PubMed Health⌕ Search

Biomedical subjects

P J Harrison

Publications and source records attributed to P J Harrison.

At least 37 records · Page 2Linked to original sources
PubMed2002

An RT-PCR study of 5-HT(6) and 5-HT(7) receptor mRNAs in the hippocampal formation and prefrontal cortex in schizophrenia.

5-Hydroxytryptamine (5-HT; serotonin) 5-HT(6) receptors (5-HT(6)R) and 5-HT(7) receptors (5-HT(7)R) have been implicated in schizophrenia and as targets of atypical antipsychotic drugs. We have studied the expression of these receptors in the hippocampal formation and dorsolateral prefrontal cortex (DLPFC) of 17 subjects with schizophrenia and 17 controls using reverse transcription-polymerase chain reaction (RT-PCR) with cyclophilin co-amplification. In schizophrenia, 5-HT(6)R mRNA was decreased in the hippocampal formation, and 5-HT(7)R mRNA was decreased in the dorsolateral prefrontal cortex. The mRNAs were unchanged in rats treated for 2 weeks with haloperidol, chlorpromazine, risperidone, olanzapine or clozapine. Regional decreases in 5-HT(6)R and 5-HT(7)R expression in schizophrenia may contribute to the overall serotonergic alterations which occur in the disorder, in part through their interactions with other neurotransmitter systems including glutamate and acetylcholine.

Animals↗
PubMed2002

In vitro evidence that 5-hydroxytryptamine increases efflux of glial glutamate via 5-HT(2A) receptor activation.

Recent studies have established the presence of 5-hydroxytryptamine (5-HT)(2A) receptors on glial cells in culture and in the brain in situ. Here we used cultured C6 glioma cells to investigate the possibility that 5-HT(2A) receptors on glia regulate glutamate release from the cell. The efflux of endogenous glutamate from cultured C6 glioma cells was increased by addition of 5-HT in a concentration-dependent manner (maximal effect +200%). The efflux of serine and aspartate was not altered. The effect of 5-HT was mimicked by both the nonselective 5-HT receptor agonist quipazine and the selective 5-HT(2) receptor agonist 4-iodo-2,5-dimethoxyamphetamine (DOI; both 0.01-100 microM). The 5-HT(2A) receptor antagonists ketanserin (1 microM) and spiperone (1 microM) inhibited the glutamate response to 5-HT, quipazine, and DOI, whereas the effect of 5-HT was not inhibited by the 5-HT(2B/C) receptor antagonist SB200646 (1 microM). The effect of 5-HT on glutamate was specific in that it was reduced in low-calcium medium but was not prevented by furosemide (5 mM), which prevents cell swelling-induced glutamate release. Finally, the glutamate uptake inhibitor 2,4,trans-pyrollidine dicarboxylic acid (50 microM) did not block the 5-HT-induced efflux of glutamate, making involvement of glutamate transport unlikely. In conclusion, 5-HT stimulates the efflux of glutamate from C6 glioma cells following 5-HT(2A) receptor activation and involves a calcium-dependent mechanism.

Animals↗
PubMed2002

Improvement of the sediment ecosystem following diversion of an intertidal sewage outfall at the Fraser river estuary, Canada, with emphasis on Corophium salmonis (Amphipoda).

Primary treated sewage effluent from the city of Vancouver, Canada was deposited directly onto the intertidal ecosystem of Sturgeon bank, Fraser river estuary between 1962 and 1988. In response to the degraded sediment conditions an azoic zone developed near the discharge outfall. Effluent discharges into the intertidal zone were almost completely stopped in 1988 with the construction of a submerged outfall. Our studies, conducted between 1994 and 1996, showed considerable improvement in the environment of the mudflat ecosystem, including increased dissolved oxygen, decreased sediment chlorophyll, decreased organic material in the sediment, reduced heavy metals in surficial sediment and increased grain size. The amphipod Corophium salmonis, important in the food web for juvenile salmon and other fish species, recolonized the previously azoic location. At reference stations, C. salmonis density was similar to that observed in previous surveys two decades earlier. Our data strongly suggest that improvement or sediment conditions near the former sewage outfall was a major factor enabling colonization by C. salmonis.

Amphipoda↗
PubMed2002

Bromocriptine use is associated with decreased smoking rates.

Dopaminergic transmission in the central nervous system is thought to underlie addictive behaviours, including smoking. One effective smoking cessation drug, bupropion, enhances dopaminergic transmission; conversely, antipsychotic drugs, which are dopamine antagonists, are associated with increased smoking. Thus we hypothesized that subfertile women treated with the potent dopamine agonist bromocriptine might smoke less as a consequence of their treatment. Among 4,608 subfertile women those conceiving on bromocriptine were half as likely to smoke as those taking other drugs or those conceiving without medication (p < 0.0001). This observation supports the role of dopamine in nicotine addiction, and suggests that bromocriptine-like drugs could be used effectively by pregnant women to aid cessation.

Bromocriptine↗
PubMed2001

The bilateral reflex control of the trapezius muscle in humans.

