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PubMed1994

Suppression of ischemia-induced fos expression and AP-1 activity by an antisense oligodeoxynucleotide to c-fos mRNA.

Activation of c-fos, an immediate early gene, and the subsequent expression of the Fos protein have been noted following focal cerebral ischemia. Fos and Jun form a heterodimer as activator protein 1 (AP-1), which transregulates the expression of several genes. To study the postischemic events related to c-fos expression, we suppressed the expression of c-fos by intraventricular infusion of an antisense oligodeoxynucleotide (anti-rncfosr115) of c-fos mRNA. The effectiveness of anti-rncfosr115 was confirmed first by its capability to block in vitro c-fos mRNA translation. In vivo, after intraventricular infusion of 32P-labeled anti-rncfosr115, the oligodeoxynucleotide was internalized within 6 hours and detectable also in the nucleic acids fraction up to 41 hours. Treatment of the recovered nucleic acids with RNase H separated the labeled oligodeoxynucleotide from the nucleic acid fraction, indicating an association of the antisense oligodeoxynucleotide and cellular RNA after uptake. When focal cerebral ischemia was induced 16 hours after the infusion of anti-rncfosr115, the postischemic increase in Fos expression and AP-1 binding activity were suppressed. Specificity of the effect of anti-rncfosr115 was suggested by its failure to suppress the DNA binding activity of nuclear cyclic AMP response elements. These results support the hypothesis that increased AP-1 binding activity following focal cerebral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c-fos oligodeoxynucleotides.

Animals↗
PubMed1988

A sensitive enzyme-linked immunosorbence assay for the c-fos and v-fos oncoproteins.

The c-fos nuclear oncoprotein is rapidly induced when the growth of normal cells is initiated by mitogens, and it is also synthesized in several cell systems in response to stimuli that do not cause cell proliferation. When expressed inappropriately, c-fos, and its retroviral counterpart v-fos, can transform susceptible cells in vivo and in vitro. We have developed a simple and sensitive ELISA for the c-fos and v-fos proteins. Fos proteins are captured from cell lysates by an antibody specific for an amino-terminal peptide substantially conserved between v-fos and c-fos; the captured proteins are recognised by a second antibody against a different peptide sequence also conserved in the two proteins. The second antibody has been conjugated to alkaline phosphatase to provide an enzyme label; bound alkaline phosphatase is measured with a sensitive cycling enzyme system that generates a coloured end-product. We show that the fos ELISA is immunologically specific and use it to monitor increased c-fos expression in serum-stimulated HeLa cells and human fibroblasts, and in mitogen-stimulated murine thymocytes.

Animals↗
PubMed1998

Medial prefrontal cortical injections of c-fos antisense oligonucleotides transiently lower c-Fos protein and mimic amphetamine withdrawal behaviours.

Prefrontal cerebral cortical areas display decreased expression of several transcription factor/immediate-early genes, including c-fos, during amphetamine withdrawal. Antisense strategies can help to test possible roles for this prefrontal c-fos down-regulation in the behavioural correlates of amphetamine withdrawal. Medial prefrontal cortical injections delivering 1.7 nmoles of anti c-fos oligonucleotides revealed an approximately 3 h half-life for phosphothioate and a 15 min half-life for phosphodiester oligonucleotides. Antisense phosphothioates complementary to the c-fos translational start site reduced levels of c-Fos protein, while exerting modest and variable effects on c-fos messenger RNA levels. Neither missense phosphorothioate nor antisense phosphodiester oligonucleotides significantly reduced levels of either c-fos messenger RNA or protein. Animals injected with anti c-fos phosphothioate oligonucleotides into the medial prefrontal cortex displayed marked reductions in linear locomotor activity and repetitive movements measured in a novel environment, effects not seen when missense oligonucleotides were used or when animals were accustomed to the activity monitor prior to antisense oligonucleotide injection. Behavioural changes produced by prefrontal cortical injections of c-fos antisense oligonucleotides closely mimic alterations recorded during amphetamine withdrawal. Prefrontal c-fos could thus conceivably play roles in the neurobiological underpinnings of psychostimulant withdrawal and of responses to stressors such as exposure to novel environments.

Amphetamine↗
PubMed1990

Phosphorylation of the C terminus of Fos protein is required for transcriptional transrepression of the c-fos promoter.

