No Heading
Purpose.
The benztropine (BZT) analogues bind with high affinity to the dopamine transporter (DAT) and demonstrate a behavioral and pharmacokinetic profile unlike that of cocaine. The development of a predictive pharmacokinetic/pharmacodynamic (PK/PD) model to characterize the concentration-effect relationship between the BZT analogues and brain dopamine (DA) levels is an important step in the evaluation of these compounds as potential cocaine abuse pharmacotherapies. Hence, the objective of this study was to mathematically characterize the PD of BZT analogues and cocaine, using appropriate PK/PD models.
Methods.
Dialysis probes were stereotaxically implanted into the nucleus accumbens of Sprague-Dawley rats (275–300 g). Extracellular fluid (ECF) DA levels were measured after intravenous administration of the BZT analogues AHN-1055 and AHN-2005, as well as cocaine using high performance liquid chromatography-electrochemical detection (HPLC-ECD). PD models were used to describe the relationship between the BZT analogues or cocaine and brain microdialysate DA, and suitability was based on standard goodness-of-fit criteria.
Results.
The BZT analogues produced a sustained increase in brain microdialysate DA levels in comparison to cocaine. The time of maximum concentration (Tmax) for brain microdialysate DA was 2 h for AHN-1055 and 1 h for AHN-2005 compared to a Tmax of 10 min for cocaine. The duration of brain microdialysate DA elevation was ∼12–24 h for the BZTs in comparison to 1 h for cocaine. An indirect model with inhibition of loss of response and a sigmoid Emax model best described the PK/PD for the BZT analogues and cocaine, respectively. The 50% of maximum inhibition (IC50) of the loss of DA was lower for AHN-2005 (226 ± 27.5 ng/ml) compared to AHN-1055 (321 ± 19.7 ng/ml). In addition, the EC50 for cocaine was 215 ± 11.2 ng/ml.
Conclusions.
The slow onset and long duration of BZT analogue–induced DA elevation may avoid the reinforcing effects and craving of cocaine. Further, the developed models will be useful in characterizing the PK/PD of other analogues and aid in the assessment of the therapeutic efficacy of the BZT analogues as substitute medications for cocaine abuse.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
1. D. A. Gorelick. The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv. Pharmacol. 42:995–997 (1998).
2. L. L. Howell and K. M. Wilcox. The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J. Pharmacol. Exp. Ther. 298:1–6 (2001).
3. A. H. Newman, A. C. Allen, S. Izenwasser, and J. L. Katz. Novel 3α-(diphenylmethoxy) tropane analogs: potent dopamine uptake inhibitors without cocaine-like behavioral profiles. J. Med. Chem. 37:2258–2261 (1994).
4. A. H. Newman, R. H. Kline, A. C. Allen, S. Izenwasser, C. George, and J. L. Katz. Novel 4′-substituted and 4′,4″-disubstituted 3α-(diphenylmethoxy) tropane analogs as potent and selective dopamine uptake inhibitors. J. Med. Chem. 38:3933–3940 (1995).
5. A. H. Newman. Novel dopamine transporter ligands: the state of the art. Med. Chem. Res. 8:1–11 (1998).
6. J. L. Katz, S. Izenwasser, R. H. Kline, A. C. Allen, and A. H. Newman. Novel 3α-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J. Pharmacol. Exp. Ther. 288:302–315 (1999).
7. A. H. Newman and S. S. Kulkarni. Probes for the dopamine transporter: new leads toward a cocaine-abuse therapeutic—a focus on analogues of benztropine and rimcazole. Med. Res. Rev. 22:1–36 (2002).
8. G. E. Agoston, J. H. Wu, S. Izenwasser, C. George, J. L. Katz, R. H. Kline, and A. H. Newman. Novel N-substituted-3a(bis (4′-fluorophenyl methoxy)) tropane analogues: selective ligands for the dopamine transporter. J. Med. Chem. 40:4329–4339 (1997).
