Abstract
Addiction exacts enormous costs on society in terms of both its clinical and social ramifications. Addiction, defined as the compulsive use of a drug despite adverse consequences, is thought to develop as a result of adaptive changes in specific brain areas. The persistence of these progressively developing adaptations in brain function suggests that long-lasting changes in the brain are important in mediating addictive phenomena. The adaptations associated with compulsive drug use are defined by the terms tolerance, sensitization, dependence, and withdrawal. Tolerance develops when repeated administration of a drug produces a decreased effect or when increasing doses must be administered to obtain the effect observed with the original dose. Sensitization describes the opposite situation, wherein repeated drug administration elicits increasing effects. Dependence refers to an altered physiological state that necessitates the continued administration of the abused drug to prevent the appearance of a withdrawal syndrome. Withdrawal is characterized by psychological and perhaps physical disturbances when the abused drug is withdrawn. The goal of this chapter is to review the evidence for a role of G proteins in these phenomena.
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References
Albert, P. R. and Morris, S. J. (1994) Antisense knockouts: molecular scalpels for the dissection of signal transduction. Trends Pharmacol. Sci 15, 250–254.
Attali, B. and Vogel, Z. (1989) Long-term opiate exposure leads to reduction of the alpha i-1 subunit of GTP-binding proteins. J. Neurochem 53, 1636–1639.
Bischofberger, N. and Shea, R. G. (1992) Oligonucleotide-based therapeutics, in Nucleic Acid Targeted Drug Design (Probpst, C L. and Perun T J., eds.), Marcel Dekker, New York, pp. 579–612.
Bozarth, M. A (1986) Neural basis of psychomotor stimulant and opiate reward: evidence suggesting the involvement of a common dopaminergic system. Behav Brain Res 22, 107–116
Brecht, S., Gass, P., Anton, F., Bravo, R, Zimmerman, M., and Herdegen, T. (1994) Induction of c-Jun and suppression of CREB transcription factor proteins in axotomized neurons of substantia nigra and covariation with tyrosine hydroxylase. Mol. Cell Neurosci. 5, 431–441.
De Vries, L, Mousli, M., Wurmser, A., and Farquhar, M. G. (1995) GAIP, a protein that specifically interacts with the trimeric G protein Gαi3, is a member of a protein family with a highly conserved core domain. Proc. Natl. Acad. Sci. USA 92, 11,916–11,920.
Druey, K. M., Blumer, K. J., Kang, V. H., and Kehrl, J. H. (1996) Inhibition of G protein mediated MAP kinase activation by a new mammalian gene family. Nature 379, 742–746.
Dworkin, S. I. and Smith, J. E (1993) Opiates/opioids and reinforcement, in Biological Basis of Substance Abuse (ai]Korenman, S. G. and Barchas, J. D., eds), Oxford University Press, New York, pp. 327–338.
Eriksson, P. S., Carlsson, B., Isaksson, O. G. P., Hansson, E., and Ronnback, L. (1992) Altered amounts of G protein mRNA and cAMP accumulation after long-term opioid receptor stimulation of neurons in primary culture from the rat cerebral cortex. Mol. Brain Res. 14, 317–325.
George, F. R. and Goldberg, S. R. (1989) Genetic approaches to the analysis of addiction processes. Trends Pharmacol. Sci. 10, 78–83.
Green, A, Johnson, J. L, and Milligan, G. (1990) Down-regulation of Gi subtypes by prolonged incubation of adipocytes with an A1 adenosine receptor agonist. J Biol. Chem. 265, 5206–5210.
Guitart, X., Beitner-Johnson, D., and Nestler, E. J. (1992a) Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and in their regulation by chronic morphine in the mesolimbic dopamine system. Synapse 12, 242–253.
Guitart, X., Thompson, M A., Mirante, C. K., Greenberg, M. E., and Nestler, E. J. (1992b) Regulation of cyclic AMP response element-binding protein (CREB) phosphorylation by acute and chronic morphine in the rat locus coeruleus. J Neurochem. 58, 1168–1171.
Guitart, X., Kogan, J. H., Berhow, M., Terwilliger, R. Z, Aghajanian, G. K., and Nestler, E. J. (1993) Lewis and Fischer rat strains display differences in biochemical, electrophysiological and behavioral parameters: studies in the nucleus accumbens and locus coeruleus of drug naive and morphine-treated animals. Brain Res. 611, 7–17.
Hummler, E., Cole, T. J., Blendy, J. A., Ganss, R., Aguzzi, A, Schmid, W., Beermann, F., and Schütz, G. (1994) Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc. Natl Acad. Sci. USA 91, 5647–5651.
Innis, R. B., Nestler, E J., and Aghajanian, G. K (1988) Evidence for G protein mediation of serotonin-and GABAB-induced hyerpolarization of rat dorsal raphe neurons Brain Res 459, 27–36.
Kleuss, C, Hescheler, J, Ewel, C, Rosenthal, W., Schultz, G., and Wittig, B. (1991) Assignment of G protein subtypes to specific receptors inducing inhibition of calcium currents. Nature 353, 43–47.
Koob, GF. (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol. Sci. 13, 177–184.
