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Metabolite involvement in the behavioral effects of bromocriptine in cats
European Journal of Pharmacology, 141 (1987) 109-115
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Elsevier EJP 00892
Metabolite involvement in the behavioral effects of bromocriptine in cats F r a n c i s c o G o n z a l e z - L i m a 1,., W i l l i a m T. H a r t 2 a n d C y n t h i a R i v e r a - Q u i n o n e s 2 1 Department of Anatomy, College of Medicine, Texas A&M University, College Station, TX 77843, and 2 Brain Research Laboratory, Ponce School of Medicine, Ponce, PR 00732, U.S.A.
Received 14 May 1987, accepted 9 June 1987
There is a lag phase of 30-60 min before the onset of bromocriptine (BC) action. This delay may be necessary for the formation of active metabolites. The objective was to determine whether the abnormal behavioral effects induced by BC involve active hepatic metabohtes. Thus, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BC-treated cats. Experiments began after six weeks of habituation and involved i.p. injections of: (1) propylene glycol (drug vehicle); (2) SKF 525A (70 mg/kg); (3) BC (10 mg/kg); and (4) SKF 525A followed 30 rain later by BC. Each cat received the four treatments with two weeks elapsing between consecutive experiments. The frequency of 12 behaviors was scored for 60 min after 1 h posttreatment. BC alone induced emergent behavioral changes (hallucinatory-like, limb flicks, abortive grooms) that were not observed following control injections (vehicle and SKF 525A). There was a complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming induced by BC was significantly reduced. SKF 525A pretreatment was correlated with a significant increase in staring and quiet sitting and a failure of BC to increase activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no changes. The data demonstrated that particular BC-induced changes in cats are antagonized by SKF 525A. The behavioral suppression caused by SKF 525A is compatible with the involvement of active hepatic metabolites from BC. The findings suggest that hepatic metabolites resulting from hydroxylation, rather than hydrolysis, of the BC parent molecule are responsible for the hallucinatory-like behavior/escape. Bromocriptine; Dopamine agonist; Hallucinogens; (Metabolite, Behavior, Cat)
1. Introduction Bromocriptine (BC) is an ergot derivative that stimulates dopamine receptors (Ungerstedt et al., 1981) and induces hallucinations (White and Murphy, 1977) and psychiatric side-effects in humans that have often developed a syndrome called 'schizophreniform psychosis' (Serby et al., 1980). BC has been extensively used to treat Parkinson's disease (Calne, 1978), hyperprolactinemic amenorrhea (Bergh et al., 1978) and acromegaly
* To whom all correspondence should be addressed.
(Fliickiger, 1980). Patients treated with BC often shown acute confusional psychoses (Serby et al., 1978) and abnormal movements (Lieberman et al., 1980). For example, hallucinations have been reported in patients after ingestion of a large amount of BC (225 m g / d a y ) (Warren and Nakfoor, 1983) and sometimes even after ingestion of extremely low amounts (four doses of 1.25 mg in two days) (Einarson and Turchet, 1983). Adverse reactions usually include visual and auditory hallucinations, delusion, confusional states, long-lasting psychotic reactions and mania (Karch, 1980). Some female patients have developed mania after a few weeks postpartum (Brook and Cookson, 1978). Ex-
0014-2999/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
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acerbation of mania (Johnson, 1981) and symptoms of schizophrenia have been also reported (Frye et al., 1982). It has been concluded that BC may induce psychotic behavior associated with hallucinosis in human patients with no previous psychiatric history and with normal EEG and brain scan (Stern et al., 1980; Lipper, 1976). It has been proposed that the hallucinations experienced by patients treated with BC may result from hydrolysis of the lysergic acid diethylamide (LSD) residue of the BC molecule (Parkes, 1980). BC is formed by a tripeptide linked to a residue of LSD. Thus the hallucinogenic effects of BC may derive from the LSD moiety. But it has been argued that BC is an amide and lacks the LSD fragment (Goodkin, 1980). The latter author suggested a dopaminergic basis for BC-induced hallucinations. The knowledge of biotransformations of BC in humans and animals is limited (Friis et al., 1979; Markey et al., 1979). Maurer et al. (1983) have shown that 90-95% of an absorbed dose of BC is extracted by the liver with only 5-10% bypassing the liver unchanged. They argued that since an average 35% of a BC dose is absorbed, the estimated bioavailability of the parent molecule is in the range of 3%, and concluded that the fate of BC is mainly dominated by the metabolism in the liver. Two major kinds of hepatic metabolites of BC have been described: (1) 2-bromolysergic acid and its amide resulting from hydrolysis, and (2) hydroxylated BC derivatives leading to the formation of glucuronidated compounds (Maurer et al., 1982). Hydroxylated BC metabolites have been implicated as the possible active agents in the BC-induced circling behavior of rodents (Reavill et al., 1980). Our previous studies in cats (Gonzalez-Lima et al., 1981; 1984a,b) showed that BC administration induced abnormal behavioral changes such as hallucinatory-like behavior, abortive grooming, and limb flicks, which do not occur in untreated animals but are characteristic of LSD-treated cats (Jacobs et al., 1976). As in the case of LSD, the frequency of occurrence of BC-induced abnormal behaviors is dose-dependent (Gonzalez-Lima et al., 1984a) and exhibits tolerance following repeated administration (Gonzalez-Lima et al., 1984b). But unlike LSD effects that are dominant
during the first hour postinjection, there is a lag phase of 30-60 min before the onset of BC action. This time before onset of action may be necessary for the formation of active hepatic metabolites from BC. Further, the effects of BC that are similar to those of LSD always last for many more hours and peak effects are separated temporally for different BC doses. The larger the dose the later the onset of peak effects (Gonzalez-Lima et al., 1984a). The delayed actions of BC may be related to active metabolite involvement as suggested by Dolphin et al. (1977) in rodents. The question guiding this investigation was whether the abnormal behavioral effects induced by BC in cats involve the formation of active hepatic metabolites. Therefore, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BCtreated cats. SKF 525A (Proadifen or B-diethylaminoethyldiphenylpropylacetate hydrochloride) is well established as an inhibitor of microsomal drug metabolism in the liver and it is capable of inhibiting the formation of active hydroxylation metabolites from BC when given as a pretreatment (Jenner et al., 1979). An abstract of our preliminary results has been publiShed (GonzalezLima et al., 1982). 2. Materials and methods 2.1. Animals and conditions