Proto-oncogene fos encodes a nuclear phosphoprotein of 380 amino acids that can modulate the transcription of other genes either by transactivation or by transrepression. The v-Fos protein (381 amino acids) shares the first 332 amino acids with the c-Fos protein (with five single amino-acid changes), but differs at the C terminus. We have previously reported that the c-Fos protein undergoes more extensive post-translational modification than v-Fos (refs 9, 10). The major modification of the c-Fos protein involves serine phosphoesterification of sites in the extreme C terminus. We therefore argued that modification of the C-terminal region of the c-Fos protein may be involved in its ability to transrepress transcription without compromising its ability to transactivate other genes. Here we show that mutant c-Fos protein which is hypophosphorylated at its C terminus is unable to repress transcription of the c-fos promoter following induction with serum or tetraphorbol acetate. The C-terminal phosphorylation-deficient mutant is, however, fully competent to activate transcription of promoters containing a phorbol response element. The requirement for phosphorylation can be offset by the introduction of a net negative charge in the C terminus of the Fos protein.

Amino Acid Sequence↗
PubMed1992

U-rich sequence-binding proteins (URBPs) interacting with a 20-nucleotide U-rich sequence in the 3' untranslated region of c-fos mRNA may be involved in the first step of c-fos mRNA degradation.

Rapid decay of the c-fos transcript plays a critical role in controlling transforming potential of the c-fos proto-oncogene. One of the mRNA instability determinants is a 75-nucleotide AU-rich element (ARE) present in the 3' untranslated region of the c-fos transcript. It appears to control two steps in the process of c-fos mRNA degradation: removal of the poly(A) tail, which does not require the AUUUA motifs, and subsequent degradation of deadenylated mRNA, which appears to be dependent on the AUUUA motifs. In this study, we report the identification of four U-rich sequence binding proteins (URBPs) that specifically interact with a 20-nucleotide U-rich sequence within the c-fos ARE. Gel mobility shift assay and competition experiments showed that these protein factors form three specific band-shifted complexes with the c-fos ARE. Binding activity of one of the protein factors, a 37-kDa protein, is significantly affected by serum induction and by pretreatment of cells with drugs known to stabilize many of the immediate-early gene mRNAs. Combining UV cross-linking with a new approach, designated sequential RNase digestion, we were able to better determine the molecular masses of these cellular proteins. The binding sites for the four proteins were all mapped to a 20-nucleotide U-rich sequence located at the 3' half of the c-fos ARE, which contains no AUUUA pentanucleotides but stretches of uridylate residues. Single U-to-A point mutations in each of the three AUUUA motifs within the c-fos ARE have little effect on formation of the mobility-shifted complexes. Our data indicate c-fos ARE-protein interaction involves recognition of U stretches rather than recognition of the AUUUA motifs. We propose that UTBP binding may be involved in the first step, removal of the Poly(A) tail, in the c-fos ARE-mediated decay pathway.

3T3 Cells↗
PubMed1997

Impaired induction of c-fos/c-jun genes and of transcriptional regulatory proteins binding distinct c-fos/c-jun promoter elements in activated human T cells during aging.

The activation of transcriptional factor c-Fos/c-Jun AP-1 is essential for normal T cell responsiveness and is often impaired in T cells during aging. In the present study, we investigated whether aberrancies in the regulation of c-fos/c-jun at the mRNA or protein level might underlie the age-associated impairments of AP-1 in human T cells. Whereas T cells from young subjects stimulated with cross-linked anti-CD3epsilon mAb OKT3 plus PMA or with the lectin PHA plus PMA demonstrated considerable increases in c-Fos protein expression, the expression of c-Fos but not c-Jun was markedly reduced in stimulated T cells from certain elderly subjects. In addition, RNase protection assays revealed that anti-CD3/PMA-stimulated T cells from a substantial proportion of elderly subjects exhibited decreased levels of c-fos and/or c-jun mRNA compared to T cells from young subjects. Using electrophoretic mobility shift assays, the levels of nuclear regulatory proteins recognizing the AP-1 consensus TRE motif, the proximal c-jun TRE-like promoter element, and the c-fos serum response element (SRE) were determined in resting and stimulated T cells. Although the stimulation of T cells from young subjects resulted in coordinated increases of nuclear protein complexes binding the AP-1 TRE, c-jun TRE, and c-fos SRE DNA sequence motifs, age-related reductions in the activation of AP-1 were accompanied by decreased levels of c-jun TRE and c-fos SRE binding complexes. Furthermore, the nuclear protein complexes binding the SRE motif induced in activated T cells of young and elderly subjects contained serum response factor and Elk-1 pointing toward age-related defects in the activation of transcriptional regulatory proteins distinct from c-jun/AP-1. These results suggest that underlying aberrancies in the induction of c-fos/c-jun as well as their nuclear regulatory proteins may contribute to the age-related impairments of AP-1 activation in human T cells.

