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PubMed2004

Modulation of morphine-induced Fos-immunoreactivity by the cannabinoid receptor antagonist SR 141716.

A growing body of evidence suggests the existence of a functional interaction between opioid and cannabinoid systems. The present study further investigated this functional interaction by examining the combined effects of morphine and the cannabinoid receptor antagonist SR 141716 on Fos-immunoreactivity (Fos-IR), a marker for neural activation. Male albino Wistar rats were treated with SR 141716 (3 mg/kg, intraperitoneally), morphine HCl (10 mg/kg, subcutaneously), vehicle, or SR 141716 and morphine combined (n = 6 per group). Rats were injected with morphine or its vehicle 30-min after administration of SR 141716 or its vehicle and perfused 3 h later. Locomotor activity and body temperature were both increased in the morphine-treated group and SR 141716 significantly inhibited these effects. Morphine increased Fos-IR in several brain regions including the caudate-putamen (CPu), cortex (cingulate, insular and piriform), nucleus accumbens (NAS) shell, lateral septum (LS), bed nucleus of the stria terminalis (BNST), median preoptic nucleus (MnPO), medial preoptic nucleus (MPO), hypothalamus (paraventricular, dorsomedial and ventromedial), paraventricular thalamic nucleus (PV), amygdala (central and basolateral nuclei), dorsolateral periaqueductal gray, ventral tegmental area (VTA), and Edinger-Westphal nucleus. SR 141716 alone increased Fos-IR in the cortex (cingulate, insular and piriform), NAS (shell), LS, BNST, hypothalamus (paraventricular, dorsomedial and ventromedial), PV, amygdala (central, basolateral and medial nuclei), VTA, and Edinger-Westphal nucleus. SR 141716 attenuated morphine-induced Fos-IR in several regions including the CPu, cortex, NAS (shell), LS, MnPO, MPO, paraventricular and dorsomedial hypothalamus, PV, basolateral amygdala, VTA, and Edinger-Westphal nucleus (EW). These results provide further support for functional interplay between the cannabinoid and opioid systems. Possible behavioural and physiological implications of the interactive effects of SR 141716 on morphine-induced Fos-IR are discussed.

Animals↗
PubMed1988

The histaminergic system in the guinea pig central nervous system: an immunocytochemical mapping study using an antiserum against histamine.

Using an antiserum against conjugated histamine we mapped the histaminergic somata and their fiber projection areas in carbodiimide-fixed guinea pig central nervous system. The neurons were large and they were found exclusively in the posterior hypothalamus, as in the rat, but in the guinea pig they were more numerous and distributed more widely in thin layer around the posterior mammillary nucleus, scattered between and within the medial mammillary nuclei, and in a dense cell cluster emerging from the caudal magnocellular nucleus and extending to the medial preoptic area. The density of histamine-immunopositive fibers was very high in the olfactory tubercle, diagonal band of Broca, nucleus accumbens, medial and cortical amygdaloid nuclei, periventricular and lateral basal hypothalamus, paraventricular thalamus, and in a region from the medial central gray to the locus coeruleus and the parabrachial nucleus. Dense fiber networks were found in the piriform and entorhinal cortex, septum, dentate gyrus, and subiculum, in most parts of amygdala, and in many areas of the hypothalamus, thalamus, substantia nigra, raphe nuclei, inferior olivary, solitary tract and medial vestibular nuclei, and neurohypophysis. Medium fiber density was observed in the internal layers of the olfactory bulb, anterior olfactory nuclei, neocortex, zone CA1 of hippocampus, and many midbrain and hindbrain regions. Low density was present in the outer layers of the olfactory bulb, other parts of hippocampus, the globus pallidus, most of the caudatus-putamen, the cerebellar cortex, and the dorsal horn of the spinal cord. The retina and most of the myelinated white matter had single or no histaminergic fibers. It may be concluded from the results that most fibers seem to follow a ventromedial route to the forebrain, reaching the amygdala ventral to the medial forebrain bundle, the hippocampus via subiculum, and the hindbrain structures via the medial central gray. As compared to the rat, the fiber projections in the guinea pig brain were denser, particularly in the hippocampus, thalamus, pons-medulla, and neurohypophysis. The fiber densities in various regions of the guinea pig brain are compared to histamine receptor densities and the possible functions of histamine are discussed.

