- Email: [email protected]
Nuclear Memory: Gene Transcription and Behavior
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References 1. Belknap, J. K., Metten, P.,Helms, M. L., O’Toole, L. A., Angeli-Gade, S., Crabbe, J. C., and Phillips, T. J. (1993). QTL applications to substances of abuse: Physical dependence studies with nitrous oxide and ethanol. Behuv. Genet. 23, 213-222. 2. Johnson, T. E., DeFries, J. C., and Markel, P. D. (1992). Mapping quantitative trait loci for behavioral traits in the mouse. Behav. Genet. 22, 635-653. 3. Grisel, J. E., Belknap, J. K., O’Toole, L. A,, Helms, M. L., Wenger, C. D., and Crabbe, J, C. (1997).Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mice. J . Neurosci. 17, 745-754. 4. Durkin, T., Ayad, G., Ebel, A., and Mandel, P. (1977).Comparative study of acetylcholinesterase and choline acetyltransferase enzyme activity in brains of DBA and C57 mice. Nut. N e w Biol. 242, 56-58. 5. Groves, P. M., Garcia-Munoz, M., Linder, J. C., Manley, M. S., Martone, M. M., and Young, S . J. (1995). Elements of the intrinsic organization and information processing in the neostriatum. In Models of Information Processing in the Basal Ganglia. J. C. Houk, J, L. Davis, and D. G. Beiser, (eds.), pp. 51-96. MIT Press, Cambridge, MA. 6. Crabbe, J. C., Belknap, J. K., and Buck, K. J. (1994). Genetic animal models of alcohol and drug abuse. Science 264, 1715-1723. 7. Crabbe, J. C., Phillips, T. J., Feller, D. J., Wenger, C. D., Lessov, C. N., and Schafer, G. L. (1996).Elevated alcohol consumption in null mutant mice lacking 5-HTIBreceptors. Nat. Genet. 14, 98-101. 8. Buck, K. J., Metten, P., Belknap, J. K., and Crabbe, J. C. Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J. Neurosci. 17, 3946-3955.
N. Hiroi and E. J. Nestler Division of Molecular Psychiatry Departments of Psychiatry and Pharmacology Yale University School of Medicine N e w Haven, Connecticut 06508
Nuclear Memory: Gene Transcription and Behavior There is an ever-increasing list of stimuli and treatments that induce a particular set of genes, called immediate early genes. Perphaps the most widely studied immediate early genes belong to the Fos family (1).This family includes c-fos, fosB, fral, and fra2. When activated, these genes transcribe their protein products, designated C-FOS,FosB, FRA1, and FRA2, respectively. The initial impetus to examine the induction of these genes and proteins was the assumption that they could be used to “map” neurons and neuronal Advonces m Phannocology, Volume 42
Copyright 0 1998 by Academic Press. All rights of rrproduction in any form reserved. 1054-3589198 $25.00
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networks activated by biologically significant stimuli. In some cases, this approach proved to be a useful one from a heuristic point of view (1).For example, noxious stimuli induce c-fos (mRNA)and c-Fos (protein) and upregulate prodynorphin mRNA in the spinal cord (2). The upregulation of prodynorphin mRNA is blocked by infusion of c-fos antisense oligonucleotides ( 3 ) .However, c-fosk-Fos turned out to be an erroneous marker for activated neurons in other cases. Acute treatment with the dopaminergic agonist apomorphine induces stereotyped behaviors in rodents, and this behavior has been shown to be dependent on activation of striatal neurons (4).Yet, the very same treatment does not induce c-Fos in normal striatum ( 5 ) .Acute treatment with a psychomotor stimulant (e.g., cocaine and amphetamine) inhibits physiological activity of neurons in the nucleus accumbens ( 6 ) but potently induces c-Fos and other Fos family proteins in these cells (7).Conversely, chronic treatment with a psychomotor stimulant can result in potentiated physiological responses by these cells (6), while c-fos induction diminishes after repeated treatment (8). These are some examples of the numerous false-positive and false-negative cases for a relationship between neuronal activation and induction of Fos family member proteins. As such, these genes and their protein products cannot be used as reliable markers of activated neurons and networks. This does not diminish the physiological importance of Fos family member proteins, however. These proteins play crucial roles in regulating particular cell functions. These proteins bind to a DNA