Adult↗
PubMed1996

Selective uptake and degradation of c-Fos and v-Fos by rat liver lysosomes.

The transcription factor c-Fos is a short-lived protein and calpains and ubiquitin-dependent systems have been proposed to be involved in its degradation. In this report, we consider a lysosomal degradation pathway for c-Fos. Using a cell-free assay, we have found that freshly isolated lysosomes can take up and degrade c-Fos with high efficiency. v-Fos, the oncogenic counterpart of c-Fos, can also be taken up by lysosomes, yet the amount of incorporated protein is much lower. c-Fos uptake is independent of its phosphorylation state but it appears to be regulated by dimerization with differentially phosphorylated forms of c-Jun, while v-Fos escapes this regulation. Moreover, we show that c-Fos is immunologically detected in lysosomes isolated from the liver of rats treated with the protease inhibitor leupeptin. Altogether, these results suggest that lysosomes can also participate in the selective degradation of c-Fos in rat liver.

Animals↗
PubMed1994

Temporal regulation of light-induced Fos and Fos-like protein expression in the ventrolateral subdivision of the rat suprachiasmatic nucleus.

We measured c-fos messenger RNA levels and Fos protein immunoreactivity in the suprachiasmatic nucleus of rats as a function of light and time of day. Immunohistochemistry demonstrated a daily rhythm of immunoreactive Fos in the ventrolateral subdivision of the suprachiasmatic nucleus of animals entrained to a 12 h/12 h light-dark cycle; expression was low during the dark phase, peaked about 2 h after light onset at dawn, and remained elevated at an intermediate level for the remainder of the light phase. Immunoblots of nuclear extracts showed a 54,000 mol. wt band that increased in density from the dark phase to the early light phase and decreased again during the late light phase. In situ hybridization using a radiolabeled cDNA probe revealed a c-fos messenger RNA signal that was detected as early as 15 min after dawn, prominent at 30 min, and absent by 2 h. The expression of c-fos messenger RNA and Fos immunoreactivity in the suprachiasmatic nucleus depended on the presence of ambient light. In rats entrained to two daily 1-h light pulses corresponding to dawn and dusk ("skeleton" photoperiod) instead of the complete light-dark cycle, immunoreactive Fos was elicited by the dawn pulse alone and was less persistent than during the complete photoperiod. In rats free-running in constant darkness, c-fos messenger RNA and Fos immunoreactivity were stimulated by 2-h light pulses administered only during the subjective night and early subjective day, but not by light pulses during the middle or late subjective day or in the absence of light pulses.

Animals↗
PubMed1998

The C-terminal domain of c-fos is required for activation of an AP-1 site specific for jun-fos heterodimers.

The proto-oncogenes jun and fos are members of the AP-1 family of transcription factors, which activate transcription of target genes via the tetradecanoyl phorbol acetate response element (TRE). Both jun and fos contain activation domains, but their relative contributions to transcriptional activation of different TREs remain unclear. It is not apparent whether the cellular availability of specific AP-1 members is the major determinant for regulation of TREs or whether other factors including the TRE sequence itself contribute to selectivity. We have identified in the promoter of the rat atrial natriuretic factor (ANF) a novel AP-1 site which is unresponsive to jun homodimers and is inducible only in the presence of c-fos. This activation is potentiated by mitogen-activated protein (MAP) kinase. The jun proteins appear to be required solely to tether c-fos to the promoter, and c-fos mutants lacking putative activation domains abrogate transactivation. Unexpectedly, the oncogenic form of c-fos which diverges most significantly in the carboxy-terminal 50 amino acids is unable to mediate transactivation at this specialized AP-1 site. Mutations within the C terminus of c-fos at serine residues that are phosphorylation targets for growth factors and MAP kinase completely abrogate transactivation and block potentiation by MAP kinase. Using GAL4 fusions, we show that the 90-amino-acid C terminus of c-fos contains autonomous activation domains and that the serine residues are essential for full activity. These results suggest that phosphorylation of the C terminus of c-fos affects its transactivation properties and provide evidence for novel regulatory mechanisms that may contribute to biologic specificities of the AP-1 transcription complex.

