- Email: [email protected]
High affinity dopamine reuptake inhibitors as potential cocaine antagonists: A strategy for drug development
Life Sciences, Vol. 46, pp. PL-17- PL-21 Printed in the U.S.A.
Pergamon Press
PHARMACOLOGYLETTERS Dialogue
HIGH AFFINITY DOPAMINE REUPTAICE INHIBITORS AS POTENTIAL COCAINE ANTAGONISTS: A STRATEGY FOR DRUG DEVELOPMENT Richard B. Rothman Unit on Receptor Studies, Laboratory of Clinical Science, National Institute of Mental Health, Bldg. lO-3D41, Bethesda, MD 28892. (Received March 6, 1990; Accepted March 7, 1990)
Abstract. The addictive and euphorogenic effects of cocaine are thought to result primarily from inhibition of dopamine reuptake. Although the potency of cocainelike drugs as inhibitors of DA reuptake is highly correlated with their potency as reinforcers in .animals, several potent DA reuptake blockers (bupropion, nomifensine, benztropine, and mazindol) have not been reported to produce addiction or euphoria in humans. Based on these observations in humans, DA reuptake inhibitors are classified into two groups; type 1 blockers, which produce addiction and euphoria, and type 2 blockers, which do not. Given that type 1 and type 2 blockers act at the same site (the DA transporter), the author suggests that type 2 agents may antagonize the effects of cocaine, and might prove useful in the treatment of cocaine addiction. Cocaine, a major drug of abuse, is thought to produce its effects primarily by inhibiting the reuptake of biogenic amines (1). Although cocaine inhibits the reuptake of norepinephrine and serotonin, its ability to inhibit the reuptake of dopamine (DA) is thought to be the main neurochemical mechanism responsible for its addictive and euphorogenic properties (2). Several lines of evidence support the DA hypothesis, including a major role of dopaminergic systems in reward mechanisms (3) and a correlation between the potency of cocaine like drugs to inhibit DA reuptake, [3H]mazindol or [3H]cocaine binding, and their potency as selfadministered agents in animals (2,441. Several DA reuptake inhibitors which produce cocaine-like effects in animals are, or were, marketed in the United States. As described in Table 1, bupropion, nomifensine, mazindol and benztropine are all more potent inhibitors of DA reuptake than cocaine. As a group, these agents have not been reported to produce in humans two key cocaine-like effects: addiction and euphoria (Table 2). Bupropion is marketed as an antidepressant, yet was not reported to produce addiction or euphoria (7) Nomifensine was marketed as an antidepressant, but was withdrawn because of blood dyscrasias. It too has not been reported to produce addiction or euphoria (8). Mazindol, which is marketed as an anorectic, similarly did not produce addiction or 0024-3205/90$3.00 + .oo
PL-18
Cocaine Antagonists
Vol. 46, No. 20, 1990
euphoria (9). Moreover, benztropine, which is widely prescribed for treatment of movement disorders, does not apparently produce addiction or euphoria (10). Consistent with a low abuse liability, bupropion, nomifensine, and benztropine were marketed as schedule III drugs. It would appear that the ability of agents to inhibit DA reuptake in vitro or be self administered by animals does not always predict addictive or euphoric effects in humans. In other words, it is possible that, as a test, selfadministration in animals has false positives. Mazindol is an excellent example of a false positive. As described by Chait et al. (9): “Of the four anorectics tested, MAZ fmazindoll produced the most unexpected results. MAZ was a strong punisher, being chosen on zero occasions by 8 or 9 of the 12 subjects. . . This finding is inconsistent with studies in rhesus monkeys, which show MAZ fo be an effective reinforcer. . . In the present study, MAZ decreased drug liking scores, and produced onZy ‘aversive’ subjective effects (increased anxiety and LSD scores). ” TABLE1 1C50 VALUES FOR DRUGS AS INHIBITORS OF DA REUPTAKE* Drug Cocaine
ED50 (nM) 690
Bupropion
648
Nomifensine
134
Benztropine Mazindol
29.4
GBR12909*
1.0 *IC50 values for various drugs as inhibitors of DA reuptake into striatal synaptosomes (13).*There are no reports of the effects of this agent in humans. Based on these observations made in humans, it seems reasonable to classify DA reuptake inhibitors into two types. Type 1 blockers refer to DA reuptake blockers which produce euphoria and addiction in humans (cocaine), whereas type 2 blockers refer to DA reuptake blockers which do not produce euphoria and addiction in humans. Type 1 drugs might also include amphetamine-like drugs, which release DA, in addition to blocking reuptake. Although pharmacokinetic factors, and effects of type 2 agents unrelated to inhibition of DA reuptake, might account for their apparent lack of cocaine-like effects in humans, it is also possible that type 2 agents interact differently with the DA transporter than do type 1 agents. In this case, given that non-abused (type 2) and abused DA (type 1) reuptake blockers act at the same site (the DA reuptake carrier), administration of a non-abused DA reuptake inhibitor might block the effects of cocaine. Preliminary data that mazindol attenuates cocaine craving and euphoria even after one day of administration support this hypothesis 01).