sequence by forming heterodimers with protein products of another immediate early gene family, Jun. The FosJun dimers bind to the consensus sequence TGACTCA, called activator protein1 (AP1) sequence. When they bind to this DNA sequence, they activate or repress the transcription of other genes. Through this mechanism, numerous external and internal stimuli exert potent effects on the properties of specific target neurons. We previously reported, as mentioned previously, that cocaine loses it ability to induce c-fos when repeatedly given to animals. However, we found that elevated AP1 binding activity persisted with chronic treatment when cfos/c-Fos was not present (8).We later showed that unique Fos-related antigens (FRAs) are associated with this long-lasting AP1 binding activity (9). These FRAs were recognized by an “anti-FRA” antiserum raised against a highly conserved amino acid sequence of all Fos family member proteins and appeared to have the molecular weights of 35-37 kDa. These FRAs have been shown to be induced in distinct brain regions by a number of chronic treatments, including cocaine, morphine, electroconvulsive seizure, apomorphine, and various lesions ( 9 - l l ), and, for this reason, they were termed chronic FRAs (9). Because these treatments induce dramatic behavioral changes ranging from sensitization-withdrawal to seizure, it has been hypothesized that chronic FRAs could play critical roles in neuronal and behavioral plasticity (9-1 1). However, the identity of chronic FRAs remained unknown. Because chronic FRAs were recognized by an anti-FRA antiserum, raised against a highly conserved amino acid sequence of all Fos family members, they could conceivably be any Fos member protein or its variants. One Fos family member protein that has a predicted molecular weight around 35 kDa is an alternatively spliced form of FosB, termed AFosB, which lacks a portion of exon 4. Despite its
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truncated nature, however, AFosB seems to have functional activity as a transcription factor (12). To further study the nature of the chronic FRAs, we used an antiserum raised against an N-terminus portion of FosB, which is present in full-length FosB and AFosB, and an antiserum raised against a C-terminus portion of fulllength FosB, which is absent in AFosB. We demonstrated that the N-terminus, but not the C-terminus, anti-FosB antiserum recognized several bands around 35 kDa in the striatum of animals treated repeatedly with cocaine ( 9 ) .This finding provided evidence that at least some of the chronic FRAs are AFosB, but the pattern of immunoreactive bands was not identical to that of chronic FRAs. This could be due to the fact that even if raised against the same protein, different antibodies do not produce identical staining patterns. Alternatively, this could indicate that not all chronic FRAs are AFosB. This latter possibility was further supported by the finding that the anti-FRA antiserum does not recognize FRAs at exactly the same positions when extracts of cells transfected with the AfosB gene and extracts of striatum of animals treated repeatedly with cocaine were compared (13). This finding suggested two possibilities. One is that some but not all of the chronic FRAs are AFosB. Alternatively, the induction of chronic FRAs, if they were all AFosB, could require cell surface stimulation that would lead to posttranslational modification of AFosB, which is absent in transfected cell lines that overexpress AFosB. We have now obtained definitive evidence that all of the chronic FRAs are indeed AFosB variants: All of the chronic FRAs were absent in mice with targeted disruption of the fosB gene ( 14). Two-dimensional gel electrophoresis and FRA Western blotting were used for a more complete analysis. Chronic cocaine treatment was found to induce five distinct FRAs in the 35- to 37-kDa range. Most of these proteins were present under basal conditions, and their induction was enhanced by repeated cocaine treatment. In addition, one protein became detectable uniquely after repeated cocaine treatment. None of these cocaine-regulated FRAs was present in the striatum of fosB mutant mice (14). The absence of the 35- to 37-kDa FRAs in fosB mutant mice was accompanied by complete loss of the long-lasting increase