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. 2004 Feb;24(1):129–136. doi: 10.1023/B:CEMN.0000012718.08443.60

Cocaine Treatment Causes Early and Long-Lasting Changes in Muscarinic and Dopaminergic Receptors

D S Macêdo 1, E E Correia 1, S M M Vasconcelos 1, L M V Aguiar 1, G S B Viana 1, F C F Sousa 1,✉
PMCID: PMC11529941  PMID: 15049517

Abstract

1. The study of changes that persist after drug discontinuation could be fundamental to understand the mechanisms involved in craving and relapse.

2. In this work the changes occurring in muscarinic, D1- and D2-like receptors after 30 min (immediate), 1 day (early), 5 and 30 days (late) withdrawal periods were studied, in the striatum of rats treated once a day for 7 days with cocaine 20 and 30 mg/kg, i.p.

3. Binding assays were performed in 10% homogenates and ligands used were [3H]-N-methylscopolamine, [3H]-SCH 23390, and [3H]-spiroperidol for muscarinic (M1 + M2-like), D1-, and D2-like receptors, respectively.

4. Muscarinic receptors presented a downregulation at all doses and discontinuation times, while the dissociation constant (Kd) for this receptor decreased after 30 min, 5 and 30 days abstinence times. In relation to D1-like receptors we found an antagonistic effect with 100% increase in receptor number 30 min after the last cocaine injection, but after 1-day withdrawal a downregulation was observed with both doses that persisted up to 30 days, only with the higher dose. The dissociation constant value (Kd) for this receptor showed a decrease only with 5 and 30 days withdrawal. An increase occurred with D2-like receptors at all doses and withdrawal periods studied, while Kd increased in 30-min, 5, and 30 days withdrawal.

5. In this work we found that the subchronic cocaine treatment produces early and long-lasting modifications in cholinergic muscarinic as well in dopaminergic receptors that persist up to 30 days of cocaine withdrawal.

Keywords: cocaine withdrawal, dopaminergic receptors, muscarinic receptors, rat striatum