Animals↗
PubMed1995

A sex comparison of increments in FOS immunoreactivity in forebrain neurons of gonadectomized, testosterone-treated rats after mounting an estrous female.

The protein product of the immediate-early gene, c-fos, was visualized immunocytochemically in forebrain neurons of gonadectomized male and female rats which were injected daily with testosterone propionate (TP) and either tested for mounting directed toward a sexually receptive female or left alone in a test arena. Lidocaine anesthetic paste was applied to the genital region of all subjects in an attempt to reduce the incidence of intromissive behavior patterns. In this way we hoped to compare the relative contribution in the two sexes of vomeronasal/olfactory, as opposed to genital/somatosensory, stimuli to mounting-induced forebrain Fos immunoreactivity (FOS-IR). Males displayed high levels of mounting, with very few intromissions; females displayed a similar level of mounting coupled with a significantly higher number of intromissive behavior patterns than males. Significant increments in the number of FOS-IR neurons were seen in the medial amygdala (mAMYG) and medial preoptic area (mPOA) of males and females killed 1 h after testing. In experiment 2, ovariectomized, TP-treated females were given a unilateral lesion of the olfactory peduncle and subsequently tested with an estrous female as in Experiment 1. Unilateral lesions significantly reduced the number of FOS-IR neurons counted in the ipsilateral piriform (primary olfactory) cortex, but failed to attenuate the ability of stimuli associated with mounting an estrous female to augment FOS-IR in ipsilateral mAMYG or mPOA neurons. The results suggest that vomeronasal/olfactory stimuli were primary determinants of the mounting-induced increments in neuronal FOS-IR observed in males, whereas in females a combination of genital/somatosensory and olfactory/vomeronasal stimuli account for the observed induction of forebrain FOS-IR.

Amygdala↗
PubMed1996

Persisting changes in brain glucose uptake following neurotoxic doses of phencyclidine which mirror the acute effects of the drug.

Phencyclidine (PCP) can induce a model psychosis which has a number of similarities to dementias and schizophrenia. In some cases the psychosis persists for prolonged periods after drug discontinuation. N-Methyl-D-aspartate (NMDA) antagonists such as PCP induce increases in glucose metabolism in a variety of brain structures but most notably in limbic regions such as retrosplenial, piriform, and entorhinal cortex, hippocampus, and olfactory tubercle. When given continuously for several days, these NMDA antagonists induced neural degeneration in these same critical limbic areas. In the present study regional 2-fluorodeoxyglucose (FDG) uptake was measured in rats at both 24 h and 10 days after neurotoxic, 5-day "binge" PCP administration. At 24 h after minipump removal there were persisting and large increases in glucose uptake in many brain regions, with maximal changes in the same limbic structures in which neurotoxicity has been observed. Surprisingly, many of these regions still showed elevated glucose metabolism after 10 days of recovery. These findings suggest an anatomical and neurochemical substrate for the persisting psychosis which can occur following PCP.

Animals↗
PubMed1997

Developmental patterns of proteoglycan-containing extracellular matrix in perineuronal nets and neuropil of the postnatal rat brain.