Experiments were conducted on 11 naive, healthy adult cats (six males and five females). The animals were housed individually in large cages (8 x 4 x 7 feet) designed for behavioral observation (Gonzalez-Lima et al., 1984a). They had free access to water and Purina Cat Chow. Observations began after six weeks of habituation to the testing environment. Baseline behavior was measured following control propylene glycol (drug vehicle) injections. 2.2 Drugs and treatments
Experiments used i.p. injections of 0.3 ml/kg of propylene glycol (Merck) alone (treatment 1) and mixed with SKF 525A (Proadifen, Smith Kline
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and French) (treatment 2) or BC (as mesylate, Sandoz) (treatment 3). Treatment 4 consisted of injection of SKF 525A followed 30 rain later by injection of BC. Dosages were 10 mg of BC salt and 70 mg of SKF 525A per kg of body weight. Using a counterbalanced design, nine cats received treatments 1-4 with two weeks elapsing between consecutive drug experiments for each animal. Two additional cats were used in another control experiment for any non-specific effects of SKF 525A. First, these cats were given i.p. injections of LSD (25 /~g/kg) and behavioral scores were recorded for 2 h post-drug. Second, two weeks later the cats received an i.p. injection of SKF 525A (70 mg/kg) followed 30 rain later by injection of LSD, and behavioral scores were recorded for 2 h after the last injection. The average effects of LSD in these cats were compared in the absence and presence of SKF 525A. 2.3. Behavioral scores
The frequency of 12 behaviors (table 1) was scored by three observers for 60 min after 1 h following the last drug injection. The same observers did always the scoring using standard criteria (Jacobs et al., 1976; Gonzalez-Lima et al., 1984a). The emergent behaviors scored are non-ex-
istent in untreated cats, but are characteristic of BC-treated cats: (1) hallucinatory-like behavior/ escape: scored only when cats clearly showed one or both of the following abnormal conditions. First, the cat stared at a point in the cage (floor, walls or ceiling), followed visually an object not seen by the observers, and then approached and actively interacted (hissing, batting, pouncing or bitting) with the non-existent object. Second, the cat escaped from the non-existent object by running and climbing the walls. In most cases the abnormal interactions and escape were both present in stereotyped and complex sequences and therefore they were classified under the same category; (2) abortive grooming: the cat orients toward the body surface as if to groom but does not do so or emits a response in mid-air; and (3) limb flick: paw is lifted and rapidly put outward from the body. Definitions of the other behaviors are self-explanatory. A one-point score was given for each occurrence of a particular behavior. An additional one-point score was given for every 30 s of uninterrupted performance of the same behavior. For example, if a cat slept continuously for 1 h a total sleep score of 120 points was assigned. Student's t-tests (two-tailed) were used for the statistical comparisons of the behavioral effects of the different treatments.
TABLE 1 Mean frequency ( 4- S.E.M.) of behaviors per hour as a function of treatment. N = 9 cats. Behavior
Limbflick Abortive groom Investigatory/play Hallucinatory-like behavior/escape Rubbing, treading, kneading Vocalization Staring and quiet sitting Head or body shake Quiet sleep Feeding Grooming Excretory
Treatment (1) Vehicle
(2) S K F 525A
(3) BC
0.0+ 0.0 0.0_+ 0.0 0.0 + 0.0 0.0 4- 0.0 0.64- 0.4 0.0+ 0.0 27.8 4-18.5 20.0 4-19.7 70.0 + 23.8 0.4+ 0.4 0.2+ 0.2 0.0 + 0.0
1.0+ 1.0 0.0+ 0.0 15.0 ± 12.0 0.0 4- 0.0 4.54- 3.3 0.0+ 0.0 47.5 + 10.4 10.7 4- 9.7 39.5 + 15.0 0.04- 0.0 1.0+ 0.5 4.2 + 1.9
14.24- 4.8 13.54- 4.2 21.0 4- 6.5 5.0 4- 1.0 12.74- 5.0 0.0+ 0.0 60.0 4- 6.1 21.2 4- 6.5 0.0 + 0.0 0.2+ 0.2 57.74-21.4 0.7 4- 0.4
(4) S K F 525A + BC ~ a a a "
~ ~
Significantly different from treatment 1, P < 0.05. b Significantly different from treatment 3, P < 0.05.
5.0+ 3.8 4.0___ 2.3 18.24- 8.3 0.0 + 0.0 2.24- 1.7 0.0 4- 0.0 90.6 4-10.6 8.8 4- 4.5 0.0 :i: 0.0 0.6 4- 0.4 6.04- 2.6 0.2 4- 0.2
b
a.b ~ b
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3. Results
3.1. General effects When treated with propylene glycol or SKF 525A the cats were generally inactive and typically slept for a large portion of the 60 rain observation period. After treatment with BC or SKF 525A the cats generally showed a brief episode of vomiting around the first 30 min post-drug. At this time, salivation, gagging and retching were observed. The only apparent difference between the effects of propylene glycol and SKF 525A injections was the investigatory behavior that followed the excretory episodes produced by SKF 525A administration. BC treatment induced emergent behavioral changes (limb flicks, abortive grooms, haUucinatory-like) that were not observed following control injections (vehicle and SKF 525A). These abnormal behaviors are characteristic of BC-treated cats (Gonzalez-Lima et al., 1981; 1984a,b). The hallucinatory-like escape was stereotyped towards a preferred side of the cage in each cat. The animals appeared to show a heightened sensitivity to once familiar external stimuli and escaped from them. Most cats showed a water seeking behavior after BC treatment. The cats oriented themselves as close as possible to their water bowls and sometimes submerged their limbs into the water. But no increase in water intake was observed. BCtreated cats adopted an unusual sitting position with front paws close to the body and their haunches splayed. Impaired balance and unsteady gait were observed as well as foot shuffling with apparent shifting of body weight to the front paws. The abnormal emergent changes dominated the behavioral profile of BC-treated cats, but normal behaviors such as grooming, investigatory/play, and rubbing, treading and kneading were also significantly increased. These changes were correlated with episodes of increase in locomotor activity produced by 10 mg/kg BC treatment. No quiet sleep periods were observed. Even while sitting for most of the observation period, the cats were awake and showing emergent behaviors until an episode of increased activity started. This period
of activity was usually followed by an increase in the frequency of emergent behaviors, leading to a stereotyped pattern of behavioral sequences: first increased normal behaviors, them emergent behaviors, and finally quiet sitting but apparently still aroused.
