Biomedical subjects

Quentin J Pittman

Publications and source records attributed to Quentin J Pittman.

29 records · Page 2Linked to original sources

PubMed2004

Long-term alterations in neuroimmune responses after neonatal exposure to lipopolysaccharide.

Fever is an integral part of the host's defense to infection that is orchestrated by the brain. A reduced febrile response is associated with reduced survival. Consequently, we have asked if early life immune exposure will alter febrile and neurochemical responses to immune stress in adulthood. Fourteen-day-old neonatal male rats were given Escherichia coli lipopolysaccharide (LPS) that caused either fever or hypothermia depending on ambient temperature. Control rats were given pyrogen-free saline. Regardless of the presence of neonatal fever, adult animals that had been neonatally exposed to LPS displayed attenuated fevers in response to intraperitoneal LPS but unaltered responses to intraperitoneal interleukin 1beta or intracerebroventricular prostaglandin E(2). The characteristic reduction in activity that accompanies fever was unaltered, however, as a function of neonatal LPS exposure. Treatment of neonates with an antigenically dissimilar LPS (Salmonella enteritidis) was equally effective in reducing adult responses to E. coli LPS, indicating an alteration in the innate immune response. In adults treated as neonates with LPS, basal levels of hypothalamic cyclooxygenase 2 (COX-2), determined by semiquantitative Western blot analysis, were significantly elevated compared with controls. In addition, whereas adult controls responded to LPS with the expected induction of COX-2, adults pretreated neonatally with LPS responded to LPS with a reduction in COX-2. Thus, neonatal LPS can alter CNS-mediated inflammatory responses in adult rats.

Animals↗

PubMed2004

A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain.

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

Analgesics, Non-Narcotic↗

PubMed2004

Lipopolysaccharide-induced febrile convulsions in the rat: short-term sequelae.

PURPOSE: Febrile convulsions (FCs) occur in children as a result of fever. The mechanisms involved in the genesis of FCs and their long-term consequences on brain development remain unclear. We have developed a model of FC, by using fever as a parameter, to test the hypothesis that fever can lower seizure threshold and to examine the neurologic sequelae of FCs. METHODS: Fourteen-day-old rat pups equipped with body-temperature telemetry devices exhibited approximately 1.5 degrees C fevers after lipopolysaccharide (Escherichia coli, 200 microg/kg). During such fevers, concurrently administered doses of kainic acid that are normally subconvulsant were used to induce convulsions with fever. Animals were then killed at varying times for pathological and immunohistochemical studies. RESULTS: The pairing of lipopolysaccharide and subconvulsant kainic acid resulted in convulsions in approximately 50% of febrile animals, with very low mortality. To study the neural correlates of these FCs, we used fos immunohistochemistry and found that animals with FCs had fos-positive immunoreactivity in brain regions involved in seizures. After a period of 72 h, we also examined brains for pathologic changes and found no differences among our groups. CONCLUSIONS: Our data indicate that a neuroimmune challenge and its accompanying fever reduce the seizure threshold. Furthermore, the FCs induced by fever in this model do not have short-term adverse effects on the brain. In addition, this model, by incorporating physiologic fever, may be useful for examining the role of fever and its constituent mediators in the genesis of FCs.

Animals↗

PubMed2003

Peptidergic activation of locomotor pattern generators in the neonatal spinal cord.

The development of motor networks in the spinal cord is partly activity-dependent. We have observed receptor-mediated excitatory effects of two peptides, arginine vasopressin (AVP) and oxytocin (OXT), on motor network activity in the neonate. With the use of an en bloc in vitro preparation of mouse spinal cord (2-3 d old), which either was isolated completely or had muscles of the hindlimb left intact, we show that the bath application of AVP or OXT can evoke an increase in population bursting of motoneurons recorded from the lumbar ventral roots. By using antagonists for AVP and OXT, we found that these peptides were binding primarily to V1a and OXT receptors, respectively. Western blot analysis revealed a 48 kDa V1a and a 55 kDa OXT receptor immunoreactive band that was expressed in tissue obtained from L1-L6 sections of spinal cord. AVP, but not OXT, could, on occasion, evoke sustained periods of locomotor-like activity. In addition, when we applied AVP or OXT in combination with a 5-HT2 agonist, bouts of locomotor-like activity could be observed in a majority of preparations. Collectively, these data point to a novel role for AVP and OXT in the activation of spinal motor networks.