Animals↗
PubMed1988

Fos C-terminal mutations block down-regulation of c-fos transcription following serum stimulation.

Transient accumulation of c-fos RNA following serum stimulation requires both a conserved 5' regulatory element and sequences at the 3' end of the gene. Here we show that mutations at the C terminus of Fos protein, of the type found in a virally-transduced actively transforming Fos variant, prevent the rapid down-regulation of c-fos transcription that occurs following serum-induced activation. Fos mutants that prevent down-regulation are dominant, acting in trans to prevent down-regulation of a co-transfected c-fos gene. Co-transfection experiments suggest that this effect is mediated by multiple sequence elements in the 5'-flanking region. Analysis of different Fos mutants showed that replacement of Fos sequences C-terminal to amino acid 337 with heterologous polypeptide, rather than simple truncation of the protein, is required to produce mutants defective in down-regulation. The results are discussed with reference to transformation by Fos.

Amino Acid Sequence↗
PubMed1993

Intracerebroventricular administration of corticotropin-releasing factor induces c-fos mRNA expression in brain regions related to stress responses: comparison with pattern of c-fos mRNA induction after stress.

Centrally administered corticotropin-releasing factor (CRF) produces a number of physiological and behavioral changes akin to those elicited by exposure to acute stress. However, the specific brain site of action responsible for the centrally activating property of CRF has not been precisely determined. In this study, we used in situ hybridization histochemistry for c-fos mRNA to map potential neuronal structures activated after intracerebroventricular (i.c.v.) injection of CRF and compared the distribution of c-fos mRNA with that after stress. Wistar male rats were sacrificed 30, 60, 120 and 180 min after the i.c.v. injection of 1 microgram ovine CRF or vehicle alone. Another group of rats was exposed to immobilization stress for 60 min or electrical foot-shock stress (1.5 mA, 1-s duration, 30 x) for 15 min and sacrificed before and 30, 60, 120 and 180 min after the beginning of stress. Centrally administered CRF rapidly (30-60 min) induced c-fos mRNA expression in most of the areas that showed hybridization signals for c-fos after stress: the limbic structures, including the piriform cortex, cingulate cortex, the lateral septal nucleus, the hippocampus, the anterior corticomedial and the medial amygdaloid nuclei, the hypothalamic nuclei, such as the paraventricular nucleus, the supraoptic nucleus (SO) and the dorsomedial nucleus (DMD), and some brainstem nuclei like the pontine nucleus, the locus ceruleus (LC) and Barrington's nucleus. The granular layer of the cerebellum, some thalamic nuclei and the habenula also showed hybridization signals after i.c.v. injection of CRF and stress. However, c-fos induction in the bed nucleus of the stria terminalis, the central nucleus of the amygdala (CeA) and the nucleus tractus solitarius (SOL) was seen only after i.c.v. administration of CRF; in the septo-hypothalamic nucleus and the superior olive, however, c-fos mRNA expression was observed only after stress. There were no differences in the pattern of c-fos mRNA expression between the two stress paradigms. In contrast, i.c.v. injection of saline-induced expression of c-fos mRNA in the piriform cortex, neocortex, cingulate cortex and the amygdala was much less than that seen after i.c.v.-administered CRF as evident in the intensity of the signals. These results suggest that CRF produces c-fos mRNA expression in the brain areas related to stress response, and that CRF may induce behavioral and neuroendocrine responses through activating these brain structures, such as the limbic system and the hypothalamic nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1989

trans-repression of the mouse c-fos promoter: a novel mechanism of Fos-mediated trans-regulation.

Fos protein can trans-activate AP-1-dependent gene expression and trans-repress the c-fos promoter. Although we find that trans-repression is enhanced by coexpression of c-Jun, it does not require any of the AP-1 or ATF sites in the mouse c-fos promoter. A major target for repression is the serum response element (SRE). Fos mutants with an impaired leucine zipper are defective in trans-repression and transformation, suggesting that these functions involve the formation of Fos protein complexes. In contrast, mutations that abolish DNA binding of Fos enhance trans-repression but destroy the transforming potential of Fos. In addition, v-Fos protein efficiently transforms but is unable to trans-repress. These findings point to different mechanisms involved in trans-activation and trans-repression and suggest that trans-repression of the type described here is neither sufficient nor required for Fos-induced transformation.