3.2. SKF 525A antagonism of BC-induced effects The most significant finding was the complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming behavior induced by BC was also significantly reduced. The lack of hallucinatory-like changes and the small frequency of grooming were the major behavioral differences between cats treated with BC alone and BC after SKF 525A. The suppression of stereotyped behavior involved in escape and grooming by SKF 525A pretreatment was correlated with a significant increase in stating and quiet sitting and a failure to increase general activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no significant changes. For example, cats pretreated with SKF 525A still showed the water seeking behavior, foot shuffling and absence of sleep characteristic of cats treated with BC alone. The brief vomiting period following BC administration was also present after SKF 525A pretreatment. Comparing scores for the male and female cats used in this study revealed no sex difference in any behavior.
3.3. SKF 525A failure to antagonize LSD-induced effects Pretreatment with SKF 525A had no significant (P>0.1, t-tests) effects on LSD-induced behavior. Cats treated with LSD showed the following emergent behaviors during 2 h post-LSD injection (mean hourly frequency +S.E.): limb flicks (28 ___12), abortive grooming (1 + 0.5) and hallucinatory-like (1 + 0.5). Pretreatment with SKF 525A did not affect the mean frequency of LSD-induced changes, namely limb flicks (39 + 13), abortive grooming (1 + 0.1) and hallucina-
113 tory-like (2 + 1). Limb flicks and abortive grooming produced by LSD and BC appeared qualitatively similar. However, the LSD-treated cats did not show the active escape behavior characteristic of BC-treated cats. 4. Discussion
The present data demonstrate that BC-induced behavioral changes in cats are antagonized by SKF 525A pretreatment and suggest that pretreatment abolishes behaviors associated with BC hydroxylation metabolites. The most significant behavioral change was the hallucinatory-like behavior/escape that was completely eliminated when BC-treated (10 mg/kg i.p.) cats received a prior injection of SKF 525A (70 mg/kg i.p.). Further, when several of these pretreated cats were observed at 18 h after BC injection they showed by that time characteristic BC-induced hallucinatorylike behavior/escape. The behavioral suppression and the delayed onset of BC effects caused by SKF 525A are compatible with the involvement of active hydroxylation metabolites from BC in the mediation of the emergent hallucinatory-like behavior/escape. Three lines of evidence further support the view that the hallucinatory-like effects of BC are related to the formation of hydroxylated metabolites and are not due to the hydrolysis of BC into LSD-like metabolites. First, pretreatment with SKF 525A affects oxidation processes in the liver leading to hydroxylated derivatives but does not appear to interfere with hydrolytic processes leading to the formation of bromo-LSD derivatives (Maurer et al., 1982, 1983). Pretreatment with SKF 525A is fully effective in eliminating hallucinatory-like effects, suggesting that these effects were prevented when the formation of hydroxylated metabolites was prevented. Second, the behavioral effect of bromo-LSD, the major LSD-like metabolite produced by hydrolysis of BC, has been tested directly in cats. Administration of the non-hallucinogen bromo-LSD, which has the same peripheral actions as LSD, has been found ineffective in eliciting the emergent behaviors in cats (Jacobs et al., 1976). Third, pretreatment with SKF 525A was ineffective in eliminating emergent
behaviors produced by LSD, suggesting that LSD effects are not dependent on the formation of active hydroxylation metabolites and that the antagonistic action of SKF 525A is not the result of some non-specific effect (i.e. general malaise) in the cats. Further, although LSD-treated cats showed several hallucinatory-like episodes, they did not show the abnormal escape behavior characteristic of BC-treated cats. Taken together these findings suggest that metabolites resulting from hydroxylation, rather than hydrolysis, of the BC parent molecule are responsible for the hallucinatory-like behavior/escape. Another interesting finding was the decrease in grooming seen after SKF 525A pretreatment. Since BC given alone resulted in a dramatic increase in the frequency of grooming, it may be concluded that hydroxylated metabolites from BC may also affect this behavior. However, since the occurrence of grooming and other BC-induced behaviors was not completely abolished by the pretreatment, the involvement of some LSD-like metabolites cannot be ruled out completely. In fact, low doses of LSD produce increases in grooming whereas higher doses are ineffective (Jacobs et al., 1976). The involuntary movements of limb flicks and abortive grooming appear to be non-specific for hallucinogenic drug action (Marini and Sheard, 1981). These movements have been observed after the administration of a large number of non-hallucinogenic compounds. For instance the non-hallucinogen lisuride, an ergoline derivative structurally related to LSD, produces limb flicks in a manner similar to drugs such as methysergide (Marini and Sheard, 1981), pilocarpine (Marini, 1982), 5,7-dihydroxytryptamine and p-chlorophenylalanine (Trulson and Jacobs, 1977). Interestingly, limb flicks elicited by lisuride and LSD can be antagonized by haloperidol, pizotifen and cocaine (White et al., 1983). On the other hand, limb flicks, but not abortive grooming elicited by lisuride and LSD can be antagonized by pretreatment with methysergide (Marini and Sheard, 1981). Some of these drugs increase arousal while others decrease arousal but all of them antagonize limb flicks elicited by lisuride and LSD. Since it is not possible to know what BC-treated
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cats are experiencing, no claim is being made that these animals are hallucinating. But BC-treated cats actively interacted and escaped from objects not seen by trained observers. We have tentatively called these abnormal activities hallucinatory-like behavior/escape. The findings presented here seem to be in general agreement with reports of hallucinogenic and abnormal motor effects of BC in humans (Serby et al., 1980). The finding of complete disappearance of hallucinatory-like effects of BC following inhibition of hepatic hydroxylation does not support the proposal that hallucinations experienced by humans treated with BC may derive from hydrolysis leading to LSD residues (Parkes, 1980). Others have suggested a dopaminergic basis for BC-induced hallucinations (Goodkin, 1980). Johnson (1981) further speculated that the exacerbation of psychotic behavior induced by BC was related to dopamine agonist activity in the mesolimbic pathway. Other dopamine agonists have beenshown to induce similar psychotic reactions in humans but the mechanisms involved remain unclear (Carlsson, 1978). Regarding the apparently similar hallucinatory-like effects of BC and LSD in cats, the mechanism of this particular action may be related to dopaminerglc systems (Christoph et al., 1978; Kehr and Speckenbach. 1978). However, BC is known to exert other significant effects on non-dopaminergic brain regions (Pizzolato et al., 1985) and these may be important in producing its behavioral end points. Further experiments are needed to determine which of the hydroxylated metabolites from BC produced in the liver (Maurer et al., 1982) are responsible for the observed hallucinatory-like and motor effects and what are the underlaying neural mechanisms for these actions.
