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PubMed1995

Acute administration of typical and atypical antipsychotic drugs induces distinctive patterns of Fos expression in the rat forebrain.

Fos expression in the rat brain was investigated by immunohistochemistry after i.p. administration of single doses of a wide range of typical neuroleptic antipsychotic drugs (including the potent dopamine D2 antagonist haloperidol and the mixed monoamine antagonist chlorpromazine) and atypical antipsychotic drugs (including the weak dopamine D2 antagonists clozapine and thioridazine, the relatively pure D2 antagonist raclopride and the mixed D2 and serotonin S2 antagonist risperidone). For comparison to the effects of the antipsychotic drugs and also because the unique clinical therapeutic effects of clozapine have been attributed to S2 blockade, the S2 antagonist ritanserin was also studied. The single shared effect of all antipsychotic drugs tested was the induction of significantly increased Fos immunoreactivity in the nucleus accumbens (NAc). Fos-positive neurons in the NAc were mostly localized in patches throughout its rostrocaudal extent. Haloperidol, chlorpromazine, raclopride and risperidone all significantly increased Fos expression in the medial and lateral striatum. Fos-positive neurons in the striatum were distributed more lateral than medial and declined from rostral to caudal levels. Haloperidol, thioridazine and risperidone also markedly increased Fos expression in the lateral septum. Distinguishing it from the other neuroleptics, clozapine did not increase Fos expression in the lateral striatum, but induced a significant increase in Fos expression in the prefrontal cortex. Ritanserin did not induce Fos expression in any brain region examined, suggesting that S2 antagonism is not responsible for the effects of antipsychotic drugs observed here. Our results suggest that there are distinctive patterns of Fos expression in the forebrain induced by typical and atypical antipsychotic drugs. Notably, Fos expression in the NAc, as a shared property of all the antipsychotic drugs, may be related to the actions mediating the therapeutic effects of these drugs in the treatment of psychotic disorders. The density of Fos-positive neurons stimulated by antipsychotic drugs in the striatum appeared to be correlated with the relative severity of extrapyramidal side-effects produced by these drugs and may be related to the mechanisms mediating these effects.

Analysis of Variance↗
PubMed1995

When is the maximal effect of pre-administered systemic morphine on carrageenin evoked spinal c-Fos expression in the rat?

This study evaluated, in awake rats, the time course of the expression of c-Fos in spinal cord neurons, in the L4-L5 segments, at various time points after intraplantar carrageenin (0.5 h, 1 h, 1.5 h, 2 h and 2.5 h). In addition, the effects of pre-administered morphine (3 mg/kg, i.v.) on the c-Fos expression, at the various time points, were studied. Very few Fos-like immunoreactive (Fos-LI) neurons were observed 0.5 h after carrageenin. However, spinal c-Fos expression increased initially (at 1 h), in the superficial laminae (I-II) of the spinal dorsal horn, and incrementally increased both in the superficial and deep (V-VI) laminae at later time points after carrageenin. Systemic morphine did not significantly decrease the number of superficial Fos-LI neurons observed 1 h after carrageenin, whereas it significantly reduced the number of superficial Fos-LI neurons induced at 1.5 h and 2 h after carrageenin (58 +/- 3% and 57 +/- 10% reduction, P < 0.001, respectively). In addition, morphine reduced the number of deep Fos-LI neurons at 1.5 h and 2 h after carrageenin (86 +/- 4%, P < 0.01 and 82 +/- 8%, P < 0.001 reduction as compared to control carrageenin expression, respectively). In contrast, morphine was less efficacious in decreasing the number of Fos-LI neurons observed in the superficial and deep laminae at 2.5 h after carrageenin (34 +/- 6% and 59 +/- 6% reduction, P < 0.001, respectively). Thus, the peak effect of pre-administered morphine on carrageenin evoked c-Fos expression was observed 1.5 h and 2 h after intraplantar carrageenin, with a weaker effect observed at 2.5 h after carrageenin. The pharmacokinetic complications between the time course of the antinociceptive effects of morphine and c-Fos expression is discussed. These results clearly demonstrate that studies of c-Fos expression with pharmacological investigations should take into consideration this finding since one delay after the stimulation does not give a full indication of the full potential of the drug tested.

Analgesics, Opioid↗
PubMed1996

Odour-induced c-fos expression in the rat olfactory bulb: involvement of centrifugal afferents.