The extracellular matrix is involved in various morphogenetic processes which are accompanied by changes in its physicochemical properties and spatial organization. In the adult brain it contributes to cellular communication and the regulation of neuronal activity. The present study deals with the postnatal appearance and transformation into adult distribution patterns of extracellular matrix components related to chondroitin-sulphate proteoglycans (CSPGs) in the rat brain. The differential accumulation of these components in neuropil and in perineuronal nets (PNs) enriched in certain regions was examined in 0-, 7-, 14-, 21- and 35-day-old rats and adult animals using the N-acetylgalactosamine-binding Wisteria floribunda agglutinin (WFA) and immunocytochemical detection of CSPGs. The lectin stained the olfactory-bulb glomerular layer and layer Ia of piriform and entorhinal cortex already in newborn animals. On postnatal day 7 diffuse neuropil staining was additionally found in certain subcortical nuclei and in deep neocortical layers. The first sharply contoured PNs were detected at this age in the brain stem, indicating the more advanced maturation of matrix components in subcortical regions. CSPG immunoreactivity yielded staining patterns largely identical to WFA-binding patterns but appeared only between postnatal day 14 and 21. The adult-like stage was revealed with both methods between 21 and 35 days after birth. The results provide further evidence that the accumulation of certain CSPGs in the extracellular space is spatiotemporally related to distinct patterns of neuronal activity at the regional and cellular level.

Animals↗
PubMed1987

Direct microinjection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology.

Rats were injected in the amygdala and other forebrain sites with nmolar amounts of the highly toxic organophosphate 'nerve agent' compounds soman or VX (O-ethyl-S-(2-diisopropylaminoethyl)-methylphosphonothioate) in an attempt to determine the mechanism(s) responsible for the permanent brain pathology that has been observed following systemic intoxication with these agents. Injections were performed using a stereotaxically guided microsyringe in animals maintained under halothane/oxygen anesthesia or using chronically implanted cannulae in conscious animals. Bilateral microsyringe injections of up to 11.0 nmol soman into the amygdala failed to evoke abnormal behavior or brain pathology. When rats were pretreated with lithium chloride, or when carbachol was coadministered, soman injections evoked repetitive clonic convulsions and neuropathology. Unilateral injections of 3.4 nmol of VX into the amygdala elicited convulsions and brain damage in 67% of the animals tested. Atropine pretreatment (15.0 mg/kg, i.p.) prevented the development of convulsions and brain damage. Neuropathology was observed only in animals that developed repetitive convulsions; the piriform and entorhinal cortex, amygdala, hippocampus and thalamus were the brain structures most consistently damaged. With unilateral injections, the damage was more severe on the side ipsilateral to the injection. The behavioral topography of the convulsions and the neuroanatomical distribution and nature of the subsequent pathology closely resemble that observed with systemic administration of these compounds. The results indicate that the nerve agents are not directly neurotoxic, that peripherally induced hypoxia or anoxia are unlikely mechanisms of the neuropathology, and that the brain damage produced by these compounds is primarily seizure-mediated.

Amygdala↗
PubMed1990

Intraventricular injection of neurotensin reduces dopamine D2 agonist binding in rat forebrain and intermediate lobe of the pituitary gland. Relationship to serum hormone levels and nerve terminal coexistence.

In order to investigate neurotensin-dopamine receptor interactions in vivo, the effects of intraventricular injection of neurotensin were analyzed on S(-)[N-propyl-3H(N)]propylnorapomorphine [( 3H]NPA) binding in cryostat sections of the forebrain, hypothalamus and pituitary gland, and on serum levels of prolactin, luteinizing hormone and corticosterone in the male rat. The relationship of modulation of [3H]NPA binding with neurotensin-dopamine coexistence in nerve terminals was analyzed by investigating coexistence of neurotensin and tyrosine hydroxylase (TH) immunoreactive nerve terminals in various brain areas, using a double immunohistofluorescence procedure. Intraventricular injections of neurotensin (0.03-3 nmol, 30 min) reduced dose-dependently specific [3H]NPA binding (0.25 nM) in the caudate-putamen (-38 +/- 4%), nucleus accumbens (-42 +/- 5%), tuberculum olfactorium (-52 +/- 7%) and in the intermediate lobe of the pituitary gland (-17 +/- 2%). Coexistence of neurotensin and TH was demonstrated in nerve terminals in the prefrontal, cingulate, piriform and entorhinal cortex and in the cortical and deep nuclei of the amygdaloid cortex. It was not possible to demonstrate coexistence in the caudate-putamen, nucleus accumbens, tuberculum olfactorium and median eminence, in view of the high density of dopamine nerve terminals present in relation to the few visualized neurotensin terminals. Nor could coexistence be demonstrated in the few remaining TH-positive nerve terminals following unilateral 6-hydroxydopamine lesions (8 micrograms per 4 microliters; one week) in spite of increased numbers of neurotensin-containing cell bodies and terminals in the ipsilateral dorsomedial caudate. Neurotensin injection markedly decreased serum prolactin levels and increased serum corticosterone levels by about 60%, whereas serum levels of luteinizing hormone were unaffected. The present study indicates that central dopamine D2 receptors may be regulated by neurotensin in vivo and that the neurotensin involved most likely is released from nerve terminals not containing dopamine, since fibers showing coexistence were only found in prefrontal and limbic cortical areas.