Acknowledgements We gratefully acknowledge the assistance of D. Velez and E.M. Gonzalez-Lima. C. Rivera-Quinones was a student of the
RAMHSS program at Ponce School of Medicine. Supported in part by NSF Grant SPE-8262061 and NIH Grant MBRSRR08067 to F.G.-L The generous donations of bromocriptine from Sandoz, SKF 525A from Smith Kline & French, and LSD from Dr. M. Trulson are gratefully acknowledged.
References Bergh, T., S.J. Niliius and L. Wide, 1978, Bromocriptine treatment of 42 hyperprolactinaemic women with secondary amenorrhoea, Acta Endocrinol. 88, 435. Brook, N. and I.B. Cookson, 1978, Bromocriptine-induced mania? Br. Med. J. 1,790. Calne, D.B., 1978, Role of ergot derivatives in the treatment of parkinsonism, Fed. Proc. 37, 2207. Carlsson, A., 1978, Antipsychotic drugs, neurotransmitters and schizophrenia, Am. J. Psychiat. 135, 164. Christoph, G.R., D.M. Kuhn and B.L. Jacobs, 1978, Dopamine agonist pretreatment alters LSD's electrophysiologieal action from dopamine agonist to antagonist, Life Sci. 23, 2099. Dolphin, A.C., P. Jenner, M.C.B. Sawaya, C.D. Marsden and B. Testa, 1977, The effect of bromocriptine on locomotor activity and cerebral eatecholamines in rodents, J. Pharm. Pharmacol. 29, 727. Einarson, T.R. and E.N. Turchet, 1983, Psychotic reaction to low-dose bromocriptine, Chn. Pharm. 2, 273. Fliickiger, E., 1980, Ergots and endocrine functions, in: Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatric Aspects, eds. M. Goldstein, D.B. Calne, A. Lieberman and M.O. Thomer (Raven Press, New York) p. 155. Friis, M.L., O.B. Panlson and M.M. Hertz, 1979, Transfer of bromocriptine across the blood-brain barrier in man, Acta Neurol. Seand. 59, 88. Frye, P.E., S.F. Pariser, M.H. Kim and R.W. O'Shaughnessy, 1982, Bromocriptine associated with symptom exacerbation during neuroleptic treatment of schizoaffective schizophrenia, J. Clin. Psychiat. 43, 252. Gonzalez-Lima, F., N.M. Keene and J.J. Keene, 1981, The dopamine agonist bromocriptine produces hallucinatorylike behavior in the eat, Sci. Ciencia 8, 76. Gonzalez.Lima, F., W.L. Stiehl and R. Medina, 1984a, Longlasting behavioral effects of bromocriptine in cats~ European J. Pharmacol. 102, 279. Gonzalez-Lima, F., W.L. Stiehl and H. Oeasio, 1984b, Tolerance to the behavioral effects of bromocriptine in cats, European J. Pharmacol. 102, 289. Gonzalez-Lima, F., W.L. Stiehl and C. Rivera, 1982, Evidence for the formation of an active metabolite of bromocriptine, (Univ. Puerto Rico Med. So. Symposium, Abst.) p. 53. Goodkin, D.A., 1980, Mechanisms of bromocriptine-induced hallucinations, N. Engl. J. Med. 302, 1479. Jacobs, B.L., M.E. Trulson and W.C. Stem, 1976, A n animal behavior model for studying the actions of LSD and related hallucinogens, Science 194, 741. Jenner, P., C.D. Marsden and C. Reavill, 1979, Evidence for metabolite involvement in bromocryptine-induced circling behaviour, Br. J. Pharmacol. 66, 103P. Johnson, J.M., 1981, Treated mania exacerbated by bromocriptine, Am. J. Psychiat. 138, 980. Karch, F.E., 1980, Drugs affecting autonomic functions or the
115 extrapyramidal system, in: Side Effects of Drugs, Annual 4, ed. M.N.G. Dukes (Excerpta Medica, Amsterdam) p. 92. Kehr, W. and W. Speckenbach, 1978, Effect of lisuride and LSD on monoamine synthesis after axotomy or reserpine treatment in rat brain, Naunyn-Schmiedeb. Arch. Pharmacol. 301, 163. Lieberman, A.N., M. Kupersmith, A. Neophytides, G. Gopinathan, I. Casson, R. Durso, S.H. Foo, M. Khatali, T. Tartaro and M. Goldstein, 1980, Bromocriptine in Parkinson's disease: Report on 106 patients treated for up to 5 years, in: Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatric Aspects, eds. M. Goldstein, D.B. Calne, A. Lieberman and M.O. Thorner (Raven Press, New York) p. 245. Lipper, S., 1976, Psychosis in patient on bromocriptine and levodopa with carbidopa, Lancet 2, 571. Marini, J.L., 1982, Pilocarpine, a non-hallucinogenic cholinergic agonist, elicits limb flicking in cats, Pharmacol. Biochem. Behav. 15, 865. Marini, J.L. and M.H. Sheard, 1981, On the specificity of a cat behavior model for the study of hallucinogens, European J. Pharmacol. 70, 479. Markey, S.P., R.W. Colburn, l.J. Kopin and R. Aamodt, 1979, Distribution and excretion in the rat and monkey of [82 Br] bromocriptine, J. Pharmacol. Exp. Ther. 211, 31. Maurer, G., E. Schreier, S. Delaborde, H.R. Loosli, R. Nufer and A.P. Shulda, 1982, Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites, European J. Drug Metab. Pharmacok. 7, 281. Maurer, G., E. Sclireier, S. Delaborde, R. Nufer and A.P. Shukla, 1983, Fate and disposition of bromocriptine in animals and man. II: Absorption, elimination and metabolism, European J. Drug Metab. Pharmacok. 8, 51. Parkes, D., 1980, Mechanisms of bromocriptine-induced hallucinations, N. Engl. J. Med. 302, 1479. Pizzolato, G., T.T. Soncrant and S.I. Rapoport, 1985, Timecourse and regional distribution of the metabolic effects of bromocriptine in the rat brain, Brain Res. 341, 303.