Vol. 46, No. 20, 1990
Cocaine Antagonists
PL-19
Published data suggest that the ability of an agent to elevate extracellular levels of DA (ECDA) in vivo may provide a meaningful index of abuse liability (12). For example, cocaine and amphetamine, as well as other drugs of abuse, produce large elevations in ECDA as measured by the technique of in vivo microdialysis (12). In contrast, certain agents such GBR12909, a highly potent DA reuptake inhibitor (13) (Table 1) produce much lower elevations of ECDA levels (14). It seems reasonable, therefore, to hypothesize that : (1) The ability of a reuptake inhibitor to elevate the levels of extracellular DA (ECDA) is related to its addictive/euphorogenic properties.
(2) Type 2 DA reuptake inhibitors are less efficacious at elevating ECDA levels than type 1 DA reuptake blockers. In other words, defining elevation of ECDA as the pharmacological end point, DA reuptake inhibitors not abused by humans (type 2 agents) are partial agonists. One potential mechanism for this is that whereas cocaine may completely inhibit the reuptake process, type 2 agents might only partially inhibit it. Although partial agonism is not observed when measuring reuptake of [3HlDA in vitro, it is possible that it might occur in vivo. TABLE 2
Agent
DA REUPTAKE BLOCKERS MARKETED FOR USE lN HUMANS Indication Abuse Liability (Euphoria/Addiction)
Bupropion
Antidepressant
None reported (7).
Nomifensine -CMerital)
Antidepressant
None reported (8).
. (Wellbutrin)
Benztropine (Cogentin)
(Taken off market because of blood dyscrasias) Movement Disorders
None reported
(10).
Mazindol Anorectic None reported (9,151. Drugs which were or are marketed in the United States which are potent inhibitors in DA reuptake. In principle, type 2 agents should attenuate the actions of cocaine, and be potentially useful in humans as cocaine antagonists. A competitive antagonist might be of limited value, since a person would simply self administer more cocaine,
PL-20
Cocaine Antagonists
Vol. 46, No. 20, 1990
overcoming the inhibition, and increasing the risk of peripheral side effects such as cardiac arrhythmias. Alternatively, administration of a tight binding (slowly dissociating) agent, such as GBR12909, should produce an insurmountable (noncompetitive) inhibition over the time period which it remains bound to the reuptake complex. Indeed, in vivo microdialysis experiments have demonstrated that administration of GBR12909 attentuates the ability of cocaine to elevate extracellular dopamine levels in the striatum of rats (16). The hypothesis that type 2 DA reuptake blockers might act as cocaine antagonists in humans provides for several testable predictions. 1) Administration of these agents to humans under controlled circumstances should not demonstrate addiction or euphoria in the majority of subjects, as has been shown for mazindol(9). 2) Pharmacokinetic studies should demonstrate that systemic administration of type 2 agents result in brain concentrations high enough to inhibit the reuptake of DA. 3) Full dose-response curves should demonstrate that type 2 agents are less effacacious at elevating ECDA than cocaine. 4) Type 2 agents should attenuate the ability of cocaine to elevate ECDA levels, as well as the euphoric and addictive effects of cocaine in humans. 5) Commonly used behavioral tests in animals will fail to demonstrate differences between type 2 and type 1 agents. Although the hypotheses discussed in this paper are speculative, it is hoped that their systematic examination will lead to the identification of a cocaine antagonist. References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13. 14.