Animals↗

PubMed2003

Vasopressin differentially modulates non-NMDA receptors in vasopressin and oxytocin neurons in the supraoptic nucleus.

Magnocellular neurons of the supraoptic nucleus release the neuropeptides oxytocin and vasopressin from their dendrites to regulate their synaptic inputs. This study aims to determine the cellular mechanism by which vasopressin modulates excitatory synaptic transmission. Presumably by electroporation through perforated patch, we were able to successfully introduce biocytin into cells in which we performed an electrophysiological study. This method enabled us to determine that roughly half of the recorded neurons were immunoreactive to oxytocin-associated neurophysin and showed two characteristic features: an inward rectification and a sustained outward rectification. The remaining half showed a linear voltage-current relationship and was immunoreactive to vasopressin-associated neurophysin. Using these electrophysiological characteristics and post hoc immunohistochemistry to identify vasopressin or oxytocin neurons, we found that vasopressin decreased evoked EPSCs in vasopressin neurons while increasing EPSCs in oxytocin neurons. In both types of neurons, EPSC decay constants were not affected, indicating that desensitization of non-NMDA receptors did not underlie the EPSC amplitude change. In vasopressin neurons, both vasopressin and a V1a receptor agonist, F-180, decreased AMPA-induced currents, an effect blocked by a V1a receptor antagonist SR49059. In oxytocin neurons, AMPA-induced currents were facilitated by vasopressin, whereas F-180 had no effect. An oxytocin receptor antagonist blocked the facilitatory effect of vasopressin. Thus, we conclude that vasopressin inhibits EPSCs in vasopressin neurons via postsynaptic V1a receptors, whereas it facilitates EPSCs in oxytocin neurons through oxytocin receptors.

Animals↗

PubMed2003

Nifedipine facilitates neurotransmitter release independently of calcium channels.

Nifedipine, a drug used for treatment of hypertension and angina, exerts its effect by calcium channel blockade and nitric oxide production. We report here a previously uncharacterized action of nifedipine on central synaptic transmission that may partially explain its side effects. Nifedipine causes a long-lasting facilitation of tetrodotoxin-insensitive spontaneous glutamate release. This effect is independent of its L-type calcium channel blocking effect, and is not mimicked by other dihydropyridines such as nimodipine, nicardipine, or Bay K 8644. The effect was dose dependent, with EC(50) of 7.8 microM, with the lowest effective dose being 100 nM, a clinically relevant dose. At 10 microM, the increase is 14.7-fold. This effect is largely calcium-independent, because Cd(2+), thapsigargin, or BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester] did not inhibit the nifedipine effect. Thus, nifedipine seems to act on the release process downstream of calcium entry or release. Protein kinases A or C do not mediate its effect, because it is not blocked by inhibitors of these kinases. Our finding indicates that nifedipine may be a useful tool as a secretagogue to directly target the release process, but raises caution for its use as an L-type calcium channel blocker.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2003

Compromised neuroimmune status in rats with experimental colitis.

In colitis, chronic and recurrent inflammation is associated with a breakdown in host defence mechanisms that leads to local and systemic infection. Whether this is due to a compromised neuroimmune response has not been studied. Our aim was to determine if colitis altered the host neuroimmune response as reflected in either body temperature rhythm or the febrile responses to lipopolysaccharide (LPS). Body temperature was monitored by telemetry from conscious, unrestrained male rats treated with trinitrobenzene sulphonic acid or saline. Twenty-six days after initial induction, colitis was reactivated. Animals were given LPS (50 microg kg-1 Escherichia coli LPS) during colitis and after reactivation. At the peak of colitis, treated rats showed a disruption of circadian body temperature rhythm, manifested as day-time fever followed by night-time hypothermia. In response to LPS, controls displayed a characteristic fever, whereas treated animals had a significantly reduced fever and low plasma levels of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha). During reactivation of colitis, treated animals did not mount a fever or exhibit increased plasma levels of IL-6 and TNF-alpha after LPS. We conclude that experimental colitis is associated with a compromised neuroimmune status.