Reavill, C., P. Jenner and C.D. Marsden, 1980, Metabolite involvement in bromocriptine-induced circling behaviour in rodents, J. Pharm. Pharmacol. 32, 278. Serby, M., B. Angrist and A. Lieberman, 1978, Mental disturbances during bromocriptine and lergotrile treatment of Parkinson's disease, Am. J. Psychiat. 135, 1227. Serby, M., B. Angrist and A. Lieberman, 1980, Psychiatric effects of bromocriptine and lergotrile in Parkinsonian patients, in: Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatric Aspects, eds. M. Goldstein, D.B. Calne, A. Lieberman and M.O. Thorner (Raven Press, New York) p. 287. Stern, G.M., A.J. Lees, K.M. Shaw and C.M. Lander, 1980, The role of bromocriptine in the treatment of Parkinson's disease, in: Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatric Aspects, eds. M. Goldstein, D.B. Calne, A. Lieberman and M.O. Thorner (Raven Press, New York) p. 267. Trulson, M.E. and B.L. Jacobs, 1977, Usefulness of an animal behavioral model in studying the duration of action of LSD and the onset and duration of tolerance to LSD in the cat, Brain Res. 132, 315. Ungerstedt, U., M. Herrera-Marschitz and M.C. Brugue, 1981, Are apomorphine, bromocriptine and the methylxanthines agonists at the same dopamine receptor?, in: Apomorphine and Other Dopaminomimetics, Vol. 1, Basic Pharmacology, eds. G.L. Gessa and G.V. Corsini (Raven Press, New York) p. 85. Warren, D.E. and E. Nakfoor, 1983, Acute overdose of bromocriptine: A case report, Drug Intell. Clin. Pharm. 17, 374. White, A.C. and J.J. Murphy, 1977, Hallucinations caused by bromocriptine, Br. J. Psychiat. 130, 104. White, F.J., A.M. Holohean and J.B. Appel, 1983, Antagonism of a behavioral effect of LSD and lisuride in the cat, Psychopharmacology 80, 83.
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Elsevier EJP 00892
Metabolite involvement in the behavioral effects of bromocriptine in cats F r a n c i s c o G o n z a l e z - L i m a 1,., W i l l i a m T. H a r t 2 a n d C y n t h i a R i v e r a - Q u i n o n e s 2 1 Department of Anatomy, College of Medicine, Texas A&M University, College Station, TX 77843, and 2 Brain Research Laboratory, Ponce School of Medicine, Ponce, PR 00732, U.S.A.
Received 14 May 1987, accepted 9 June 1987
There is a lag phase of 30-60 min before the onset of bromocriptine (BC) action. This delay may be necessary for the formation of active metabolites. The objective was to determine whether the abnormal behavioral effects induced by BC involve active hepatic metabohtes. Thus, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BC-treated cats. Experiments began after six weeks of habituation and involved i.p. injections of: (1) propylene glycol (drug vehicle); (2) SKF 525A (70 mg/kg); (3) BC (10 mg/kg); and (4) SKF 525A followed 30 rain later by BC. Each cat received the four treatments with two weeks elapsing between consecutive experiments. The frequency of 12 behaviors was scored for 60 min after 1 h posttreatment. BC alone induced emergent behavioral changes (hallucinatory-like, limb flicks, abortive grooms) that were not observed following control injections (vehicle and SKF 525A). There was a complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming induced by BC was significantly reduced. SKF 525A pretreatment was correlated with a significant increase in staring and quiet sitting and a failure of BC to increase activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no changes. The data demonstrated that particular BC-induced changes in cats are antagonized by SKF 525A. The behavioral suppression caused by SKF 525A is compatible with the involvement of active hepatic metabolites from BC. The findings suggest that hepatic metabolites resulting from hydroxylation, rather than hydrolysis, of the BC parent molecule are responsible for the hallucinatory-like behavior/escape. Bromocriptine; Dopamine agonist; Hallucinogens; (Metabolite, Behavior, Cat)
1. Introduction Bromocriptine (BC) is an ergot derivative that stimulates dopamine receptors (Ungerstedt et al., 1981) and induces hallucinations (White and Murphy, 1977) and psychiatric side-effects in humans that have often developed a syndrome called 'schizophreniform psychosis' (Serby et al., 1980). BC has been extensively used to treat Parkinson's disease (Calne, 1978), hyperprolactinemic amenorrhea (Bergh et al., 1978) and acromegaly
* To whom all correspondence should be addressed.