Animals↗
PubMed1983

Changes of immunoreactive somatostatin and beta-endorphin content in rat brain after amygdaloid kindling.

A possible contribution of brain beta-endorphin and somatostatin to the epileptogenicity established by amygdaloid kindling was investigated in rats. Fourteen male rats were chronically implanted with electrodes placed bilaterally into the amygdala. The rats received 1 sec of electrical stimulation to the left amygdala each day. Generalized seizures were observed on average 10 days after initiation of kindling and the electrical stimulation was continued up to twenty-one days. Two months after the completion of the kindling procedure, each kindled and control rat was killed by microwave irradiation and the brains were dissected on ice into thirteen subregions. Each region was homogenized and centrifuged twice in 0.1 N acetic acid. The supernatant extracts were decanted and stored at - 20 degrees C until assay. Immunoreactive beta-endorphin and somatostatin were measured by radioimmunoassays. There were no significant differences in brain beta-endorphin contents between the two groups. In kindled rats, immunoreactive somatostatin was increased significantly in amygdala, sensorimotor, piriform, and entorhinal cortex. The results suggest that changes in somatostatin may be associated with epileptic susceptibility induced by the electrical kindling procedure.

Amygdala↗
PubMed1992

The putative 5-HT1A antagonist BMY 7378 blocks 8-OH-DPAT-induced changes in local cerebral glucose utilization in the conscious rat.

It has previously been shown that the 5-HT1A agonist, 8-OH-DPAT, caused discrete changes in cerebral glucose utilization in the rat, as assessed by quantitative 2-deoxyglucose autoradiography. Here, the effect of the putative 5-HT1A antagonist, BMY 7378, on regional cerebral glucose utilization was examined, when injected alone and in rats treated with 8-OH-DPAT. In control rats, BMY 7378 (5 mg/kg, s.c.) markedly increased glucose utilization in the lateral habenular nucleus and moderately reduced glucose utilization in the hippocampal formation. Pretreatment with BMY 7378 (5 mg/kg) significantly attenuated the reductions in glucose utilization in the hippocampus, entorhinal, piriform and cingulate cortex, induced by 8-OH-DPAT (0.25 mg/kg). The 8-OH-DPAT-induced increase in glucose utilization in the copula pyramis, that is putatively associated with the appearance of the 5-HT behavioural syndrome, was also blocked by BMY 7378, as was the behavioural syndrome. In summary, BMY 7378 produced few of the discrete changes in cerebral glucose utilization that are seen with 8-OH-DPAT. However, many of the changes induced by 8-OH-DPAT were reversed by BMY 7378. These data are consistent with the hypothesis that the effects of 8-OH-DPAT on regional cerebral glucose utilization are mediated by 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus.