Expression of the proto-oncogene c-fos is known to increase in granule cells of the olfactory bulb following a sustained olfactory stimulation. Most granule cells displaying high levels of Fos accumulation are located in the bulbar columns defined by the odour-induced foci of high 2-deoxyglucose glomerular uptake. The present studies were undertaken in order to assess the possible involvement of centrifugal afferents in the modulation of odour-induced patterns of either 2-deoxyglucose accumulation or c-fos expression in the olfactory bulb. A unilateral olfactory peduncle section had no effect on the odour-induced 2-deoxyglucose foci but induced a significant decrease in the number of Fos-containing neurons in odour-selective areas of both olfactory bulbs, ipsilateral and contralateral to the lesion. This suppressive effect was much more pronounced in the side ipsilateral to the peduncle section. It is concluded that c-fos expression induced by a sustained stimulation with propionic acid vapours is not only determined by the olfactory peripheral input but also by afferents of central origin. In order to estimate the contingent involvements of the cholinergic and noradrenergic afferents in this control of c-fos expression, we attempted to mimic the effects of the surgical deafferentation on odour-induced c-fos expression by using a pharmacological approach with selective cholinergic and noradrenergic antagonists. The beta-adrenergic antagonist propanolol induced a suppression of the odour-related patterns of Fos accumulation similar to the one caused by the surgical deafferentation of the olfactory bulb. The muscarinic antagonist scopolamine did not alter c-fos expression in the odour-selective area but increased significantly Fos labelling in the other bulbar aspects. Pharmacological investigations indicate that the noradrenergic and cholinergic centrifugal systems are likely involved in the central modulation of c-fos expression in the OB. The Fos protein could be expressed as an early nuclear signal triggering further long-term modifications of the neuronal phenotype, in certain conditions of sensory stimulation involving the activation of centrifugal systems.

Adrenergic beta-Antagonists↗
PubMed1995

Carrageenin-evoked c-Fos expression in rat lumbar spinal cord: the effects of indomethacin.

This study evaluated the effects of systemic indomethacin on carrageenin evoked c-Fos expression in rat lumbar spinal cord neurons. Fos-like immunoreactivity was not observed after the intraplantar injection of the control vehicle saline. 2 h after administration of carrageenin (6 mg/150 microliters) into the hind limb, Fos-like immunoreactive neurons were observed in the lumbar spinal cord (64 labelled neurons per L4-L5 sections) and were numerous in the superficial laminae (I-II), whereas at 3-4 h both superficial and deeper laminae (V, VI and ventral horn) were labelled. 3 h after carrageenin administration, maximal Fos-like immunoreactivity was observed (104 labelled neurons per L4-L5 sections). At later time points Fos-like immunoreactivity was observed predominantly in the deeper laminae. Fos-like immunoreactivity was rarely observed within laminae III-IV at any of the time points. At 24 h, the number of Fos-like immunoreactive neurons decreased (36 labelled neurons per L4-L5 sections). With increasing doses of carrageenin, an increase in the number of Fos-like immunoreactive neurons was observed. The number of Fos-like immunoreactive neurons induced by the carrageenin stimulation (6 mg, at 3 h) was clearly reduced by oral pretreatment with indomethacin (20 mg/kg). In addition, i.v. indomethacin (1, 2.5 or 5 mg/kg) dose dependently reduced the number of Fos-like immunoreactive neurons and the inflammation of the paw and the ankle of the injected foot. A strong relationship between the effect of indomethacin on c-Fos expression and its effect on inflammatory processes was observed. These results suggest that Fos-like immunoreactivity induced by carrageenin inflammation may be a very useful tool to study the effects of anti-inflammatory drugs, at both peripheral and central levels of inflammation.

Animals↗
PubMed1995

Developmental changes in the inducibility of fos-like immunoreactivity in primary embryonic spinal cord cultures.

The immediate early gene (IEG) transcription factor c-fos coordinates changes in the pattern of long term gene expression and, therefore, it may be involved in mediating epigenetic control during neurodevelopment. We used pharmacological treatments mimicking various environmental and intracellular signals and assessed the inducibility of fos-like immunoreactivity (LIR) at various stages of neurodifferentiation in a primary embryonic spinal cord culture system by immunohistochemistry. Constitutive fos LIR exclusively found in neurons, was driven by the onset and extent of spontaneous electrical activity, as it was blockable by tetrodotoxin (TTX) at all developmental stages. Phorbol myristate 13 acetate (PMA) increased the number of fos-LIR cells equally effectively at all stages, but the predominant cellular localization of fos-LIR changed through ontogeny. The effect of veratridine, kainate and serum-derived factors in significantly inducing fos-LIR was restricted to the earliest developmental stage (4 days in vitro; DIV) investigated; whereas forskolin, the GABAA antagonist picrotoxin and NMDA failed to induce fos-LIR at this stage, but increased the number of fos-LIR neurons at later stages. Dihydropyridine agonists of the voltage-sensitive calcium channels (VSCC) raised the number of fos-LIR neurons and also prevented TTX-mediated down-regulation; whereas antagonists markedly reduced fos-LIR at all ages. Either type of NMDA antagonists (AP5 and MK801) and the GABAA agonist muscimol significantly reduced fos-LIR at all ages. These findings demonstrate that the inducibility of fos-LIR is substantially different in embryonic neurons than in adult ones and that inducibility by various first and second messengers is dependent on the development stage.