M.P. GALLOWAY, Trends in the Pharmacological Sciences, 9 451-454, (1988). MC. RITZ, R.J. LAMB, S.R. G0LDBERG;M.J. KUHAR, Science,= 1219-1223, (1987). R.A. WISE, Theorv in Psvchonharmacoloev, S.J. Cooper fed), 103-122, Academic Press, London, NY, (1981). B.K. MADRAS, M.A. FAHEY, J. BERGMAN, D.R CANFIELD, R.D. SPEALMAN, J. Pharmacol. Exp. Ther., 251 131-141, (1989). RD. SPEALMAN, B.K. MADRAS, J. BERGMAN, J. Pharmacol. Exp. Ther., 251 142-149, (1989). J. BERGMAN, B.K. MADRAS, S.E. JOHNSON, RD. SPEALMAN, J. Pharmacol. Exp. Ther., a 150-155, (1989). W.C. STERN, N. HARTO-TRUAX, J. ROGERS, L. MILLER, Adv. Biochem. Psychopharmaaol., 32 21-34, (1982). K. RICKELS, C.C. WEISE, K. SANDLER, A. SCHLESS, M. ZAL, N. NORSTAD, Int. Pharqacopsychiatry, 12 73-88, (1982). L.D. CHAIT, E.H. UHLENHUTH, C.E. JOHANSON, J. Pharmacol. Exp. Ther., a 777-783, (1987x J.R BIANCHINE, &odman and Gilman’s The Pharmacological Basis of
Theraneutics, A.G. Gilman, L.S. Goodman and A. Gilman feds), 484485, McMillan, New York, (1980). -P. BERGER, F. GAWIN, T.R. KOSTEN, Lancet., I 283-283, (1989). G.D. DICHIARA, A. IMPERATO, Proc. Natl. Acad. Sci.U.S.A., @ 52745278, (1988). P.I-& ANDERSEN, J. Neurochem., %g 1887-1896, (1987). B.H.,w, G. DAMSMA, J.@. DE VRIES, H. KONING, Eur. J. Pharmacol., m 123-128, (1987).
Vol. 46, No. 20, 1990
15. 16.
Cocaine Antagonists
A.J. HADLER, J Clin Pharmacol New Drugs, 12 453-458, (1972). R B. ROTHMAN, A. MELE, A. A. REID, H. AKUNNE, N. GREIG, A. THURKAUF, K. C. RICE, A. PERT, EEBS LETT., m 341-344, (1989).
PL-21
Pergamon Press
PHARMACOLOGYLETTERS Dialogue
HIGH AFFINITY DOPAMINE REUPTAICE INHIBITORS AS POTENTIAL COCAINE ANTAGONISTS: A STRATEGY FOR DRUG DEVELOPMENT Richard B. Rothman Unit on Receptor Studies, Laboratory of Clinical Science, National Institute of Mental Health, Bldg. lO-3D41, Bethesda, MD 28892. (Received March 6, 1990; Accepted March 7, 1990)
Abstract. The addictive and euphorogenic effects of cocaine are thought to result primarily from inhibition of dopamine reuptake. Although the potency of cocainelike drugs as inhibitors of DA reuptake is highly correlated with their potency as reinforcers in .animals, several potent DA reuptake blockers (bupropion, nomifensine, benztropine, and mazindol) have not been reported to produce addiction or euphoria in humans. Based on these observations in humans, DA reuptake inhibitors are classified into two groups; type 1 blockers, which produce addiction and euphoria, and type 2 blockers, which do not. Given that type 1 and type 2 blockers act at the same site (the DA transporter), the author suggests that type 2 agents may antagonize the effects of cocaine, and might prove useful in the treatment of cocaine addiction. Cocaine, a major drug of abuse, is thought to produce its effects primarily by inhibiting the reuptake of biogenic amines (1). Although cocaine inhibits the reuptake of norepinephrine and serotonin, its ability to inhibit the reuptake of dopamine (DA) is thought to be the main neurochemical mechanism responsible for its addictive and euphorogenic properties (2). Several lines of evidence support the DA hypothesis, including a major role of dopaminergic systems in reward mechanisms (3) and a correlation between the potency of cocaine like drugs to inhibit DA reuptake, [3H]mazindol or [3H]cocaine binding, and their potency as selfadministered agents in animals (2,441. Several DA reuptake inhibitors which produce cocaine-like effects in animals are, or were, marketed in the United States. As described in Table 1, bupropion, nomifensine, mazindol and benztropine are all more potent inhibitors of DA reuptake than cocaine. As a group, these agents have not been reported to produce in humans two key cocaine-like effects: addiction and euphoria (Table 2). Bupropion is marketed as an antidepressant, yet was not reported to produce addiction or euphoria (7) Nomifensine was marketed as an antidepressant, but was withdrawn because of blood dyscrasias. It too has not been reported to produce addiction or euphoria (8). Mazindol, which is marketed as an anorectic, similarly did not produce addiction or 0024-3205/90$3.00 + .oo