The influence of kainic acid (KA)-induced limbic seizure activity on the expression of mRNA for nerve growth factor (NGF) in adult rat brain was studied using in situ hybridization and S1 nuclease protection techniques with RNA probes complementary to murine and rat NGF mRNA. Within hippocampus, intracerebroventricular injection of 0.5 microgram KA caused a dramatic bilateral increase in hybridization of the 35S-labeled cRNA within stratum granulosum. This increase was first evident 1 h post-KA, appeared maximal at approximately 20-fold control levels at 2-3 h post-injection, and declined to control levels by 48 h post-injection. During the period of maximal hybridization, all but the deepest cells within stratum granulosum appeared to be autoradiographically labeled. Hybridization of the NGF cRNA probe was also increased within superficial layers of piriform and entorhinal cortex and, to much lesser extent, within scattered neurons of layers II and III of neocortex in KA-treated rats. In olfactory cortical areas, hybridization was maximally elevated 15.5-24.5 h after KA injection. In contrast to these effects, KA treatment did not consistently influence the density of hybridization, or number of neurons labeled, within the dentate gyrus hilus or the hippocampus proper (CA1-CA3). In agreement with the in situ hybridization results, S1 nuclease protection assay detected KA-induced increases in hybridization within pooled dentate gyrus/CA1 samples, but not hippocampal CA3 samples. These data support the conclusion that seizure activity stimulates a transient increase in NGF expression by select populations of forebrain neurons and indicates that experimental seizure paradigms might be further exploited for analyses of the mechanisms of NGF regulation and processing in the adult brain.

Animals↗
PubMed1994

The age-related increase in galanin binding sites in the rat brain correlates with behavioral impairment.

The regional distribution of [125I]galanin specific binding sites was determined in young (three- to four-month-old), 14-15-month-old and aged (26-27-month-old) male Sprague-Dawley rats, previously tested for their performances in the Morris water-maze task, using the radioautographic method on brain sections. A significant increase in specific binding was observed in piriform and entorhinal cortex, ventral subiculum, and dorsal dentate gyrus in the aged rats, whereas no significant changes were observed in dorsal subiculum, amygdala, septal area and various subcortical structures. The area-specific regional increase in specific binding density in aged rats was significantly correlated with the impairment of the behavioral performance in the Morris water-maze task. The change in [125I]galanin specific binding was a result of an increase in the number of galanin binding sites, but not of an increase in affinity.

Aging↗
PubMed1995

Massive activation of c-fos in forebrain after mechanical stimulation of the locus coeruleus.

Brief implantation of a 33-ga cannula in the locus coeruleus (LC) of the rat caused widespread and intense ipsilateral activation of c-fos throughout the forebrain. Areas showing heavy staining included the cingulate, piriform, parietal, frontal cortex, and the olfactory tubercle. Prior lesion of the LC with 6-hydroxydopamine (6-OHDA) abolished the response. It is concluded that the mechanical stimulation and/or trauma involved in the implantation of a cannula in the LC is sufficient to cause widespread activation of noradrenergic neurotransmission throughout the forebrain. The use of this procedure for drug delivery should therefore be reevaluated.

Animals↗
PubMed1995

Evidence of internucleosomal DNA fragmentation and identification of dying cells in X-ray-induced cell death in the developing brain.

Newborn Sprague-Dawley rats received a single dose of 2 Gy X-rays and were killed 6 hr later. Dying cells were characterized by extreme chromatin condensation and nuclear fragmentation. Dying cells were distributed in the primary and secondary germinal zones and in other brain regions. Among these latter, dying cells occurred in the cortical layers of the olfactory bulb, layers II-III and VIb of the neocortex, piriform and entorhinal cortex, stratum oriens and pyramidale of the hippocampus, striatum, thalamus, amygdala, brainstem, internal granular layer of the cerebellum, and cerebral and cerebellar white matter. Dying cells were immature cells, neurons and glial cells (including radial glia). In-situ labeling of nuclear DNA fragmentation identified individual cells bearing fragmented DNA. Since the number of cells stained with this method was larger than the number of dying cells, as revealed with current histological techniques, it is suggested that nuclear DNA fragmentation precedes chromatin condensation and nuclear fragmentation in X-ray-induced apoptosis. Furthermore, agarose gel electrophoresis of extracted DNA from irradiated brains showed a "ladder" pattern which is typical of internucleosomal DNA fragmentation and endonuclease activation.