Animals↗
PubMed1995

Definition of the developmental transition from dopaminergic to photic regulation of c-fos gene expression in the rat suprachiasmatic nucleus.

D1-dopamine receptor stimulation induces c-fos gene expression in the fetal suprachiasmatic nucleus (SCN), but not in the adult rat SCN. Light exposure at night induces c-fos gene expression in the adult SCN. The present experiments were designed to define the developmental transition from dopaminergic to photic regulation of c-fos gene expression in the SCN. Treatment with the D1-dopamine receptor agonist SKF 38393 (10 mg/kg) increased SCN c-fos gene expression during both day and night on postnatal day (PD) 0, 1, and at night on PD 2, but the c-fos response disappeared by PD 4. Photic induction of c-fos gene expression was apparent during both day and night at each age examined, from PD 0 through PD 6. The magnitude and distribution of c-fos expression following light during the daytime was distinguishable from the response to light at night beginning on PD 2, indicating that the circadian clock regulates (gates) the c-fos response by PD 2. Orbital enucleation prevents the induction of c-fos by light at night on PD 2, indicating retinal mediation. Developmental loss of the c-fos response to SKF is not precipitated by the arrival of the retinohypothalamic tract; animals enucleated on PD 0 were insensitive to SKF on PD 6, as were visually intact controls. The results demonstrate that both dopaminergic and photic inputs can regulate SCN c-fos gene expression early in the neonatal period, and that the developmental loss of sensitivity to SKF is not due to the arrival of photic input to the SCN. The developmental transition from dopaminergic to photic regulation of c-fos gene expression roughly parallels the developmental transition from maternal to photic entrainment of the developing biological clock.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Fenfluramine-induced activation of the immediate-early gene c-fos in the striatum: possible interaction between serotonin and dopamine.

DL-Fenfluramine, a serotonin (5-HT) releasing agent, induces rapid expression of Fos-like immunoreactivity (Fos-LI) in the striatum as well as in other brain structures receiving a dense 5-HT innervation. Fenfluramine-induced Fos-LI expression in the striatum may result directly from the activation of 5-HT receptors or may be the result of interactions between dopamine (DA) and 5-HT neurotransmitter systems. To discriminate between these two possibilities, various groups of rats were pretreated with different 5-HT antagonists or a DA D1 antagonist, 20 min before fenfluramine administration. Animals were killed 60 min later. In the striatum, fenfluramine-induced expression of Fos-LI was almost completely blocked by SCH 23390, methysergide and S(-)-propranolol. The immediate-early gene response to fenfluramine was only slightly affected by pretreatment with the 5-HT2A/2C antagonist ritanserin. Fenfluramine was also administered to sham-operated and to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. In the 6-OHDA-lesioned rats, fen-fluramine-induced Fos-LI was decreased by 60% on the DA denervated side compared to the intact side and to sham-operated rats. To further probe the possibility of a direct activation of Fos-LI by 5-HT receptor subtypes, we evaluated the expression of Fos-LI after the administration of different 5-HT agonists. Our results demonstrate that neither 8-OH-DPAT, CGS-12066B, RU 24969 nor phenyl-biguanide was able to reproduce the effects of fenfluramine. Only a high dose of DOI (8.5 mg/kg) produced a moderate expression of Fos-LI in the dorsomedial part of the striatum. This contrasted with the Fos-LI expression in other brain areas where 8-OH-DPAT and DOI (2.5 and 8.5 mg/kg) reproduced the effects of the 5-HT releasing agent. Our results suggest that the release of 5-HT by fenfluramine induced Fos-LI expression predominantly in a striatal region related to associative functions and, that this c-fos response may be under the control of both 5-HT and DA. Moreover, the mechanism by which fenfluramine induces c-fos expression in the striatum differs from other brain regions.

Animals↗
PubMed1991

Follicle-stimulating hormone increases c-fos mRNA levels in rat granulosa cells via a protein kinase C-dependent mechanism.