Animals↗
PubMed2003

Effects of U-50488H and U-50488H withdrawal on c-fos expression in the rat paraventricular nucleus. Correlation with c-fos in brainstem catecholaminergic neurons.

1. In the present work, we have studied the expression of Fos during acute and chronic administration of the kappa-opioid receptor agonist U-50488H and after U-5088H withdrawal in the rat hypothalamic paraventricular nucleus (PVN). Fos production was also studied in brainstem regions that innervate the PVN: the A(2) cell group of the nucleus of solitary tract (NTS-A(2)) and the A(1) cell group of the ventrolateral medulla (VLM-A(1)), combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurons after acute U-50488H administration. 2. For acute experiments, male rats were treated with saline i.p. for 4 days. On day 5, rats were given saline or U-50488H (15 mg x kg(-1), i.p.). Other groups of rats were rendered tolerant/dependent on U-50488H by injecting the drug twice daily (15 mg x kg(-1), i.p.) for 4 days. Control animals received saline i.p. on the same time schedule. On day 5, rats were treated with vehicle i.p., with U-50488H (15 mg x kg(-1)) or with the selective kappa opioid-receptor antagonist nor-binaltorphimine (Nor-BNI, 5 mg x kg(-1), i.p.). 3. Using immunohistochemical staining of Fos, present results indicate that acute administration of U-50488H produced an increase in Fos expression in the PVN and in the noradrenergic A(1) and A(2) cell groups. Moreover, when double-label immunohistochemistry was used to identify Fos and catecholaminergic-positive neurons in the brainstem, it was found that catecholaminergic-positive neurons in the NTS and VLM showed a significant increase in Fos expression in response to acute U-50488H injection. Chronic application of U-50488H leads to the development of tolerance towards their effects on Fos expression in the PVN as well as in the NTS and VLM. However, administration of Nor-BNI to U-50488H-dependent rats did not induce any changes in Fos immunoreactivity in the PVN or in the brainstem. 4. These findings demonstrate that acute activation of kappa-opioid receptors results in different altered patterns of immediate-early gene expression in the PVN, which occurs concurrently with an increased activity of their inputs from the brainstem. Interestingly in contrast to morphine withdrawal, present results demonstrate that rats withdrawn from U-50488H did show no changes in Fos-immunoreactivity in the PVN, NTS or VLM, indicating the absence of dependence on the kappa-agonist under the present experimental conditions.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

A new cat Fos antibody to localize the immediate early gene c-fos in mammalian visual cortex after sensory stimulation.

We developed a novel antibody against cat Fos by immunizing rabbits with a 26-amino-acid peptide. Immunocytochemistry on visual cortex of cats undergoing different visual manipulations was applied to test the reliability and the efficacy of this antiserum. One hour of light stimulation after an overnight dark adaptation resulted in strongly induced Fos expression in supra- and infragranular layers of cat primary visual cortex. Short-term monocular deprivation changed the Fos expression profile into a columnar immunostaining related to ocular dominance columns. Fos expression has also been analyzed in cats in which visual input was confined to the right hemisphere by sectioning the left optic tract and the corpus callosum. In the right hemisphere, visual stimulation elicited Fos induction, whereas in the contralateral hemisphere a very low Fos signal was observed. The specificity of this newly synthesized antibody was confirmed by Western blotting. To further establish the applicability of this Fos antiserum, we performed immunostaining on monkey and rat visual cortex. This new cat Fos antibody appears to be excellent for study of Fos expression as a marker for mapping neuronal activity in mammalian brain.

Animals↗
PubMed2000

Local morphine withdrawal increases c-fos gene, Fos protein, and oxytocin gene expression in hypothalamic magnocellular neurosecretory cells.