(Fliickiger, 1980). Patients treated with BC often shown acute confusional psychoses (Serby et al., 1978) and abnormal movements (Lieberman et al., 1980). For example, hallucinations have been reported in patients after ingestion of a large amount of BC (225 m g / d a y ) (Warren and Nakfoor, 1983) and sometimes even after ingestion of extremely low amounts (four doses of 1.25 mg in two days) (Einarson and Turchet, 1983). Adverse reactions usually include visual and auditory hallucinations, delusion, confusional states, long-lasting psychotic reactions and mania (Karch, 1980). Some female patients have developed mania after a few weeks postpartum (Brook and Cookson, 1978). Ex-
0014-2999/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
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acerbation of mania (Johnson, 1981) and symptoms of schizophrenia have been also reported (Frye et al., 1982). It has been concluded that BC may induce psychotic behavior associated with hallucinosis in human patients with no previous psychiatric history and with normal EEG and brain scan (Stern et al., 1980; Lipper, 1976). It has been proposed that the hallucinations experienced by patients treated with BC may result from hydrolysis of the lysergic acid diethylamide (LSD) residue of the BC molecule (Parkes, 1980). BC is formed by a tripeptide linked to a residue of LSD. Thus the hallucinogenic effects of BC may derive from the LSD moiety. But it has been argued that BC is an amide and lacks the LSD fragment (Goodkin, 1980). The latter author suggested a dopaminergic basis for BC-induced hallucinations. The knowledge of biotransformations of BC in humans and animals is limited (Friis et al., 1979; Markey et al., 1979). Maurer et al. (1983) have shown that 90-95% of an absorbed dose of BC is extracted by the liver with only 5-10% bypassing the liver unchanged. They argued that since an average 35% of a BC dose is absorbed, the estimated bioavailability of the parent molecule is in the range of 3%, and concluded that the fate of BC is mainly dominated by the metabolism in the liver. Two major kinds of hepatic metabolites of BC have been described: (1) 2-bromolysergic acid and its amide resulting from hydrolysis, and (2) hydroxylated BC derivatives leading to the formation of glucuronidated compounds (Maurer et al., 1982). Hydroxylated BC metabolites have been implicated as the possible active agents in the BC-induced circling behavior of rodents (Reavill et al., 1980). Our previous studies in cats (Gonzalez-Lima et al., 1981; 1984a,b) showed that BC administration induced abnormal behavioral changes such as hallucinatory-like behavior, abortive grooming, and limb flicks, which do not occur in untreated animals but are characteristic of LSD-treated cats (Jacobs et al., 1976). As in the case of LSD, the frequency of occurrence of BC-induced abnormal behaviors is dose-dependent (Gonzalez-Lima et al., 1984a) and exhibits tolerance following repeated administration (Gonzalez-Lima et al., 1984b). But unlike LSD effects that are dominant
during the first hour postinjection, there is a lag phase of 30-60 min before the onset of BC action. This time before onset of action may be necessary for the formation of active hepatic metabolites from BC. Further, the effects of BC that are similar to those of LSD always last for many more hours and peak effects are separated temporally for different BC doses. The larger the dose the later the onset of peak effects (Gonzalez-Lima et al., 1984a). The delayed actions of BC may be related to active metabolite involvement as suggested by Dolphin et al. (1977) in rodents. The question guiding this investigation was whether the abnormal behavioral effects induced by BC in cats involve the formation of active hepatic metabolites. Therefore, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BCtreated cats. SKF 525A (Proadifen or B-diethylaminoethyldiphenylpropylacetate hydrochloride) is well established as an inhibitor of microsomal drug metabolism in the liver and it is capable of inhibiting the formation of active hydroxylation metabolites from BC when given as a pretreatment (Jenner et al., 1979). An abstract of our preliminary results has been publiShed (GonzalezLima et al., 1982). 2. Materials and methods 2.1. Animals and conditions
Experiments were conducted on 11 naive, healthy adult cats (six males and five females). The animals were housed individually in large cages (8 x 4 x 7 feet) designed for behavioral observation (Gonzalez-Lima et al., 1984a). They had free access to water and Purina Cat Chow. Observations began after six weeks of habituation to the testing environment. Baseline behavior was measured following control propylene glycol (drug vehicle) injections. 2.2 Drugs and treatments
Experiments used i.p. injections of 0.3 ml/kg of propylene glycol (Merck) alone (treatment 1) and mixed with SKF 525A (Proadifen, Smith Kline
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and French) (treatment 2) or BC (as mesylate, Sandoz) (treatment 3). Treatment 4 consisted of injection of SKF 525A followed 30 rain later by injection of BC. Dosages were 10 mg of BC salt and 70 mg of SKF 525A per kg of body weight. Using a counterbalanced design, nine cats received treatments 1-4 with two weeks elapsing between consecutive drug experiments for each animal. Two additional cats were used in another control experiment for any non-specific effects of SKF 525A. First, these cats were given i.p. injections of LSD (25 /~g/kg) and behavioral scores were recorded for 2 h post-drug. Second, two weeks later the cats received an i.p. injection of SKF 525A (70 mg/kg) followed 30 rain later by injection of LSD, and behavioral scores were recorded for 2 h after the last injection. The average effects of LSD in these cats were compared in the absence and presence of SKF 525A. 2.3. Behavioral scores
The frequency of 12 behaviors (table 1) was scored by three observers for 60 min after 1 h following the last drug injection. The same observers did always the scoring using standard criteria (Jacobs et al., 1976; Gonzalez-Lima et al., 1984a). The emergent behaviors scored are non-ex-
istent in untreated cats, but are characteristic of BC-treated cats: (1) hallucinatory-like behavior/ escape: scored only when cats clearly showed one or both of the following abnormal conditions. First, the cat stared at a point in the cage (floor, walls or ceiling), followed visually an object not seen by the observers, and then approached and actively interacted (hissing, batting, pouncing or bitting) with the non-existent object. Second, the cat escaped from the non-existent object by running and climbing the walls. In most cases the abnormal interactions and escape were both present in stereotyped and complex sequences and therefore they were classified under the same category; (2) abortive grooming: the cat orients toward the body surface as if to groom but does not do so or emits a response in mid-air; and (3) limb flick: paw is lifted and rapidly put outward from the body. Definitions of the other behaviors are self-explanatory. A one-point score was given for each occurrence of a particular behavior. An additional one-point score was given for every 30 s of uninterrupted performance of the same behavior. For example, if a cat slept continuously for 1 h a total sleep score of 120 points was assigned. Student's t-tests (two-tailed) were used for the statistical comparisons of the behavioral effects of the different treatments.