Recent evidence has been presented that follicle-stimulating hormone (FSH) stimulates the induction of granulosa cell c-fos protooncogene mRNA in vivo (Pennybacker and Herman (1989) J. Cell Biol. 109, 151A; Delidow et al. (1990) Endocrinology 126, 2302-2306), yet the mechanisms by which FSH induces c-fos mRNA expression have not been delineated. To elucidate the mechanisms of FSH-dependent c-fos mRNA expression, we measured the time and dose dependence of c-fos mRNA levels using Northern blot analysis in intact ovaries and cultured granulosa cells in response to FSH. In intact ovaries, FSH-induced c-fos mRNA expression was time dependent with maximal expression at 90 min post FSH injection, while in cultures of granulosa cells obtained from estrogen-primed immature female rats, c-fos mRNA levels were highest after 30 min exposure to FSH and at a concentration of 100 ng/ml. Neither 8-bromo adenosine 3',5'-cyclic monophosphate (8-br-cAMP), at doses ranging from 0.1 to 10 mM, nor 100 microM forskolin (in the presence or absence of 200 microM isobutyl-methylxanthine) or luteinizing hormone (LH, 100 ng/ml) were able to mimic FSH-induced c-fos mRNA expression in granulosa cell cultures. However, tetradecanoyl-13-phorbol acetate (TPA, 200 nM) was able to induce c-fos mRNA expression. The protein kinase C (PKC) inhibitors H-7 (0.3-30 microM) and staurosporine (0.75 micrograms/ml) blocked FSH-induced c-fos mRNA expression in cultured granulosa cells while HA 1004, an inhibitor of cGMP- and cAMP-dependent protein kinases at 30 microM had no effect on TPA-induced c-fos expression, and only minimally inhibited FSH-induced c-fos expression. Both FSH (100 ng/ml) and forskolin (3 microM) increased progesterone production in cultured granulosa cells. These data support the hypothesis that FSH specifically induces c-fos mRNA expression by a PKC-dependent mechanism and that the cAMP arm of the FSH response pathway is operant in these cells.

Animals↗
PubMed1991

The antinociceptive action of supraspinal opioids results from an increase in descending inhibitory control: correlation of nociceptive behavior and c-fos expression.

In an earlier report, we demonstrated that subcutaneous injection of formalin in the rat hindpaw evokes a characteristic pattern of expression of the fos protein product of the c-fos protooncogene in spinal cord neurons, and that systemic morphine reversed the fos-like immunoreactivity in a dose-dependent, naloxone-reversible manner. The present study compared the effects of intracerebroventricular administration of the mu-selective opioid ligand [D-Ala2, NMe-Phe4, Gly-ol5] enkephalin, on the pain behavior and spinal cord fos-like immunoreactivity produced by subcutaneous formalin. Formalin injection produced a biphasic pain behavioral response which lasted about 1 h. There was a significant correlation between the formalin pain score and overall fos-like immunoreactivity in the lumbar enlargement. The greatest numbers of labeled cells and most intense fos-like immunoreactivity were found in laminae I, IIo and V of the L4-5 segments, ipsilateral to the formalin-injected paw. Considerable staining was also found in the ipsilateral ventral horn laminae VII and VIII. [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin produced a dose-related, naloxone-reversible inhibition of both the formalin-evoked pain behavior and fos expression in the cord. The behavioral response to formalin, however, could be completely blocked without eliminating the expression of fos in spinal neurons. Moreover, subpopulations of neurons were differentially regulated. Thus, 100% inhibition of pain behavior was produced at a dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which reduced fos-like immunoreactivity in the superficial laminae by only 64% and in the neck and ventral cord by 85%. Furthermore, the dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which produced approximately 50% inhibition of fos-like immunoreactivity in the neck and ventral regions of the spinal cord was without effect in the superficial dorsal horn. Since the potencies for inhibition of pain behavior and fos-like immunoreactivity in the neck and ventral horn were comparable, these data suggest that the activity of neurons in these regions is directly related to the pain behavior produced by nociceptive inputs. Finally, we found that bilateral, midthoracic lesions of the dorsal part of the lateral funiculus blocked both the antinociception and fos suppression produced by intracerebroventricular [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin. These results are consistent with the hypothesis that the analgesic action of supraspinally administered opiates results from an increase in descending inhibitory controls that regulate the firing of subpopulations of spinal cord nociresponsive neurons.

Amino Acid Sequence↗
PubMed1995

D1 and D2 dopamine receptors differentially increase Fos-like immunoreactivity in accumbal projections to the ventral pallidum and midbrain.