We measured stimulation of c-fos and oxytocin gene expression during excitation of oxytocin cells induced by systemic or local morphine withdrawal. Female rats were made morphine-dependent by intracerebroventricular morphine infusion over 5 d. Morphine withdrawal, induced by systemic injection of the opioid antagonist naloxone (5 mg/kg) in conscious or anesthetized rats, increased the density of c-fos messenger RNA and of oxytocin heterogeneous nuclear RNA in supraoptic nucleus cells compared with those of nonwithdrawn rats; c-fos messenger RNA was also increased in the magnocellular and parvocellular paraventricular nuclei of withdrawn rats. Morphine withdrawal increased the number of Fos-immunoreactive cells in the supraoptic and magnocellular paraventricular nuclei of conscious or pentobarbitone-anesthetized rats. Morphine withdrawal also increased Fos-immunoreactive cell numbers in the parvocellular paraventricular nucleus of conscious but not anesthetized rats. Central administration of the alpha(1)-adrenoreceptor antagonist benoxathian (5 microg/min) did not prevent morphine withdrawal-induced increases in the numbers of Fos-immunoreactive neurons in the supraoptic or magnocellular paraventricular nucleus. Unilateral microdialysis administration of naloxone (10(-5) M) into the supraoptic nucleus of anesthetized morphine-dependent rats increased Fos-immunoreactive cell numbers compared with the contralateral nucleus. Finally, we investigated whether dependence could be induced by chronic unilateral infusion of morphine into a supraoptic nucleus; systemic naloxone (5 mg/kg) increased Fos-immunoreactive cell numbers in the morphine-infused nucleus compared with the contralateral nucleus. Thus, morphine withdrawal excitation increases c-fos and oxytocin gene expression in supraoptic nucleus neurons. This occurs independently from excitation of their ascending noradrenergic inputs, and both dependence and withdrawal can be induced within the supraoptic nucleus.

Adrenergic alpha-Antagonists↗
PubMed1989

The Fos and Jun/AP-1 proteins are involved in the downregulation of Fos transcription.

The low basal expression of Fos and the rapid and effective turn-off of serum induced Fos transcription is due to autoregulation. Fos and Jun/AP-1 protein cooperate in the repression mechanism. Overexpressions of Fos and Jun decrease basal and induced transcription from Fos-CAT constructs and from the endogenous gene in NIH3T3 cells. The introduction into cells of either antisense Fos or antisense Jun sequences leads to elevated basal Fos promoter activity. Gel retardation experiments with synthetic oligonucleotides define two target sequences in the Fos promoter which bind Fos-Jun/AP-1 (centering at about -296 and -60). In vivo competition with these oligonucleotides relieves repression.

Chloramphenicol O-Acetyltransferase↗
PubMed1988

Transforming potential and growth stimulating activity of the v-fos and c-fos genes carried by avian retrovirus vectors.

To study transforming potential as well as growth stimulating activity of the fos genes on primary cells, we have developed avian retrovirus vectors by constructing derivatives of Rous sarcoma virus DNA in which the v-src gene was replaced by either the v-fos gene of FBJ-MuSV or the mouse c-fos gene. After each derivative was introduced into chicken embryo fibroblasts by transfection, replication-competent viruses that carry the v-fos gene (FJ2) or the c-fos gene (FM4) were recovered. FM4 and FJ2 introduced the fos genes into almost all chicken embryo fibroblasts within 3 days after infection, expressed their gene products, and induced morphological transformation and colony formation in soft agar. Results show that overproduction of the c-fos gene product is enough for cellular transformation not only of rat established fibroblasts as reported previously but also of avian primary fibroblasts. Using this vector system, we have further shown that the c-fos gene and the v-fos gene have biological activities that induce cellular proliferation of chicken neuroretinal cells, which normally stay in the resting stage of growth in monolayer culture.

Animals↗
PubMed1994

Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of fos and produces a behavioral effect.

While many studies have examined the numerous physiological and pharmacological factors which can induce the expression of c-fos and other immediate-early genes, few have examined the physiological/biochemical consequences of altering their expression pattern. Using antisense oligonucleotides to c-fos, we demonstrate that D-amphetamine-induced c-fos expression can be attenuated in specific brain regions in vivo. This unilateral attenuation of c-fos expression in D-amphetamine-stimulated animals results in a directed rotational behavior. We show that animals rotate only when they express a difference in Fos-like immunoreactivity between hemispheres. The attenuation of Fos-like immunoreactivity by the antisense oligonucleotides appears to be dependent on the c-fos messenger RNA site that these antisense oligonucleotides target and the degree of chemical protection of the oligonucleotide against degradation. The attenuation of Fos-like immunoreactivity and the increase in unilaterally directed rotation are both time- and dose-dependent. These results demonstrate that manipulating immediate-early gene expression by the direct infusion of antisense oligonucleotides in specific brain regions can have behavioral consequences.

Amphetamine↗