Meyer, T E and Habener, J. F. (1993) Cyclic adenosine 3′, 5′-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev. 14, 269–290.
Milligan, J. F, Mateucci, M. D., and Martin, J. C (1993) Current concepts in antisense drug design. J Med. Chem. 36, 1923–1937
Nestler, E J. (1992) Molecular mechanisms of drug addiction. J Neurosci 12, 2439–2450.
Nestler, E. J, Hope, B. T., and Widnell, K. L. (1993) Drug addiction a model for the molecular basis of neural plasticity. Neuron 11, 995–1006.
Parolaro, D., Rubino, T, Gori, E., Massi, P., Bendotti, C, Patrini, G., Mar-cozzi, C, and Parenti, M. (1993) In situ hybridization reveals specific increases in Gαs and Gαo mRNA in discrete brain regions of morphine-tolerant rats Eur.J Pharmacol. Mol Pharmacol. 244, 211–222
Raymond, J R. (1995) Multiple mechanisms of receptor-G protein signaling specificity Am. J Physiol. 269, F141–158
Roush, W (1996) Regulating G protein signaling. Science 271, 1056–1058
Rubino, T., Massi, P., Patrini, G., Venier, I., Giagnoni, G., and Parolaro, D (1994) Effect of chronic exposure to naltrexone and opioid selective agonists on G protein mRNA levels in the rat nervous system Mol Brain Res 23, 333–337
Russell, D. S., Widnell, K. L, and Nestler, E. J (1996). Use of antisense oligonucleotides to investigate brain function The Neuroscientist, 2, 79–82.
Self, D W and Nestler, E. J (1995) Molecular mechanisms of drug reinforcement and addiction. Annu. Rev. Neurosci. 18, 463–495
Self, D. W., Terwilliger, R. Z., Nestler, E. J., and Stein, L (1994) Inactivation of Gi and Go proteins in nucleus accumbens reduces both cocaine and heroin reinforcement J. Neurosci. 14, 6239–6247.
Stein, C. A and Chen, Y.-C (1993) Antisense oligonucleotides as therapeutic agents—is the bullet really magical? Science 261, 1004–1012
Struthers, R S, Vale, W. W, Arias, C, Sawchenko, P E., and Montmmy, M R (1991) Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant Nature (Lond ) 350, 622–624.
Suzuki, T., George, F R., and Meisch, R. A. (1988) Differential establishment and maintenance of oral ethanol reinforced behaviour in Lewis and Fischer 344 inbred rat strains J. Pharm Exp Ther. 245, 164–170
Terwilliger, R Z, Beitner-Johnson, D, Sevarino, K A., Crain, S M., and Nestler, E. J (1991) A general role for adaptations in G proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function Brain Res. 548, 100–110
Van Vliet, B. J., Van Rijswijk, A L, Warden, G., Mulder, A H, and Schoffelmeer, A. N (1993) Adaptive changes in the number of Gs-and Gi proteins underlie adenylyl cyclase sensitization in morphine-treated rat striatal neurons Eur J Pharmacol 245, 23–29
Walker, W. H., Fucci, L., and Habener J. F. (1995) Expression of the gene encoding transcription factor cyclic adenosine 3′5′-monophosphate (cAMP) response element-binding protein (CREB) Regulation by follicle stimulating hormone-induced cAMP signaling in primary rat sertoli cells. Endocrinology 136, 3534–3545.
Wang, H., Watkins, D. C, Malbon, C C (1992) Antisense oligodeoxynucleotides to Gs protein α-subunit sequence accelerate differentiation of fibroblasts to adipocytes. Nature (Lond.) 358, 334–337
Widnell, K L., Russell, D. S., and Nestler, E. J. (1994) Regulation of expression of cAMP response element-binding protein in the locus coeruleus in vivo and in a locus coeruleus-like cell line in vitro. Proc Natl. Acad Sci USA 91, 10,947–10,951
Widnell, K. L., Self, D. W., Lane, S. B., Russell, D. S., Vaidya, V., Miserendino, M, Rubin, C S., Duman, R. S., and Nestler, E. J. (1996) Regulation of CREB expression: in vivo evidence for a functional role in morphine action in the nucleus accumbens J Pharmacol Exp. Ther. 276, 306–315.
Wise, R. A (1990) The role of reward pathways in the development of drug dependence, in Psychotropic Drugs of Abuse (Balfour, D. J. K., ed), Pergamon, Oxford, pp. 23–57.
Woolf, T M, Jennings, C. G B., Rebagliati, M., and Melton, D. A. (1990) The stability, toxicity and effectiveness of unmodified and phosphorothioate antisense oligodeoxynucleotides in Xenopus oocytes and embryos Nucleic Acids Res. 18, 1763–1769
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Widnell, K.L., Mestler, E.J. (1997). Molecular Mechanisms of Opiate Addiction in the Nucleus Accumbens. In: Mishra, R.K., Baker, G.B., Boulton, A.A. (eds) G Protein Methods and Protocols. Neuromethods, vol 31. Humana Press. https://doi.org/10.1385/0-89603-490-9:189
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DOI: https://doi.org/10.1385/0-89603-490-9:189
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