Alterations in dopaminergic neurotransmission have profound effects on neuronal expression of the putative activity marker, Fos, in both the dorsal and ventral striatum. Stimulants such as D-amphetamine and cocaine increase Fos-like immunoreactivity by enhancing the activation of D1 dopamine receptors. In contrast, neuroleptics such as haloperidol and raclopride increase Fos-like immunoreactivity by blocking striatal D2 dopamine receptors. In the dorsal striatum, D1 receptor stimulation elevates Fos-like immunoreactivity predominantly in neurons projecting to the midbrain (substantia nigra), whereas D2 receptor antagonism enhances Fos-like immunoreactivity principally in neurons projecting to the pallidum (globus pallidus). These findings are consistent with the proposal that D1 receptors are located chiefly on striatonigral neurons, whereas D2 receptors reside mainly on striatopallidal neurons. Since the nucleus accumbens (largest component of the ventral striatum) also sends projections to the midbrain (ventral tegmental area and substantia nigra) and pallidum (ventral pallidum), the present study utilized retrograde tract-tracing techniques to determine if there was a similar segregation of D1 agonist- and D2 antagonist-induced Fos-like immunoreactivity in these accumbal projections. In addition, we examined whether these relationships were the same in the core and shell regions of the nucleus accumbens. Like the dorsal striatum, D1 agonists (D-amphetamine and CY 208-243), but not D2 antagonists (haloperidol and clozapine), increased Fos-like immunoreactivity in accumbal neurons projecting to the midbrain (ventral tegmental area and substantia nigra). Also like the dorsal striatum, D2 antagonist-induced Fos-like immunoreactivity was located preferentially in accumbal neurons projecting to the pallidum (ventral pallidum). However, unlike the dorsal striatum, where the vast majority of neurons which display D1 agonist-induced Fos-like immunoreactivity project to the midbrain, nearly 50% of those neurons in the nucleus accumbens which were Fos-immunoreactive after D-amphetamine or CY 208-243 projected to the ventral pallidum. Thus, a similar number of accumbal neurons which expressed D1 agonist-induced Fos-like immunoreactivity were retrogradely labelled from the midbrain and ventral pallidum. Accumbal projections to the midbrain and ventral pallidum were retrogradely labelled with different retrograde tracers in order to determine the degree of collateralization between these pathways. Approximately 20% of retrogradely labelled neurons displayed both tracers, indicating that collateralization and damage to fibres of passage could not account for all of those cases in which D1 agonist-induced Fos-like immunoreactivity was detected in accumbal neurons projecting to the ventral pallidum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Receptor mechanisms mediating clozapine-induced c-fos expression in the forebrain.

The atypical antipsychotic clozapine produces distinctly different regional patterns of c-fos expression in rat forebrain than does the prototypical neuroleptic haloperidol. While haloperidol-induced c-fos expression appears to be mediated by its D2 dopamine receptor antagonist properties, the mechanisms by which clozapine increases c-fos expression remain uncertain. Using a combination of brain lesion, pharmacological and immunohistochemical techniques, the present study sought to determine the receptor mechanisms by which clozapine increases the number of Fos-like immunoreactive neurons in various regions of the forebrain. To test whether serotonergic and/or noradrenergic systems are involved in clozapine-induced c-fos expression, rats received either 5,7-dihydroxytryptamine lesions of the medial forebrain bundle or 6-hydroxydopamine lesions of the dorsal noradrenergic bundle two weeks prior to clozapine (20 mg/kg) injections. Neither type of lesion affected clozapine-induced c-fos expression in the rat forebrain, suggesting that neither serotonergic nor noradrenergic mechanisms are involved in this action of clozapine. In another experiment, the 5-hydroxytryptamine2 receptor antagonist ritanserin (5 mg/kg), either alone or in combination with haloperidol (1 mg/kg), failed to mimic the pattern of c-fos expression produced by clozapine. This suggests that clozapine's antagonist actions at 5-hydroxytryptamine2 receptors cannot explain the unique pattern of regional c-fos expression produced by this compound. To determine whether the blockade of subtypes of the D2 dopamine receptor family may contribute to clozapine's effects, the dopamine receptor agonists quinpirole and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) were injected 15 min prior to clozapine. Quinpirole produced a small but significant decrease in clozapine-induced c-fos expression in the medial prefrontal cortex, had larger effects in the lateral septum, and blocked clozapine's actions in the nucleus accumbens and major island of Calleja. Pretreatment with 7-OH-DPAT attenuated clozapine-induced c-fos expression in the nucleus accumbens and lateral septum, completely blocked the expression in the major island of Calleja, but was without effect in the medial prefrontal cortex. Given the different affinities of quinpirole and 7-OH-DPAT for D2, D3 and D4 receptors, these data suggest that clozapine-induced increases in c-fos expression in the nucleus accumbens, major island of Cajella and lateral septal nucleus are due to antagonist actions of this antipsychotic at D3 dopamine receptors. They also indicate that while antagonist actions at D4 receptors may contribute, the primary mechanisms by which clozapine increases c-fos expression in the medial prefrontal cortex remain to be determined.

Animals↗
PubMed2005

Role of protein kinase C beta in phorbol ester-induced c-fos gene expression in neurons of normotensive and spontaneously hypertensive rat brains.