REFERENCES

  1. Callahan, P. M., de la Garza, R., and Cunningham, K. A. (1997). Mediation of the discriminative stimulus properties of cocaine by mesocorticolimbic dopamine systems. Pharmacol. Biochem. Behav.57:601-607. [DOI] [PubMed] [Google Scholar]
  2. Chausmer, A. L., and Katz, J. L. (2001). The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice. Psychopharmacology, 155:69-77. [DOI] [PubMed] [Google Scholar]
  3. Consolo, S., Wu, C. F., and Fusi, R. (1987). D1 receptor linked mechanism modulates cholinergic neurotransmission in rat striatum. J. Pharmacol. Exp. Ther.242:300-305. [PubMed] [Google Scholar]
  4. Dombrowski, A. M., Jerkins, A. A., and Kauffman, F. C. (1983). Muscarinic receptor binding and oxidative activities in the adult rat superior cervical ganglion: Effects of 6-hydroxy-dopamine on nerve growth factor. J. Neurosci.3:1963-1970 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Feldman, D. J., Frank, R. A., Kehne, J. H., Flannery, R., Brown, D., Soni, S., Byrd, G., and Shah, S. (1997). Mixed D2/5-HT2 antagonism differentially affects apomorphine and amphetamine-induced stereotyped behavior. Pharmacol. Biochem. Behav.58:565-572. [DOI] [PubMed] [Google Scholar]
  6. Henry, D. J., and White, F. J. (1991). Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J. Pharmacol. Exp. Ther.258:882-890. [PubMed] [Google Scholar]
  7. Kessler, R. M., Ansari, M. S., Schmidt, D. E., De Paulis, T., Clanton, J. A., Innis, R., Tikriti, M., Manning, R. G., and Gillespie, D. (1991). High affinity dopamine D2 receptors. Life Sci.49:617-629. [DOI] [PubMed] [Google Scholar]
  8. Kleven, M. S., Perry, B. D., Woolverton, W. L., and Seiden, L. S. (1990). Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain. Brain Res.532:265-270. [DOI] [PubMed] [Google Scholar]
  9. Koob, G. F., Caine, S. B., Parsons, L., Markou, A., and Weiss, F. (1997). Opponent process model and psychostimulant addiction. Pharmacol. Biochem. Behav.57:513-521. [DOI] [PubMed] [Google Scholar]
  10. Kreuter, J., Tsukada, H., Schlussman, S. D., Kakiuchi, T., Nishiyama, S., Maggos, C. E., Unterwald, E. M., and Kreek, M. J. (1998). Effects of withdrawal from binge pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain as measured by PET. Problems of drug dependence 1994. In Proceedings of the 59th Annual Scientific Meeting, The College on Problems of Drug Dependence, NIDA Research Monograph, Washington, DC. [Google Scholar]
  11. Kuhar, M., and Pilotte, N. S. (1996). Neurochemical changes in cocaine withdrawal. Tips17:260-264. [DOI] [PubMed] [Google Scholar]
  12. Kupfermann, I., Kandel, E. R., and Iversen, S. (2000). Motivational and addictive states. In: Kandel, E. R., Schwartz, J. H., and Jessell, T. M. (eds.), Principles of Neural Sciences, McGraw-Hill, New York, pp. 998-1013. [Google Scholar]
  13. Laurier, L. G., Corrigall, W. A., and George, S. R. (1994). Dopamine receptor density, sensitivity and mRNA levels are altered following self-administration of cocaine in the rat. Brain Res.634:31-40. [DOI] [PubMed] [Google Scholar]
  14. Leshner, A. I. (1996). Molecular mechanisms of cocaine addiction. N. Engl. J. Med.335:128-129. [DOI] [PubMed] [Google Scholar]
  15. Lipton, J. W., Olsen, R. W., and Ellison, G. D. (1995). Lengh of continuous cocaine exposure determines the persistence of muscarinic and benzodiazepine receptor alterations. Brain Res.676:378-385. [DOI] [PubMed] [Google Scholar]
  16. Lowry, H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurements with the folin phenol reagent. J. Biol Chem.193:265-275. [PubMed] [Google Scholar]
  17. Macêdo, D. S., Sousa, F. C. F., Vasconcelos, S. M. M., Lima, V. T. M., and Viana, G. S. B. (2001). Different times of withdrawal from cocaine administration cause changes in muscarinic and dopaminergic receptors in rat premotor cortex. Neurosci. Lett.312:129-132. [DOI] [PubMed] [Google Scholar]
  18. Maggos, C. E., Tsukada, H., Kakiuchi, T., Nishiyama, S., Myers, J. E., Kreuter, J., Schlussman, S. D., Unterwald, E. M., Ho, A., and Kreek, M. J. (1998). Sustained withdrawal allows normalization of in vivo [11C]N-methylspiperone dopamine D2 receptor binding after chronic binge cocaine: A Positron emission tomography study in rats. Neuropsychopharmacology19:146-153. [DOI] [PubMed] [Google Scholar]
  19. Meltzer, H. Y., Matsubara, S., and Lee, J. C. (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1-and D2-and serotonin 2 pK1 values. J. Pharmacol. Exp. Ther.251:238-246. [PubMed] [Google Scholar]
  20. Neisewander, J. L., Lucki, L., and McGonigle, P. (1994). Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats. Synapse16:1-10. [DOI] [PubMed] [Google Scholar]
  21. Sharkey, J., Ritz, M. C., Schenden, J. A., Hanson, R. C., and Kuhar, M. J. (1988). Cocaine inhibits muscarinic cholinergic receptors in heart and brain. J. Pharmacol. Exp. Ther.246:1048-1052. [PubMed] [Google Scholar]
  22. Sousa, F. C. F., Gomes, P. B., Macêdo, D. S., Marinho, M. M. F., and Viana, G. S. B. (1999). Early withdrawal from repeated cocaine administration upregulates muscarinic and dopaminergic D2-like receptors in rat neostriatum. Pharmacol. Biochem. Behav.62:15-20. [DOI] [PubMed] [Google Scholar]

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