in AM-binding activity. These findings demonstrated that AFosB variants constitute the long-lasting AP1 activity induced in the striatum after repeated cocaine treatment. Related work indicated that the other constituent of this AP1 activity is JunD (13). A remaining question regarding the chronic FRAs concerned their physiological roles. Repeated cocaine treatment induces a host of behavioral changes. One such behavioral change is locomotor sensitization. When animals are treated repeatedly with cocaine or amphetamine, their locomotor activation gradually increases. Behavioral studies have shown that locomotor sensitization to cocaine is mediated by the mesolimbic dopamine pathway projecting to the nucleus accumbens, a ventral portion of the striatum (15). Three correlations prompted us to examine the physiological role of AFosB variants in the sensitization paradigm. First, AFosB variants are induced after repeated cocaine treatment in parallel to the development of behavioral sensitization. Second, AFosB variants are induced in the nucleus accumbens, a brain region implicated in cocaine sensitization. Third, the induction of AFosB vari-
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ants and the development of cocaine sensitization are both blocked by a D1 dopamine-receptor antagonist, SCH 23390 (16, 17). We used fosB mutant mice to further study their relationship (14).Cocaine acutely induced more robust behavioral activation in fosB mutant mice than in wild-type littermates. However, wild-type littermates exhibited greater locomotor sensitization: they increased their locomotor activity by 300% during 6 days of testing, while fosB mutant mice increased their locomotor activity by 150%. This was not due to focused stereotypy, which would behaviorally compete with and replace hyperactivity. Despite the fact that fosB mutant mice showed attenuated cocaine sensitization, they exhibited normal conditioned locomotor activity when placed in the same test boxes with saline injections. These findings suggest several intriguing possibilities. First, the normal development of cocaine sensitization depends on transcriptional regulation by AFosB variants and perhaps FosB. Second, a certain element of sensitization, expressed as a low level of sensitization of fosB mutant mice, does not seem to require fosB gene products. Third, the development and expression of conditioned locomotor activity do not require fosB gene products, consistent with the view that sensitization and conditioned locomotor activity occur via distinct mechanisms. The present set of findings shows that the long-lasting AP1 complex contains AFosB variants and that fosB gene products could play a crucial role in cocaine sensitization. In more general terms, this set of findings suggests that transcriptional regulation in the cell nucleus could play a critical role in the formation of certain types of memory.
References 1. Hughes, P., and Dragunow, M. (1995).Induction of immediate-early genes and the control of neurotransmitter-related gene expression within the nervous system. Pharmacol. Rev. 45, 133-178. 2. Fitzgerald, M. (1990).c-Fos and the changing face of pain. Trends Neurosci. 13,439-440. 3. Lucas, J. J., Mellstrom, B., Colado, M. I., andNaranjo, J. R. (1993).Molecular mechanisms of pain: Serotonin,, receptor agonists trigger transactivation by c-fos of the prodynorphin gene in spinal cord neurons. Neuron 10, 599-611. 4. Kelly, P. H., Seviour, P. W., and Iversen, S. D. (1975). Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Bruin Res. 94, 507-522. 5 . Pennypacker, K. R., Zhang, W. Q., Ye, H., and Hong, J. S. (1992).Apomorphine induction of AP-1 DNA binding in the rat striatum after dopamine depletion. Mol. Bruin Res. 15,151-155. 6. Henry, D. J., and White, F. J. (1995).The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. J . Neurosci. 15,6287-6299. 7. Graybiel, A. M., Moratalla, R., and Robertson, H. A. (1990). Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix and limbic subdivisions of the striatum. Proc. Nutl. Acad. Sci. U.S.A. 87, 6912-6916. 8. Hope, B. T., Kosofsky, B., Hyman, S. E., and Nestler, E. J. (1992).Regulation of immediateearly gene expression and AP-lbinding in the rat nucleus accumbens by chronic cocaine. Proc. Natl. Acad. Sci. U.S.A. 89, 5764-5768.