9. M. J. Robarge, G. E. Agoston, S. Izenwasser, T. Kopajtic, C. George, J. L. Katz, and A. H. Newman. Highly selective chiral N-substituted 3alpha-(bis(4′-fluorophenyl)methoxy)tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis. J. Med. Chem. 43:1085–1093 (2000).
10. S. Raje, J. Cao, A. H. Newman, H. Gao, and N. D. Eddington. Evaluation of the blood brain barrier transport, population pharmacokinetics and brain distribution of benztropine analogs and cocaine using in vitro and in vivo techniques. J. Pharmacol. Exp. Ther. 307:801–808 (2003).
11. J. Dingemanse, M. Danhof, and D. D. Breimer. Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: an overview. Pharmacol. Ther. 38:1–52 (1988).
12. D. Jolly and P. Vezina. In vivo microdialysis in the rat: low cost and low labor construction of a small diameter, removable, concentric-style microdialysis probe system. J. Neurosci. Methods 68:259–267 (1996).
13. G. Paxinos and C. Watson. The Rat Brain in Stereotaxic Coordinates, 4th ed., Academic Press, Orlando (1998).
14. Z. You, Y. Chen, and R. A. Wise. Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation. Neuroscience 107:629–639 (2001).
15. Y. L. Hurd, J. Kehr, and U. Ungerstedt. In vivo microdialysis as a technique to monitor drug transport: correlation of extracellular cocaine levels and dopamine overflow in the rat brain. J. Neurochem. 51:1314–1316 (1998).
16. N. L. Dyaneka, V. Garg, and W. J. Jusko. Comparison of four baic models of indirect pharmacodynamic responses. J. Pharmacokin Biopharm. 24:457–478 (1993).
17. W. J. Pan and M. A. Hedaya. An animal model for simultaneous pharmacokinetic/pharmacodynamic investigations: application to cocaine. J. Pharmacol. Toxicol. Methods 39:1–8 (1998).
18. P. W. Czoty, J. B. Justice Jr., and L. L. Howell. Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys. Psychopharmacology (Berl.) 148:299–306 (2000).
19. P. W. Kalivas and P. Duffy. Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 5:48–58 (1990).
20. H. Tsukada, N. Harada, S. Nishiyama, H. Ohba, and T. Kakiuchi. Cholinergic neuronal modulation alters dopamine D2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: positron emission tomography studies with microdialysis in the conscious monkey brain. J. Neurosci. 20:7067–7073 (2000).
21. R. B. Rothman. High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development. Life Sci. 46:PL17–PL21 (1990).
22. R. B. Rothman, A. Mele, A. A. Reid, H. C. Akunne, N. Greig, A. Thurkauf, B. R. De Costa, K. C. Rice, and A. Pert. GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine. Pharmacol. Biochem. Behav. 40:387–397 (1991).
23. B. K. Tolliver, A. H. Newman, J. L. Katz, L. B. Ho, L. M. Fox, K. Hsu Jr., and S. P. Berger. Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo. J. Pharmacol. Exp. Ther. 289:110–122 (1999).
24. A. Hutchaleelaha, J. Sukbuntherng, and M. Mayersohn. Simple apparatus for serial blood sampling in rodents permitting simultaneous measurement of locomotor activity as illustrated with cocaine. J. Pharmacol. Toxicol. Methods 37:9–14 (1997).
25. P. W. Kalivas and C. D. Barnes. Limbic Motor Circuits and Neuropsychiatry, CRC Press, Boca Raton (1993).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Raje, S., Cornish, J., Newman, A. et al. Pharmacodynamic Assessment of the Benztropine Analogues AHN-1055 and AHN-2005 Using Intracerebral Microdialysis to Evaluate Brain Dopamine Levels and Pharmacokinetic/Pharmacodynamic Modeling. Pharm Res 22, 603–612 (2005). https://doi.org/10.1007/s11095-005-2488-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-005-2488-8