TABLE 1 Mean frequency ( 4- S.E.M.) of behaviors per hour as a function of treatment. N = 9 cats. Behavior
Limbflick Abortive groom Investigatory/play Hallucinatory-like behavior/escape Rubbing, treading, kneading Vocalization Staring and quiet sitting Head or body shake Quiet sleep Feeding Grooming Excretory
Treatment (1) Vehicle
(2) S K F 525A
(3) BC
0.0+ 0.0 0.0_+ 0.0 0.0 + 0.0 0.0 4- 0.0 0.64- 0.4 0.0+ 0.0 27.8 4-18.5 20.0 4-19.7 70.0 + 23.8 0.4+ 0.4 0.2+ 0.2 0.0 + 0.0
1.0+ 1.0 0.0+ 0.0 15.0 ± 12.0 0.0 4- 0.0 4.54- 3.3 0.0+ 0.0 47.5 + 10.4 10.7 4- 9.7 39.5 + 15.0 0.04- 0.0 1.0+ 0.5 4.2 + 1.9
14.24- 4.8 13.54- 4.2 21.0 4- 6.5 5.0 4- 1.0 12.74- 5.0 0.0+ 0.0 60.0 4- 6.1 21.2 4- 6.5 0.0 + 0.0 0.2+ 0.2 57.74-21.4 0.7 4- 0.4
(4) S K F 525A + BC ~ a a a "
~ ~
Significantly different from treatment 1, P < 0.05. b Significantly different from treatment 3, P < 0.05.
5.0+ 3.8 4.0___ 2.3 18.24- 8.3 0.0 + 0.0 2.24- 1.7 0.0 4- 0.0 90.6 4-10.6 8.8 4- 4.5 0.0 :i: 0.0 0.6 4- 0.4 6.04- 2.6 0.2 4- 0.2
b
a.b ~ b
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3. Results
3.1. General effects When treated with propylene glycol or SKF 525A the cats were generally inactive and typically slept for a large portion of the 60 rain observation period. After treatment with BC or SKF 525A the cats generally showed a brief episode of vomiting around the first 30 min post-drug. At this time, salivation, gagging and retching were observed. The only apparent difference between the effects of propylene glycol and SKF 525A injections was the investigatory behavior that followed the excretory episodes produced by SKF 525A administration. BC treatment induced emergent behavioral changes (limb flicks, abortive grooms, haUucinatory-like) that were not observed following control injections (vehicle and SKF 525A). These abnormal behaviors are characteristic of BC-treated cats (Gonzalez-Lima et al., 1981; 1984a,b). The hallucinatory-like escape was stereotyped towards a preferred side of the cage in each cat. The animals appeared to show a heightened sensitivity to once familiar external stimuli and escaped from them. Most cats showed a water seeking behavior after BC treatment. The cats oriented themselves as close as possible to their water bowls and sometimes submerged their limbs into the water. But no increase in water intake was observed. BCtreated cats adopted an unusual sitting position with front paws close to the body and their haunches splayed. Impaired balance and unsteady gait were observed as well as foot shuffling with apparent shifting of body weight to the front paws. The abnormal emergent changes dominated the behavioral profile of BC-treated cats, but normal behaviors such as grooming, investigatory/play, and rubbing, treading and kneading were also significantly increased. These changes were correlated with episodes of increase in locomotor activity produced by 10 mg/kg BC treatment. No quiet sleep periods were observed. Even while sitting for most of the observation period, the cats were awake and showing emergent behaviors until an episode of increased activity started. This period
of activity was usually followed by an increase in the frequency of emergent behaviors, leading to a stereotyped pattern of behavioral sequences: first increased normal behaviors, them emergent behaviors, and finally quiet sitting but apparently still aroused.
3.2. SKF 525A antagonism of BC-induced effects The most significant finding was the complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming behavior induced by BC was also significantly reduced. The lack of hallucinatory-like changes and the small frequency of grooming were the major behavioral differences between cats treated with BC alone and BC after SKF 525A. The suppression of stereotyped behavior involved in escape and grooming by SKF 525A pretreatment was correlated with a significant increase in stating and quiet sitting and a failure to increase general activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no significant changes. For example, cats pretreated with SKF 525A still showed the water seeking behavior, foot shuffling and absence of sleep characteristic of cats treated with BC alone. The brief vomiting period following BC administration was also present after SKF 525A pretreatment. Comparing scores for the male and female cats used in this study revealed no sex difference in any behavior.