PL-18
Cocaine Antagonists
Vol. 46, No. 20, 1990
euphoria (9). Moreover, benztropine, which is widely prescribed for treatment of movement disorders, does not apparently produce addiction or euphoria (10). Consistent with a low abuse liability, bupropion, nomifensine, and benztropine were marketed as schedule III drugs. It would appear that the ability of agents to inhibit DA reuptake in vitro or be self administered by animals does not always predict addictive or euphoric effects in humans. In other words, it is possible that, as a test, selfadministration in animals has false positives. Mazindol is an excellent example of a false positive. As described by Chait et al. (9): “Of the four anorectics tested, MAZ fmazindoll produced the most unexpected results. MAZ was a strong punisher, being chosen on zero occasions by 8 or 9 of the 12 subjects. . . This finding is inconsistent with studies in rhesus monkeys, which show MAZ fo be an effective reinforcer. . . In the present study, MAZ decreased drug liking scores, and produced onZy ‘aversive’ subjective effects (increased anxiety and LSD scores). ” TABLE1 1C50 VALUES FOR DRUGS AS INHIBITORS OF DA REUPTAKE* Drug Cocaine
ED50 (nM) 690
Bupropion
648
Nomifensine
134
Benztropine Mazindol
29.4
GBR12909*
1.0 *IC50 values for various drugs as inhibitors of DA reuptake into striatal synaptosomes (13).*There are no reports of the effects of this agent in humans. Based on these observations made in humans, it seems reasonable to classify DA reuptake inhibitors into two types. Type 1 blockers refer to DA reuptake blockers which produce euphoria and addiction in humans (cocaine), whereas type 2 blockers refer to DA reuptake blockers which do not produce euphoria and addiction in humans. Type 1 drugs might also include amphetamine-like drugs, which release DA, in addition to blocking reuptake. Although pharmacokinetic factors, and effects of type 2 agents unrelated to inhibition of DA reuptake, might account for their apparent lack of cocaine-like effects in humans, it is also possible that type 2 agents interact differently with the DA transporter than do type 1 agents. In this case, given that non-abused (type 2) and abused DA (type 1) reuptake blockers act at the same site (the DA reuptake carrier), administration of a non-abused DA reuptake inhibitor might block the effects of cocaine. Preliminary data that mazindol attenuates cocaine craving and euphoria even after one day of administration support this hypothesis 01).
Vol. 46, No. 20, 1990
Cocaine Antagonists
PL-19
Published data suggest that the ability of an agent to elevate extracellular levels of DA (ECDA) in vivo may provide a meaningful index of abuse liability (12). For example, cocaine and amphetamine, as well as other drugs of abuse, produce large elevations in ECDA as measured by the technique of in vivo microdialysis (12). In contrast, certain agents such GBR12909, a highly potent DA reuptake inhibitor (13) (Table 1) produce much lower elevations of ECDA levels (14). It seems reasonable, therefore, to hypothesize that : (1) The ability of a reuptake inhibitor to elevate the levels of extracellular DA (ECDA) is related to its addictive/euphorogenic properties.
(2) Type 2 DA reuptake inhibitors are less efficacious at elevating ECDA levels than type 1 DA reuptake blockers. In other words, defining elevation of ECDA as the pharmacological end point, DA reuptake inhibitors not abused by humans (type 2 agents) are partial agonists. One potential mechanism for this is that whereas cocaine may completely inhibit the reuptake process, type 2 agents might only partially inhibit it. Although partial agonism is not observed when measuring reuptake of [3HlDA in vitro, it is possible that it might occur in vivo. TABLE 2
Agent
DA REUPTAKE BLOCKERS MARKETED FOR USE lN HUMANS Indication Abuse Liability (Euphoria/Addiction)
Bupropion
Antidepressant
None reported (7).
Nomifensine -CMerital)
Antidepressant
None reported (8).