Aging↗
PubMed2004

Increased expression of the multidrug transporter P-glycoprotein in limbic brain regions after amygdala-kindled seizures in rats.

Increased expression of the multidrug transporter P-glycoprotein (Pgp; ABCB1) has previously been found in epileptogenic brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE) as well as in the hippocampus and other limbic brain regions in the rat kainate model of TLE. Approaches to the quantification of Pgp expression have mainly been based on subjective visual estimation of the level of Pgp immunoreactivity in brain sections. In the present study, computer-assisted image analysis based on optical density (OD) measurements was used to examine immunohistochemical expression of Pgp in the kindling model of TLE. Sections from kainate-treated rats were used for comparison. Using diaminobenzidine as chromogen, Pgp was exclusively located in brain capillary endothelial cells, which was confirmed by double-labeling with an antibody against the endothelial glucose transporter (GLUT-1). After kainate-induced seizures, the intensity of endothelial Pgp staining significantly increased by 70-80% in the dentate gyrus. A significant, albeit less marked increase in Pgp expression in this area was also seen after amygdala-kindled seizures. Furthermore, Pgp was upregulated after kindling in the hilus of the dentate gyrus, the CA1 and CA3 sectors of the hippocampus, and the piriform and cerebral cortex. In kindled rats, most Pgp alterations occurred ipsilateral to the electrode in the basolateral amygdala. The data demonstrate that computer-assisted image analysis using OD is an accurate and rapid method to determine the relative amount of Pgp protein in brain sections and the effects of seizures on this multidrug transporter. The fact that Pgp overexpression in brain capillary endothelial cells occurs in two established models of difficult-to-treat TLE substantiates the notion that seizure-induced upregulation of Pgp contributes to multidrug resistance (MDR) in epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection.

Herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.

Acyclovir↗
PubMed2006

Improved methods for fMRI studies of combined taste and aroma stimuli.

Previous neuroimaging studies of the cortical representation of gustatory and olfactory stimuli have often delivered tastants to the mouth in very small quantities or stimulated olfaction orthonasally. In studies of retro-nasal olfaction, swallowing was generally delayed to reduce head motion artefacts. The present fMRI study aims to improve upon such methodological limitations to allow investigation of the cortical representation of flavour (taste and aroma combination) as it typically occurs during the consumption of liquid foods. For this purpose we used (1) a novel, automated, sprayed stimulus delivery system and a larger volume of liquid sample (containing sweet tastants and banana/pear aroma volatiles) to achieve more extensive stimulation of the oral cavity taste receptors, (2) a pseudo-natural delivery paradigm that included prompt swallowing after each sample delivery to obtain physiological retro-nasal olfactory stimulation, (3) fMRI acquisition with wide brain coverage and double-echo EPI to improve sensitivity. We validated our paradigm for the delivery of volatiles using atmospheric pressure chemical ionisation mass spectrometry. This showed that the main retro-nasal delivery of volatiles in the paradigm occurs immediately after the swallow. Several brain areas were found to be activated, including the insula, frontal operculum, rolandic operculum/parietal lobe, piriform, dorsolateral prefrontal cortex, anterior cingulate cortex, ventro-medial thalamus, hippocampus and medial orbitofrontal cortex.

Adult↗
PubMed2003

Effects of chronic dizocilpine on acute pain and on mRNA expression of neuropeptides and the dopamine and glutamate receptors.