3.3. SKF 525A failure to antagonize LSD-induced effects Pretreatment with SKF 525A had no significant (P>0.1, t-tests) effects on LSD-induced behavior. Cats treated with LSD showed the following emergent behaviors during 2 h post-LSD injection (mean hourly frequency +S.E.): limb flicks (28 ___12), abortive grooming (1 + 0.5) and hallucinatory-like (1 + 0.5). Pretreatment with SKF 525A did not affect the mean frequency of LSD-induced changes, namely limb flicks (39 + 13), abortive grooming (1 + 0.1) and hallucina-
113 tory-like (2 + 1). Limb flicks and abortive grooming produced by LSD and BC appeared qualitatively similar. However, the LSD-treated cats did not show the active escape behavior characteristic of BC-treated cats. 4. Discussion
The present data demonstrate that BC-induced behavioral changes in cats are antagonized by SKF 525A pretreatment and suggest that pretreatment abolishes behaviors associated with BC hydroxylation metabolites. The most significant behavioral change was the hallucinatory-like behavior/escape that was completely eliminated when BC-treated (10 mg/kg i.p.) cats received a prior injection of SKF 525A (70 mg/kg i.p.). Further, when several of these pretreated cats were observed at 18 h after BC injection they showed by that time characteristic BC-induced hallucinatorylike behavior/escape. The behavioral suppression and the delayed onset of BC effects caused by SKF 525A are compatible with the involvement of active hydroxylation metabolites from BC in the mediation of the emergent hallucinatory-like behavior/escape. Three lines of evidence further support the view that the hallucinatory-like effects of BC are related to the formation of hydroxylated metabolites and are not due to the hydrolysis of BC into LSD-like metabolites. First, pretreatment with SKF 525A affects oxidation processes in the liver leading to hydroxylated derivatives but does not appear to interfere with hydrolytic processes leading to the formation of bromo-LSD derivatives (Maurer et al., 1982, 1983). Pretreatment with SKF 525A is fully effective in eliminating hallucinatory-like effects, suggesting that these effects were prevented when the formation of hydroxylated metabolites was prevented. Second, the behavioral effect of bromo-LSD, the major LSD-like metabolite produced by hydrolysis of BC, has been tested directly in cats. Administration of the non-hallucinogen bromo-LSD, which has the same peripheral actions as LSD, has been found ineffective in eliciting the emergent behaviors in cats (Jacobs et al., 1976). Third, pretreatment with SKF 525A was ineffective in eliminating emergent
behaviors produced by LSD, suggesting that LSD effects are not dependent on the formation of active hydroxylation metabolites and that the antagonistic action of SKF 525A is not the result of some non-specific effect (i.e. general malaise) in the cats. Further, although LSD-treated cats showed several hallucinatory-like episodes, they did not show the abnormal escape behavior characteristic of BC-treated cats. Taken together these findings suggest that metabolites resulting from hydroxylation, rather than hydrolysis, of the BC parent molecule are responsible for the hallucinatory-like behavior/escape. Another interesting finding was the decrease in grooming seen after SKF 525A pretreatment. Since BC given alone resulted in a dramatic increase in the frequency of grooming, it may be concluded that hydroxylated metabolites from BC may also affect this behavior. However, since the occurrence of grooming and other BC-induced behaviors was not completely abolished by the pretreatment, the involvement of some LSD-like metabolites cannot be ruled out completely. In fact, low doses of LSD produce increases in grooming whereas higher doses are ineffective (Jacobs et al., 1976). The involuntary movements of limb flicks and abortive grooming appear to be non-specific for hallucinogenic drug action (Marini and Sheard, 1981). These movements have been observed after the administration of a large number of non-hallucinogenic compounds. For instance the non-hallucinogen lisuride, an ergoline derivative structurally related to LSD, produces limb flicks in a manner similar to drugs such as methysergide (Marini and Sheard, 1981), pilocarpine (Marini, 1982), 5,7-dihydroxytryptamine and p-chlorophenylalanine (Trulson and Jacobs, 1977). Interestingly, limb flicks elicited by lisuride and LSD can be antagonized by haloperidol, pizotifen and cocaine (White et al., 1983). On the other hand, limb flicks, but not abortive grooming elicited by lisuride and LSD can be antagonized by pretreatment with methysergide (Marini and Sheard, 1981). Some of these drugs increase arousal while others decrease arousal but all of them antagonize limb flicks elicited by lisuride and LSD. Since it is not possible to know what BC-treated
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cats are experiencing, no claim is being made that these animals are hallucinating. But BC-treated cats actively interacted and escaped from objects not seen by trained observers. We have tentatively called these abnormal activities hallucinatory-like behavior/escape. The findings presented here seem to be in general agreement with reports of hallucinogenic and abnormal motor effects of BC in humans (Serby et al., 1980). The finding of complete disappearance of hallucinatory-like effects of BC following inhibition of hepatic hydroxylation does not support the proposal that hallucinations experienced by humans treated with BC may derive from hydrolysis leading to LSD residues (Parkes, 1980). Others have suggested a dopaminergic basis for BC-induced hallucinations (Goodkin, 1980). Johnson (1981) further speculated that the exacerbation of psychotic behavior induced by BC was related to dopamine agonist activity in the mesolimbic pathway. Other dopamine agonists have beenshown to induce similar psychotic reactions in humans but the mechanisms involved remain unclear (Carlsson, 1978). Regarding the apparently similar hallucinatory-like effects of BC and LSD in cats, the mechanism of this particular action may be related to dopaminerglc systems (Christoph et al., 1978; Kehr and Speckenbach. 1978). However, BC is known to exert other significant effects on non-dopaminergic brain regions (Pizzolato et al., 1985) and these may be important in producing its behavioral end points. Further experiments are needed to determine which of the hydroxylated metabolites from BC produced in the liver (Maurer et al., 1982) are responsible for the observed hallucinatory-like and motor effects and what are the underlaying neural mechanisms for these actions.
Acknowledgements We gratefully acknowledge the assistance of D. Velez and E.M. Gonzalez-Lima. C. Rivera-Quinones was a student of the
RAMHSS program at Ponce School of Medicine. Supported in part by NSF Grant SPE-8262061 and NIH Grant MBRSRR08067 to F.G.-L The generous donations of bromocriptine from Sandoz, SKF 525A from Smith Kline & French, and LSD from Dr. M. Trulson are gratefully acknowledged.
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