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9. Hope, B. T., Nye, H. E., Kelz, M. B., Self, D., Iadarola, M. J., Nakabeppu, Y., Duman, R. S., and Nestler, E. J. (1994). Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235-1244. 10. Pennypacker, K. R., Hong, J. S . , and McMillian, M. K. (1995). Implications of prolonged expression of Fos-related antigens. T r e ~ d sPharmacol. Sci. 16, 3 17-321. 11. Hiroi, N., Chen, J. S., Nye, H. E., and Nestler, E. J. (1996). Chronic FRAs: Novel transcription factors regulated in the basal ganglia by chronic neuronal perturbations. In The Basal Ganglia. V. (C. Ohye, M. Kimura, and J. S. McKenzie, eds.). Plenum Press, New York. 12. Mumberg, D., Lucibello, F. C., Schuermann, M., and Muller, R. (1991). Alternative splicing of fosB transcripts results in differentially expressed mRNAs encoding functionally antagonistic proteins. Genes Dev. 5, 1212-1223. 13. Chen, J. S., Nye, H. E., Kelz, M. B., Hiroi, N., Nakabeppu, Y., Hope, B. T., and Nestler, E. J. (1995).Regulation of AFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. Mol. Pharmacol. 48, 880-889. 14. Hiroi, N., Brown, J. R., Haile, C., Greenberg, M. E., and Nestler, E. J. (1996). FosB mutant mice: Lack of chronic FRAs and abnormalities in cocaine-regulated behaviors. Soc. Neurosci. Abstr. 22, 386. 15. Hemby, S. E., Jones, G. H., Justice, J. B. Jr., andNeill, D. B. (1992).Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine. Psychopharmacology 106, 330-336. 16. McCreary, A. C., and Marsden, C. A. (1993). Cocaine-induced behavior: Dopamine D1 receptor antagonism by SCH23390 prevents expression of conditioned sensitization following repeated administration of cocaine. Neuropharmacology 32, 387-391. 17. Nye, H. E., Hope, B. T., Kelz, M., Iadarola, M., and Nestler, E. J. (1995).Pharmacological studies of the regulation of chronic Fos-related antigen induction by cocaine in the striatum and nucleus accumbens. 1. Pharmacol. Exp. Tber. 275,1671-1680.
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References 1. Belknap, J. K., Metten, P.,Helms, M. L., O’Toole, L. A., Angeli-Gade, S., Crabbe, J. C., and Phillips, T. J. (1993). QTL applications to substances of abuse: Physical dependence studies with nitrous oxide and ethanol. Behuv. Genet. 23, 213-222. 2. Johnson, T. E., DeFries, J. C., and Markel, P. D. (1992). Mapping quantitative trait loci for behavioral traits in the mouse. Behav. Genet. 22, 635-653. 3. Grisel, J. E., Belknap, J. K., O’Toole, L. A,, Helms, M. L., Wenger, C. D., and Crabbe, J, C. (1997).Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mice. J . Neurosci. 17, 745-754. 4. Durkin, T., Ayad, G., Ebel, A., and Mandel, P. (1977).Comparative study of acetylcholinesterase and choline acetyltransferase enzyme activity in brains of DBA and C57 mice. Nut. N e w Biol. 242, 56-58. 5. Groves, P. M., Garcia-Munoz, M., Linder, J. C., Manley, M. S., Martone, M. M., and Young, S . J. (1995). Elements of the intrinsic organization and information processing in the neostriatum. In Models of Information Processing in the Basal Ganglia. J. C. Houk, J, L. Davis, and D. G. Beiser, (eds.), pp. 51-96. MIT Press, Cambridge, MA. 6. Crabbe, J. C., Belknap, J. K., and Buck, K. J. (1994). Genetic animal models of alcohol and drug abuse. Science 264, 1715-1723. 7. Crabbe, J. C., Phillips, T. J., Feller, D. J., Wenger, C. D., Lessov, C. N., and Schafer, G. L. (1996).Elevated alcohol consumption in null mutant mice lacking 5-HTIBreceptors. Nat. Genet. 14, 98-101. 8. Buck, K. J., Metten, P., Belknap, J. K., and Crabbe, J. C. Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J. Neurosci. 17, 3946-3955.
