should be recognized, however, that both cocaine and amantadine produce a variety of effects at neurotransmitter systems other than dopamine. It is possible that these unshared effects may contribute to the differences in the reinforcing efficacy between amantadine and cocaine. Several groups of investigators have suggested that during chronic cocaine use the dopamine systems are depleted and that this dopamine deficiency may be a driving force in cocaine dependence and abuse [3]. Based on this hypothesis, treatment with drugs that have direct or indirect dopamine agonist properties
has been tried in an attempt to prevent ‘cocaine craving’ during cocaine withdrawal [3,6 - 81. Specifically, in human cocaine abusers, low oral doses of bromocriptine and amantadine during 2 weeks of cocaine withdrawal have been reported to reduce or alleviate complaints of cocaine craving [7,8] and reduce self-administration of cocaine [7]. The present study shows that chronic amantadine administration did not alter cocaine self-injection in the baboon. Cocaine self-injection behavior was both maintained and re-initiated during periods of chronic amantadine exposure. These results provide no evidence to support the promising, but preliminary, clinical observations that amantadine may be useful in treating cocaine abuse [7]. It should be noted, however, that the failure to block the reinitiation of cocaine selfinjection is not necessarily incompatible with the observation that amantadine can reduce complaints of cocaine craving in cocaine abstinent abusers. The present study did reveal some potential toxicity of amantadine in combination with cocaine. Evidence of psychomotor stimulant toxicity was apparent in 3 baboons exposed to the highest dose of amantadine (32 mg/kg per day) in combination with an intermediate cocaine dose (0.32 mg/kg per injection). Such toxicity has not been previously observed in baboons self-injecting these intermediate doses of cocaine alone, although the profile of behavioral effects and toxicity is similar to that previously observed during chronic high dose exposure to cocaine (Griffiths, unpublished observations1 and other psychomotor stimultants such as d-amphetamine [15]. A mechanism for this effect may be that amantadine may potentiate cocaine effects via its ability to augment release and delay reuptake of dopamine and other catecholamines. If amantadine does potentiate actions of cocaine, patients so treated may be at increased risk of experiencing overdose reactions or other drug related toxicity. It is also possible that amantadine-treated patients may be able to use relatively less cocaine in order to achieve a desired subjective or behavioral effect.
202
Acknowledgements We thank S. Womack, S. Knipp, E. Koehler and S. James for their technical assistance in conducting this study. This study was supported by National Institute on Drug Abuse Grant DA 01147 and National Institute on Drug Abuse Contract No. 271-86-8113. During this project, C.A. Sannerud was supported by National Institute on Drug Abuse National Research Service Award DA 05233. References
6
6 7 8 9 10 11 12 13 14
N.J. Kozel and E.H. Adams fEdsI, In: Cocaine Use in America: Epidemiological and Clinical Perspectives, National Institute of Drug Abuse Monograph No. 61. U.S. Government Printing Office, Washington, D.C., 1935. R.A. Wise, Neural mechanisms of the reinforcing actions of cocaine, in: J. Grabowski (Ed.), Cocaine: Pharmacology Effects and Treatment of Abuse, National Institute of Drug Abuse Monograph No. 50. U.S. Government Printing Office, Washington, D.C., 1984, pp. 15-33. C.A. Da&s and M.S. Gold, Neurosci. Biobehav. Rev., 9 (1985) 469. R. Kuczenski, Biochemical actions of amphetamine and
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