We have previously demonstrated that pressure application of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) onto some neurons in the anterior hypothalamic area of rats increases neural activity in vivo and that this PKC activation-induced increase of neural activity is enhanced in spontaneously hypertensive rats (SHR), an animal model for genetic hypertension. Activation of PKC increases expression of the c-fos gene, an important transcription factor and proto-oncogene thought to be a marker of neural activity. To evaluate PKC isoforms responsible for neural activation, we examined which isoforms of PKC are involved in the PKC activation-induced c-fos gene expression in neuronal cultures of Wistar rat and spontaneously hypertensive rat (SHR) brains. PMA increased c-fos gene expression in neuronal cultures of Wistar rat brain and the PMA-induced c-fos gene expression was inhibited by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). The PKCalpha,beta,gamma activator thymeleatoxin also increased c-fos gene expression, while the PKCdelta,epsilon activator ingenol did not affect it. In addition, the PMA-induced c-fos gene expression was inhibited by PKCbetaantisense oligonucleotides (AON) but not by PKCalpha and PKCgammaAONs. In SHR brain neuronal cultures, the PMA-induced c-fos gene expression was enhanced as compared with that of Wistar Kyoto rats (WKY), while basal c-fos gene expression was almost the same in both neuronal cultures. The enhancement of PMA-induced c-fos gene expression in SHR brain cultures was abolished by PKCbetaAON. These findings suggest that in rat brain neuronal cultures, PMA increases c-fos gene expression via activation of PKC and that PKCbetaisoforms are partly involved in the PMA-induced c-fos gene expression. In neuronal cultures of SHR brain, it appears that the PMA-induced c-fos gene expression is also enhanced via PKCbeta.

Animals↗
PubMed2006

Dissociation between post-surgical pain behaviors and spinal Fos-like immunoreactivity in the rat.

Previous studies have demonstrated that Fos-like immunoreactivity is increased in spinal dorsal horn neurons in several pain models, and have suggested that Fos-like immunoreactivity could be used as a marker of neurons activated by painful stimulation. In the present study, we evaluated nociceptive behaviors and spinal Fos-like immunoreactivity in a rat skin incision model of post-operative pain. In this model, evoked and non-evoked pain behaviors were observed at least for 2 days after paw surgery, an increased number of Fos-like immunoreactive neurons was observed in the spinal dorsal horn at lumbar levels 4-5 two-hour post-surgery. The number of Fos-like immunoreactive neurons was significantly greater in animals with skin-muscle incision compared to animals with skin-alone incision. Interestingly, spinal Fos-like immunoreactivity was quickly normalized in rats with paw surgery at later time points (8 and 24 h post-surgery), whereas nociceptive behaviors were still observed. Furthermore, at 24 h post-surgery, spinal Fos-like immunoreactivity induced by thermal stimulation (42, 44, 46, 48, 52 degrees C for 15 s) was not significantly different between sham animals and animals with surgery. In both groups, an increase in spinal Fos-like immunoreactive neurons was observed with increasing temperatures, with similar laminar distribution. Finally, systemic morphine reduced post-operative pain and Fos-like immunoreactivity in a naloxone reversible manner, with greater potency and efficacy on behavioral endpoints than on Fos-like immunoreactivity. These results demonstrate a different profile of nociceptive behaviors and spinal Fos-like immunoreactivity in the rat skin incision model, suggesting a limited potential of spinal Fos-like immunoreactivity to study post-surgical pain and its pharmacology.

Analgesics, Opioid↗
PubMed2005

Dopamine and norepinephrine transporter-dependent c-Fos production in vitro: relevance to neuroadaptation.

Cocaine, methylphenidate and other drugs that block dopamine transport indirectly promote immediate early gene expression, via dopamine-mediated activation of D1 dopamine receptors. Increased expression of the immediate early gene (IEG) c-fos, initiates a cascade of intracellular events that may underlie neuroadaptive changes following repeated exposure to the drugs. We investigated whether substrates (dopamine, norepinephrine) of the human dopamine (hDAT) and norepinephrine (hNET) transporters can directly induce c-Fos protein in HEK-293 (HEK) cells transfected with the hDAT and hNET and whether PKC modulators affect this process. Dopamine and norepinephrine robustly induced c-Fos immunofluorescence in both hDAT and hNET cells, but not in untransfected HEK-293 cells, demonstrating that catecholamine-induced c-Fos induction was DAT- and NET-dependent. The PKC activator PMA induced c-Fos in hDAT, hNET and HEK cell lines indicating that PKC stimulated c-Fos independent of transporters. The PKC inhibitor bisindolylmaleimide I (BIS) significantly increased c-Fos expression in hDAT cells, but not in hNET or HEK-293 cells, suggesting that inhibition of DAT-mediated phosphorylation results in c-Fos induction. BIS pretreatment abolished norepinephrine-induced c-Fos expression hNET but not dopamine-induced c-Fos induction in hDAT cells. In conclusion, induction of c-Fos by dopamine and norepinephrine requires the presence of hDAT and hNET but the contributions of hDAT and hNET to c-Fos induction is distinguishable on the basis of differing responses to a PKC inhibitor. These findings present a cell system and methodology for investigating the potential contribution of monoamine transporters to pre-synaptic neuroadaptation.