N. Hiroi and E. J. Nestler Division of Molecular Psychiatry Departments of Psychiatry and Pharmacology Yale University School of Medicine N e w Haven, Connecticut 06508
Nuclear Memory: Gene Transcription and Behavior There is an ever-increasing list of stimuli and treatments that induce a particular set of genes, called immediate early genes. Perphaps the most widely studied immediate early genes belong to the Fos family (1).This family includes c-fos, fosB, fral, and fra2. When activated, these genes transcribe their protein products, designated C-FOS,FosB, FRA1, and FRA2, respectively. The initial impetus to examine the induction of these genes and proteins was the assumption that they could be used to “map” neurons and neuronal Advonces m Phannocology, Volume 42
Copyright 0 1998 by Academic Press. All rights of rrproduction in any form reserved. 1054-3589198 $25.00
I038
N. Hiroi and E. J. Nestler
networks activated by biologically significant stimuli. In some cases, this approach proved to be a useful one from a heuristic point of view (1).For example, noxious stimuli induce c-fos (mRNA)and c-Fos (protein) and upregulate prodynorphin mRNA in the spinal cord (2). The upregulation of prodynorphin mRNA is blocked by infusion of c-fos antisense oligonucleotides ( 3 ) .However, c-fosk-Fos turned out to be an erroneous marker for activated neurons in other cases. Acute treatment with the dopaminergic agonist apomorphine induces stereotyped behaviors in rodents, and this behavior has been shown to be dependent on activation of striatal neurons (4).Yet, the very same treatment does not induce c-Fos in normal striatum ( 5 ) .Acute treatment with a psychomotor stimulant (e.g., cocaine and amphetamine) inhibits physiological activity of neurons in the nucleus accumbens ( 6 ) but potently induces c-Fos and other Fos family proteins in these cells (7).Conversely, chronic treatment with a psychomotor stimulant can result in potentiated physiological responses by these cells (6), while c-fos induction diminishes after repeated treatment (8). These are some examples of the numerous false-positive and false-negative cases for a relationship between neuronal activation and induction of Fos family member proteins. As such, these genes and their protein products cannot be used as reliable markers of activated neurons and networks. This does not diminish the physiological importance of Fos family member proteins, however. These proteins play crucial roles in regulating particular cell functions. These proteins bind to a DNA sequence by forming heterodimers with protein products of another immediate early gene family, Jun. The FosJun dimers bind to the consensus sequence TGACTCA, called activator protein1 (AP1) sequence. When they bind to this DNA sequence, they activate or repress the transcription of other genes. Through this mechanism, numerous external and internal stimuli exert potent effects on the properties of specific target neurons. We previously reported, as mentioned previously, that cocaine loses it ability to induce c-fos when repeatedly given to animals. However, we found that elevated AP1 binding activity persisted with chronic treatment when cfos/c-Fos was not present (8).We later showed that unique Fos-related antigens (FRAs) are associated with this long-lasting AP1 binding activity (9). These FRAs were recognized by an “anti-FRA” antiserum raised against a highly conserved amino acid sequence of all Fos family member proteins and appeared to have the molecular weights of 35-37 kDa. These FRAs have been shown to be induced in distinct brain regions by a number of chronic treatments, including cocaine, morphine, electroconvulsive seizure, apomorphine, and various lesions ( 9 - l l ), and, for this reason, they were termed chronic FRAs (9). Because these treatments induce dramatic behavioral changes ranging from sensitization-withdrawal to seizure, it has been hypothesized that chronic FRAs could play critical roles in neuronal and behavioral plasticity (9-1 1). However, the identity of chronic FRAs remained unknown. Because chronic FRAs were recognized by an anti-FRA antiserum, raised against a highly conserved amino acid sequence of all Fos family members, they could conceivably be any Fos member protein or its variants. One Fos family member protein that has a predicted molecular weight around 35 kDa is an alternatively spliced form of FosB, termed AFosB, which lacks a portion of exon 4. Despite its