The mesocorticolimbic circuitry has been implicated in the pathophysiology of several neuropsychiatric syndromes like chronic pain and addiction. The aim of this study was to evaluate the effects of dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on sensorimotor behaviors and the consequent changes in the dopamine, glutamate, and opiate systems in rats. Five groups of rats were subjected to acute tests for nociception (hot plate and paw pressure) before and after MK-801 (0.05, 0.1, 0.2 and 0.4 mg/kg, i.p.) or saline. Another two groups received daily i.p. saline or MK-801 (0.4 mg/kg) for 15 days. The nociceptive tests were performed on days 1, 7, and 14. On day 15 the rats received the last injection and were immediately sacrificed. We measured the mRNA expression, by in situ hybridization (ISH), of various dopamine and glutamate receptors, and enkephalin (Enk), dynorphin (Dyn), and substance P (SP) in the striatum, nucleus accumbens (NAC), piriform and cingulate cortex. Acute MK-801, dose-dependently, resulted in hyperalgesia. The chronic effects of 0.4 mg/kg MK-801 showed an extinction of the acute hyperalgesic effects especially with the hot plate test. The ISH studies revealed a decrease in mRNA expression of Enk and SP in the striatum and NAC. Our results indicate that the reversal of acute MK-801-induced hyperalgesia, with repeated exposure to systemic MK-801, is not directly related to changes in dopamine and glutamate receptors and might involve alteration of the striatal neuropeptide system.

Animals↗
PubMed1998

Effects of gestational methylmercury exposure on immunoreactivity of specific isoforms of PKC and enzyme activity during post-natal development of the rat brain.

Protein kinase C (PKC)-mediated phosphorylation has been implicated in neuronal growth and differentiation [R.S. Turner, R.L. Mazzei, G.J. Raynor, P.R. Girard, J.F. Kuo, Proc. Natl. Acad. Sci. U.S.A., 81 (1984) 3143-3147.]. We examined effects of gestational exposure to the neurotoxicant, methylmercury (CH3Hg), on the developmental profile of immunoreactivity (IR) for alpha, beta, gamma and epsilon PKC isoforms and cytosolic PKC activity. Long-Evans dams were dosed on gestational days (GD)6-15 (p.o.) with 0, 1, or 2 mg kg-1 day-1 CH3Hg dissolved in saline. Pups were sacrificed and perfused with buffered paraformaldehyde on post-natal days (PND) 1, 4, 10, 21, 45 and 85. The brains were sectioned sagittally, stained immunohistochemically, and examined throughout the medial to lateral extent. IR in neuronal cell bodies for PKC isoforms alpha, beta, gamma, and epsilon was densest in the olfactory bulb, hippocampus, shell of the inferior colliculus, pons, cerebral, piriform, and cerebellar cortex, whereas axonal staining was prominent in the brainstem, internal capsule, corpus callosum, anterior commissure, fornix and olfactory tract. In controls, the PKC alpha and epsilon IR was highest on PND1-4, decreased dramatically by PND10, and decreased further by PND21. In the neonate, the regional and cellular distributions of alpha and epsilon IR were similar. The PKC gamma IR was greater at post-weaning ages (PND21-85) with the greatest regional density apparent in the hippocampus, cortex, and cerebellum. Only the highest dose of CH3Hg (2 mg kg-1 day-1; GD6-15) produced a persistent decrease in regional alpha and epsilon, but not beta or gamma IR during the post-natal period. These regional and time-dependent changes in PKC isoforms were complemented by the examination of PKC activity in cortex, olfactory bulb, cerebellum and brainstem. Cytosolic PKC activity increased from PND1 to 10 in cortex, olfactory bulb, and cerebellum. On PND21, PKC activity decreased in the cortex and olfactory bulb, but remained high in the cerebellum. By contrast, PKC activity in the brainstem was highest on PND1 and 4 and decreased dramatically by PND21. CH3Hg (2 mg kg-1 day-1) significantly decreased PKC activity on PND1 and 4 in the cortex. The present results characterize the cellular and regional ontogeny of PKC isoenzymes alpha, beta, gamma and epsilon, and indicate that developmental exposure to CH3Hg can alter the ontogeny of specific isoforms and regional PKC activity.

Animals↗