Animals↗

PubMed2003

AVP V1a-R expression in the rat hypothalamus around parturition: relevance to antipyresis at term.

An endogenous antipyresis has been observed around parturition in several species, including rats. It has been proposed that the neuropeptide vasopressin is responsible for this antipyresis via an action on the V(1a) receptor subtype, but this concept is controversial. We therefore addressed the question of the regulation of V(1a) receptor expression within the rat hypothalamus around parturition, to assess its possible involvement in the antipyresis phenomenon observed at term. We analyzed V(1a) receptor mRNA and protein levels in the hypothalamus/preoptic area of female rats at Days 15 and 22 (parturition) of gestation, and at Day 5 of lactation. We used quantitative RT-PCR to assess the mRNA levels and designed a semiquantitative Western blot assay to analyze changes in protein levels between the three stages studied. No significant changes either in V(1a) receptor mRNA or protein levels were observed between the three stages, suggesting that variations in the hypothalamic V(1a) receptor expression levels alone cannot account for the endogenous antipyresis observed at term.

Animals↗

PubMed2003

Talking back: dendritic neurotransmitter release.

Classical transmitters and neuropeptides can be released from the dendrites of many neuronal populations, to act as retrograde signals that modulate synaptic transmission, electrical activity and, in some cases, morphology of the cell of origin. For the hypothalamic neuroendocrine cells that release vasopressin and oxytocin, the stimuli, mechanisms and physiological functions of dendritic release have been revealed in detail that is not yet available for other neurons. The regulation of dendritic transmitter release is complex and at least partially independent from axon terminal release. Here, we provide an overview of recent findings on the mechanisms and physiological consequences of dendritic neuropeptide release and place this in the context of discoveries of dendritic neurotransmitter release in other brain regions.

Animals↗

PubMed2003

Backtalk in neurons.

A recent paper investigates retrograde transmission from dendrites of the oxytocin neurons of the supraoptic nucleus. Dendrites appear to have release properties different from those of axon terminals, and release appears to be enhanced if intracellular Ca2+ has been previously elevated, suggesting that cells can be 'primed'.

Animals↗

PubMed1998

Vasopressin-induced antipyresis. Sex- and experience-dependent febrile responses.

There is now good evidence that vasopressin (AVP) acts, in the male rat, as a neurotransmitter in the ventral septal area to reduce fever. In light of the well known sexual dimorphism in the AVP innervation of the brain, we asked if female rats would (a) display fevers different from those seen in male rats, (b) respond to AVP with antipyresis, (c) display evidence of endogenous AVP-induced antipyresis during fever, and (d) display altered fevers and AVP involvement as a function of hormonal status. Our experiments indicate that female rats display larger fevers to intracranial prostaglandin E2 (PGE2) but not to systemic lipopolysaccharide or interleukin-1 beta than do male rats. The larger fevers may be due, in part, to a lack of AVP-induced antipyresis, as an AVP antagonist elevates PGE2 fever in male but not in female rats and dialysates of the ventral septal area show increased AVP levels only in male rats during defervescence. Nonetheless, females respond to exogenous AVP with antipyresis. Throughout late pregnancy, parturition, and lactation, PGE2 fevers are reduced, but this appears to be due to a general suppression of autonomic output not involving enhanced AVP antipyresis. Fevers due to lipopolysaccharide and interleukin-1 beta are also suppressed at this time, and in some animals, fevers are dramatically suppressed at about the time of parturition. Our results indicate that female rats may utilize different strategies for antipyresis than do male rats and that hormonal status may influence both peripherally generated and centrally activated fevers.

Analgesics, Non-Narcotic↗