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truncated nature, however, AFosB seems to have functional activity as a transcription factor (12). To further study the nature of the chronic FRAs, we used an antiserum raised against an N-terminus portion of FosB, which is present in full-length FosB and AFosB, and an antiserum raised against a C-terminus portion of fulllength FosB, which is absent in AFosB. We demonstrated that the N-terminus, but not the C-terminus, anti-FosB antiserum recognized several bands around 35 kDa in the striatum of animals treated repeatedly with cocaine ( 9 ) .This finding provided evidence that at least some of the chronic FRAs are AFosB, but the pattern of immunoreactive bands was not identical to that of chronic FRAs. This could be due to the fact that even if raised against the same protein, different antibodies do not produce identical staining patterns. Alternatively, this could indicate that not all chronic FRAs are AFosB. This latter possibility was further supported by the finding that the anti-FRA antiserum does not recognize FRAs at exactly the same positions when extracts of cells transfected with the AfosB gene and extracts of striatum of animals treated repeatedly with cocaine were compared (13). This finding suggested two possibilities. One is that some but not all of the chronic FRAs are AFosB. Alternatively, the induction of chronic FRAs, if they were all AFosB, could require cell surface stimulation that would lead to posttranslational modification of AFosB, which is absent in transfected cell lines that overexpress AFosB. We have now obtained definitive evidence that all of the chronic FRAs are indeed AFosB variants: All of the chronic FRAs were absent in mice with targeted disruption of the fosB gene ( 14). Two-dimensional gel electrophoresis and FRA Western blotting were used for a more complete analysis. Chronic cocaine treatment was found to induce five distinct FRAs in the 35- to 37-kDa range. Most of these proteins were present under basal conditions, and their induction was enhanced by repeated cocaine treatment. In addition, one protein became detectable uniquely after repeated cocaine treatment. None of these cocaine-regulated FRAs was present in the striatum of fosB mutant mice (14). The absence of the 35- to 37-kDa FRAs in fosB mutant mice was accompanied by complete loss of the long-lasting increase in AM-binding activity. These findings demonstrated that AFosB variants constitute the long-lasting AP1 activity induced in the striatum after repeated cocaine treatment. Related work indicated that the other constituent of this AP1 activity is JunD (13). A remaining question regarding the chronic FRAs concerned their physiological roles. Repeated cocaine treatment induces a host of behavioral changes. One such behavioral change is locomotor sensitization. When animals are treated repeatedly with cocaine or amphetamine, their locomotor activation gradually increases. Behavioral studies have shown that locomotor sensitization to cocaine is mediated by the mesolimbic dopamine pathway projecting to the nucleus accumbens, a ventral portion of the striatum (15). Three correlations prompted us to examine the physiological role of AFosB variants in the sensitization paradigm. First, AFosB variants are induced after repeated cocaine treatment in parallel to the development of behavioral sensitization. Second, AFosB variants are induced in the nucleus accumbens, a brain region implicated in cocaine sensitization. Third, the induction of AFosB vari-
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ants and the development of cocaine sensitization are both blocked by a D1 dopamine-receptor antagonist, SCH 23390 (16, 17). We used fosB mutant mice to further study their relationship (14).Cocaine acutely induced more robust behavioral activation in fosB mutant mice than in wild-type littermates. However, wild-type littermates exhibited greater locomotor sensitization: they increased their locomotor activity by 300% during 6 days of testing, while fosB mutant mice increased their locomotor activity by 150%. This was not due to focused stereotypy, which would behaviorally compete with and replace hyperactivity. Despite the fact that fosB mutant mice showed attenuated cocaine sensitization, they exhibited normal conditioned locomotor activity when placed in the same test boxes with saline injections. These findings suggest several intriguing possibilities. First, the normal development of cocaine sensitization depends on transcriptional regulation by AFosB variants and perhaps FosB. Second, a certain element of sensitization, expressed as a low level of sensitization of fosB mutant mice, does not seem to require fosB gene products. Third, the development and expression of conditioned locomotor activity do not require fosB gene products, consistent with the view that sensitization and conditioned locomotor activity occur via distinct mechanisms. The present set of findings shows that the long-lasting AP1 complex contains AFosB variants and that fosB gene products could play a crucial role in cocaine sensitization. In more general terms, this set of findings suggests that transcriptional regulation in the cell nucleus could play a critical role in the formation of certain types of memory.