Adaptation, Physiological↗
PubMed2000

Chronic tooth pulp inflammation causes transient and persistent expression of Fos in dynorphin-rich regions of rat brainstem.

We have analyzed central Fos immunoreactivity (Fos-IR) brainstems of adult rats after three clinically relevant dental injuries: filled dentin (DF) cavities that cause mild pulp injury and heal within 1-2 weeks; open pulp exposures (PX) that cause gradual pulp loss and subsequent periodontal lesions; and filled pulp exposures (PXF). By 1 week after DF cavities, no Fos-IR remained except for sites such as lateral-ventral periolivary nucleus (LVPO) that had Fos-IR in all rats including controls. PX injury induced (1) a delayed transient expression of Fos at 1-2 weeks at three loci (ipsilateral neurons in dorsomedial nucleus oralis, paratrigeminal nucleus, and trigeminal tract), (2) persistent ipsilateral Fos for at least 4 weeks after injury in dynorphin (Dyn)-rich regions (rostral lateral solitary nucleus, periobex dorsal nucleus caudalis), and (3) late Fos-IR at 2-4 weeks (bilateral superficial cervical dorsal horn, contralateral dorsal nucleus caudalis, contralateral rostral lateral solitary nucleus). Rats with PXF injury were examined at 2 weeks, and they had greater numbers and more extensive rostro-caudal distribution of Fos neurons than the PX group. One week after PX injury, Fos-IR neurons were found in regions with strong Dyn-IR central fibers. Co-expression of Dyn and Fos was found in some unusually large neurons of the ipsilateral rostral lateral solitary nucleus, trigeminal tract, and dorsal nucleus caudalis. Immunocytochemistry for the p75 low affinity neurotrophin receptor (p75NTR) or for calcitonin gene-related peptide (CGRP) showed no consistent change in trigeminal central endings in any Fos-reactive brainstem areas, despite the extensive structural and cytochemical reorganization of the peripheral endings of the dental neurons. The Fos responses of central neurons to tooth injury have some unusual temporal and spatial patterns in adult rats compared to other trigeminal injury models.

Animals↗
PubMed2002

Neuronal expression of fos protein in the forebrain of diabetic rats.

We sought to identify the areas that have altered neuronal activity within the hypothalamus of diabetic rats by mapping neuronal expression of c-fos protein (Fos) and Fos-related antigens. After a standard PAP immunocytochemical protocol, Fos-like immunoreactivity was observed in the paraventricular nucleus (PVN), supraoptic nucleus (SON), median preoptic area (MnPO), anterior hypothalamus (AH) and posterior hypothalamus (PH) of control (vehicle; n=6) and diabetic rats (Sprague-Dawley rats injected with STZ 65 mg/kg/ip 4 weeks prior to the experiment; n=6). Blood glucose levels were significantly elevated in the diabetic group (370+/-8 mg/dl) compared to control group (104+/-3 mg/dl). Diabetic rats had a significantly higher number of Fos-positive cells in PVN (2.5x), SON (7x) and MnPO (2x) compared to the control rats. However, diabetic rats had significantly fewer Fos-positive cells in the AH (0.3x) and no difference was observed in the PH between the diabetic and control rats. Despite the elevated number of Fos-positive cells in the diabetic rats, dehydration (water withdrawal for 24 h) or hypertonic challenge (1.5 ml of 0.1 M NaCl i.p. injection) produced a further increase in the number of Fos-positive cells in the PVN, SON and MnPO. Dehydration did not alter the number of Fos-positive cells in the AH or PH, but hypertonic challenge produced a significant increase in the Fos-positive cells in both the AH and PH of diabetic rats. This study demonstrates that: (1) there is increased basal neuronal activity in the PVN, SON and MnPO, a decrease in neuronal activity in the AH and no change in neuronal activity in the PH as indicated by Fos staining in diabetic rats; and (2) dehydration or hypertonic challenge produces a further increase in the number of Fos-positive cells in the PVN, SON, and MnPO which is comparable to control rats. These data support the conclusion that vasopressin producing neurons in the PVN and SON and autonomic areas within the lamina terminalis and hypothalamus are activated during diabetes and may contribute to the elevated levels of vasopressin and autonomic dysfunction during diabetes.

Animals↗
PubMed1997

The c-Fos transcription factor in the auditory pathway of the juvenile rat: effects of acoustic deprivation and repetitive stimulation.