. (Wellbutrin)
Benztropine (Cogentin)
(Taken off market because of blood dyscrasias) Movement Disorders
None reported
(10).
Mazindol Anorectic None reported (9,151. Drugs which were or are marketed in the United States which are potent inhibitors in DA reuptake. In principle, type 2 agents should attenuate the actions of cocaine, and be potentially useful in humans as cocaine antagonists. A competitive antagonist might be of limited value, since a person would simply self administer more cocaine,
PL-20
Cocaine Antagonists
Vol. 46, No. 20, 1990
overcoming the inhibition, and increasing the risk of peripheral side effects such as cardiac arrhythmias. Alternatively, administration of a tight binding (slowly dissociating) agent, such as GBR12909, should produce an insurmountable (noncompetitive) inhibition over the time period which it remains bound to the reuptake complex. Indeed, in vivo microdialysis experiments have demonstrated that administration of GBR12909 attentuates the ability of cocaine to elevate extracellular dopamine levels in the striatum of rats (16). The hypothesis that type 2 DA reuptake blockers might act as cocaine antagonists in humans provides for several testable predictions. 1) Administration of these agents to humans under controlled circumstances should not demonstrate addiction or euphoria in the majority of subjects, as has been shown for mazindol(9). 2) Pharmacokinetic studies should demonstrate that systemic administration of type 2 agents result in brain concentrations high enough to inhibit the reuptake of DA. 3) Full dose-response curves should demonstrate that type 2 agents are less effacacious at elevating ECDA than cocaine. 4) Type 2 agents should attenuate the ability of cocaine to elevate ECDA levels, as well as the euphoric and addictive effects of cocaine in humans. 5) Commonly used behavioral tests in animals will fail to demonstrate differences between type 2 and type 1 agents. Although the hypotheses discussed in this paper are speculative, it is hoped that their systematic examination will lead to the identification of a cocaine antagonist. References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13. 14.
M.P. GALLOWAY, Trends in the Pharmacological Sciences, 9 451-454, (1988). MC. RITZ, R.J. LAMB, S.R. G0LDBERG;M.J. KUHAR, Science,= 1219-1223, (1987). R.A. WISE, Theorv in Psvchonharmacoloev, S.J. Cooper fed), 103-122, Academic Press, London, NY, (1981). B.K. MADRAS, M.A. FAHEY, J. BERGMAN, D.R CANFIELD, R.D. SPEALMAN, J. Pharmacol. Exp. Ther., 251 131-141, (1989). RD. SPEALMAN, B.K. MADRAS, J. BERGMAN, J. Pharmacol. Exp. Ther., 251 142-149, (1989). J. BERGMAN, B.K. MADRAS, S.E. JOHNSON, RD. SPEALMAN, J. Pharmacol. Exp. Ther., a 150-155, (1989). W.C. STERN, N. HARTO-TRUAX, J. ROGERS, L. MILLER, Adv. Biochem. Psychopharmaaol., 32 21-34, (1982). K. RICKELS, C.C. WEISE, K. SANDLER, A. SCHLESS, M. ZAL, N. NORSTAD, Int. Pharqacopsychiatry, 12 73-88, (1982). L.D. CHAIT, E.H. UHLENHUTH, C.E. JOHANSON, J. Pharmacol. Exp. Ther., a 777-783, (1987x J.R BIANCHINE, &odman and Gilman’s The Pharmacological Basis of
Theraneutics, A.G. Gilman, L.S. Goodman and A. Gilman feds), 484485, McMillan, New York, (1980). -P. BERGER, F. GAWIN, T.R. KOSTEN, Lancet., I 283-283, (1989). G.D. DICHIARA, A. IMPERATO, Proc. Natl. Acad. Sci.U.S.A., @ 52745278, (1988). P.I-& ANDERSEN, J. Neurochem., %g 1887-1896, (1987). B.H.,w, G. DAMSMA, J.@. DE VRIES, H. KONING, Eur. J. Pharmacol., m 123-128, (1987).
Vol. 46, No. 20, 1990
15. 16.
Cocaine Antagonists
A.J. HADLER, J Clin Pharmacol New Drugs, 12 453-458, (1972). R B. ROTHMAN, A. MELE, A. A. REID, H. AKUNNE, N. GREIG, A. THURKAUF, K. C. RICE, A. PERT, EEBS LETT., m 341-344, (1989).
PL-21