References 1. Hughes, P., and Dragunow, M. (1995).Induction of immediate-early genes and the control of neurotransmitter-related gene expression within the nervous system. Pharmacol. Rev. 45, 133-178. 2. Fitzgerald, M. (1990).c-Fos and the changing face of pain. Trends Neurosci. 13,439-440. 3. Lucas, J. J., Mellstrom, B., Colado, M. I., andNaranjo, J. R. (1993).Molecular mechanisms of pain: Serotonin,, receptor agonists trigger transactivation by c-fos of the prodynorphin gene in spinal cord neurons. Neuron 10, 599-611. 4. Kelly, P. H., Seviour, P. W., and Iversen, S. D. (1975). Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Bruin Res. 94, 507-522. 5 . Pennypacker, K. R., Zhang, W. Q., Ye, H., and Hong, J. S. (1992).Apomorphine induction of AP-1 DNA binding in the rat striatum after dopamine depletion. Mol. Bruin Res. 15,151-155. 6. Henry, D. J., and White, F. J. (1995).The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. J . Neurosci. 15,6287-6299. 7. Graybiel, A. M., Moratalla, R., and Robertson, H. A. (1990). Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix and limbic subdivisions of the striatum. Proc. Nutl. Acad. Sci. U.S.A. 87, 6912-6916. 8. Hope, B. T., Kosofsky, B., Hyman, S. E., and Nestler, E. J. (1992).Regulation of immediateearly gene expression and AP-lbinding in the rat nucleus accumbens by chronic cocaine. Proc. Natl. Acad. Sci. U.S.A. 89, 5764-5768.
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9. Hope, B. T., Nye, H. E., Kelz, M. B., Self, D., Iadarola, M. J., Nakabeppu, Y., Duman, R. S., and Nestler, E. J. (1994). Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235-1244. 10. Pennypacker, K. R., Hong, J. S . , and McMillian, M. K. (1995). Implications of prolonged expression of Fos-related antigens. T r e ~ d sPharmacol. Sci. 16, 3 17-321. 11. Hiroi, N., Chen, J. S., Nye, H. E., and Nestler, E. J. (1996). Chronic FRAs: Novel transcription factors regulated in the basal ganglia by chronic neuronal perturbations. In The Basal Ganglia. V. (C. Ohye, M. Kimura, and J. S. McKenzie, eds.). Plenum Press, New York. 12. Mumberg, D., Lucibello, F. C., Schuermann, M., and Muller, R. (1991). Alternative splicing of fosB transcripts results in differentially expressed mRNAs encoding functionally antagonistic proteins. Genes Dev. 5, 1212-1223. 13. Chen, J. S., Nye, H. E., Kelz, M. B., Hiroi, N., Nakabeppu, Y., Hope, B. T., and Nestler, E. J. (1995).Regulation of AFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. Mol. Pharmacol. 48, 880-889. 14. Hiroi, N., Brown, J. R., Haile, C., Greenberg, M. E., and Nestler, E. J. (1996). FosB mutant mice: Lack of chronic FRAs and abnormalities in cocaine-regulated behaviors. Soc. Neurosci. Abstr. 22, 386. 15. Hemby, S. E., Jones, G. H., Justice, J. B. Jr., andNeill, D. B. (1992).Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine. Psychopharmacology 106, 330-336. 16. McCreary, A. C., and Marsden, C. A. (1993). Cocaine-induced behavior: Dopamine D1 receptor antagonism by SCH23390 prevents expression of conditioned sensitization following repeated administration of cocaine. Neuropharmacology 32, 387-391. 17. Nye, H. E., Hope, B. T., Kelz, M., Iadarola, M., and Nestler, E. J. (1995).Pharmacological studies of the regulation of chronic Fos-related antigen induction by cocaine in the striatum and nucleus accumbens. 1. Pharmacol. Exp. Tber. 275,1671-1680.