The expression of the inducible transcription factors (ITF) c-Fos and JunB was investigated in the dorsal cochlear nucleus (DCN), ventral cochlear nucleus (VCN) and inferior colliculus (IC) of juvenile and adult rats following deprivation and repetitive stimulation paradigms using 8 kHz tone bursts at 5 min duration and 70 dB, 90 dB or 120 dB sound pressure level (SPL). (1) During postnatal development without stimulation, c-Fos is absent in DCN and VCN from postnatal day (P) 12 to adulthood, but shows a strong expression in the IC which declines during maturation. A similar decrease was also seen in the pons. (2) Between P15 and P35 stimulation of rats with 8 kHz for 5 min at 70 dB SPL evoked expression of c-Fos in a moderate number of cells of DCN, VCN and IC. Higher sound pressure levels increased the number of c-Fos immunoreactive neurons as studied at P21. (3) Deprivation of acoustic stimulation up to P21 reduced the expression of c-Fos when rats were stimulated with 90 dB immediately after the restoration of acoustic input. In contrast to 90 dB SPL, c-Fos immunoreactivity (IR) did not significantly differ between deprived and normal rats following application of 120 dB SPL at P21. Stimulation at P28, i.e., 7 days after the end of the deprivation, evoked an increase of c-Fos only in the IC compared to otherwise normally stimulated rats. At P35, effects of the former deprivation on the c-Fos expression were not longer detectable. (4) In a repetitive stimulation paradigm, 8 kHz tone bursts 5 min in duration were applied each second day between P23 and P35 or each day between P29 and P35. When compared with acutely stimulated rats at P35, both repetitive acoustic stimulation protocols reduced the c-Fos immunoreactivity by 50%-75% in the DCN, VCN and IC. In adult 4-month-old rats, repetitive stimulation did not reduce the c-Fos immunoreactivity from its moderate levels as compared with acute stimulation. (5) In some experiments, we studied also the expression of the JunB protein. JunB paralleled the expression of c-Fos following single acoustic stimulation, but was expressed in a substantially lower number of cells. In contrast to c-Fos, however, repetitive stimulation as described in section 4 did not evoke a decrease of JunB in the lower acoustic pathway.

Acoustic Stimulation↗
PubMed1997

Atipamezole-precipitated clonidine withdrawal induces c-Fos expression in rat central nervous system.

We sought to identify a clonidine withdrawal syndrome in conscious rats by investigating the effects of a single injection of the specific alpha2-adrenergic antagonist atipamezole (1.5 mg/kg i.p.) after chronic treatment with the alpha2-adrenergic agonist clonidine (200 microg/kg per day via osmotic mini-pump for 7-10 days). Rats treated chronically with clonidine followed by atipamezole injection (clonidine-atipamezole) demonstrated dramatic behavioral effects including shaking, vigorous digging, and whole-body seizure-like movements. Control groups (saline-saline, clonidine-saline and saline-atipamezole) showed no overt unusual behavioral effects following injection. The brains of the clonidine-atipamezole group showed massive c-Fos expression (especially in di- and telencephalon) while the other groups showed either background levels of c-Fos-immunopositive cells (saline-saline and clonidine-saline groups) or a slight increase over background in selected areas (saline-atipamezole group). Maps of c-Fos-immunolabeled cells were generated at five representative coronal planes for each treatment group. C-Fos-immunopositive cells were counted in three representative brainstem structures (locus coeruleus, nucleus of the solitary tract, rostral ventrolateral medulla (RVL)) and in three regions of the thoracic spinal cord (dorsal horn, intermediate zone and ventral horn). In the three brainstem structures the number of c-Fos-positive cells was elevated 8-10-fold in the clonidine-atipamezole group compared to the other groups. No other treatment group was significantly different from the saline-saline group. An increased number of c-Fos-positive neurons was also noted in the dorsal horn and intermediate layers of the thoracic spinal cord in the clonidine-atipamezole group compared to a sham-operated atipamezole-injected group. In the RVL, 59% of c-Fos-positive cells contained alpha2A-adrenergic receptor-like immunoreactivity in clonidine-atipamezole treated (withdrawing) rats. In addition, one-third of the tyrosine hydroxylase (TH)-immunopositive cells in RVL were also c-Fos-positive in clonidine withdrawing rats where no TH-positive cells were also c-Fos-positive in RVL of control groups. Atipamezole injected 10 min after a single injection of clonidine (200 microg/kg, i.p.) produced no behavioral effect and did not increase c-Fos expression in brainstem. Injection of the opiate antagonist naltrexone (100 mg/kg, i.p.) in rats chronically treated with clonidine did not elicit behavioral effects or result in increased c-Fos expression in brainstem. In conclusion, administration of the selective alpha2-antagonist atipamezole to rats chronically treated with the alpha2-adrenergic agonist clonidine triggers a powerful withdrawal syndrome associated with massive CNS expression of c-Fos protein. The intensity of the withdrawal syndrome indicates that chronic exposure to alpha2-adrenergic receptor agonists produces strong dependence.

Adrenergic alpha-2 Receptor Antagonists↗