Abstract. Electromyographic recordings were made from the trapezius muscle in 18 healthy subjects using surface electrodes placed bilaterally. A mechanical tap applied to the insertion of the lower fibres of trapezius evoked a reflex at 11.9 +/- 1.4 ms (mean plus minus SD) in the ipsilateral trapezius muscle. In addition and surprisingly, short latency, facilitatory reflexes were also seen on the contralateral side at a latency of 14.3 +/- 1.7 ms. Electrical stimulation of the afferent nerve to trapezius, the cervical nerve of C3/4, also evoked short latency, facilitatory reflexes from both the ipsilateral and contralateral muscles. Since this nerve carries the Ia fibres from trapezius, this reflex would appear to be the equivalent of the H reflex seen in the soleus muscle. The latency of this reflex was 10.9 +/- 1.4 ms ipsilaterally and 11.9 +/- 1.5 ms contralaterally, the difference being only 1.0 +/- 0.7 ms. Voluntary activity of the ipsilateral trapezius increased the amplitude of both mechanically and electrically evoked ipsilateral and crossed reflexes, and vibration of the ipsilateral trapezius decreased the amplitude of both reflexes. These results together suggest that the earliest parts of both ipsilateral and crossed reflexes are monosynaptic in origin. If the crossed reflex is, in part, due to a common Ia presynaptic input, correlation of bilateral trapezius activity should produce a peak in the cross-correlogram. Indeed, cross-correlation of the bilateral trapezius activity during elevation of the arms produced a short duration peak. Moreover, this was significantly larger when compared to that constructed from activity of the upper and lower fibres of trapezius from one side. These results imply that muscle spindle afferents from the ipsilateral trapezius monosynaptically activate motoneurones contralaterally.

Action Potentials↗
PubMed2001

Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins.

There are several reports of ultrastructural and protein changes affecting synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture has also been described in this region in schizophrenia as well as in mood disorders. In this paper we review the literature and present a new study investigating synaptic abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation brain series. We used Western blotting to assess four synaptic proteins: synaptophysin, growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin II and GAP-43 were reduced in bipolar disorder. The decreases correlated with the duration of illness and tended to be greater in subjects without a family history. Complexin II was also reduced in major depression. Complexin I and the housekeeping protein beta-actin did not differ between groups. None of the proteins changed significantly in schizophrenia. The results indicate the presence of a synaptic pathology in the anterior cingulate cortex in mood disorders, especially bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate neural circuits. The loss of synaptophysin is suggestive of decreased synaptic density whilst the decrease in GAP-43 may denote impaired synaptic plasticity and the reduction of complexin II but not complexin I implies that the alterations particularly affect excitatory connections. The reductions may be progressive.

Adaptor Proteins, Vesicular Transport↗
PubMed2001

Electroconvulsive shock increases tachykinin NK(1) receptors, but not the encoding mRNA, in rat cortex.

Recent studies have suggested that the substance P (tachykinin NK(1)) receptor may be a pharmacological target for the treatment of mood disorders. Here, the effects of electroconvulsive shock on tachykinin NK(1) receptor gene expression in the rat brain was investigated. Rats received either a single electroconvulsive shock or five shocks on alternate days. Quantitative autoradiography with [(125)I]Bolton Hunter-substance P, and in situ hybridisation histochemistry, were used to measure tachykinin NK(1) receptor-binding site densities and mRNA abundance, respectively. Densities of tachykinin NK(1) receptor-binding sites were significantly increased in the cerebral cortex following repeated electroconvulsive shock compared to sham treated animals. Densities remained unchanged in the hippocampus, striatum and amygdala. Neither single nor repeated electroconvulsive shock altered tachykinin NK(1) receptor mRNA in the brain regions examined. Hence, repeated electroconvulsive shock increases tachykinin NK(1) receptors in the rat brain in a regionally specific way. Upregulation of receptor-binding sites without a change in mRNA indicates that translational or post-translational mechanisms underlie this process.

Amygdala↗
PubMed2001

Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia.

Cytoarchitectural changes in the hippocampal formation have been prominent among the various neuropathological abnormalities reported in schizophrenia. Replicated positive findings include decreased neuronal size and alterations in presynaptic and dendritic markers. These findings, in the absence of neurodegenerative changes, suggest that there are alterations in the neural circuitry in schizophrenia. These may represent the anatomical correlate of the aberrant functional connectivity described in neuroimaging studies, which in turn contributes to the psychotic and cognitive symptomatology of the disorder. The identity of the affected hippocampal circuits remains unclear; there is evidence for both glutamatergic and GABAergic involvement, and perhaps for a gradient of pathology in which changes are most apparent in CA4 and the subiculum, and least in CA1. The data, their interpretation, and their limitations are discussed, with particular emphasis upon molecular and immunological studies of synaptic protein gene expression.

Hippocampus↗
PubMed2001

A CUB-serine protease in the olfactory organ of the spiny lobster Panulirus argus.

csp, a gene encoding a protein with high sequence identity to trypsinlike serine protease and CUB domains, was identified from a cDNA library from the olfactory organ (antennular lateral flagellum) of the spiny lobster Panulirus argus. The full-length cDNA sequence of csp is 1801 bp, encoding a protein of 50.25 kD, with three domains: signal peptide, trypsinlike serine protease, and CUB (named for a class of compounds including Complement subcomponents Clr/Cls, Uegf, and Bone morphogenic protein-1). RT-PCR, Northern blots, and immunoblots showed that csp is predominantly expressed in the lateral flagellum and eyestalk. Immunocytochemistry showed that Csp is present in olfactory (aesthetasc) sensilla around auxiliary cells (glia that surround the inner dendrites of olfactory receptor neurons, ORNs) and ORN outer dendrites. We propose that Csp is expressed and secreted by auxiliary cells, associates with ORN cell membranes or extracellular matrix via the CUB domain, and has trypsinlike activity. In the eyestalk, Csp is associated with cells surrounding axons between neuropils of the eyestalk ganglia. Possible functions in the olfactory organ and eyestalk are discussed. To our knowledge, this is the first report from any olfactory system of a gene encoding a protein with serine protease and CUB domains.

Amino Acid Sequence↗
PubMed2001

Postembryonic proliferation in the spiny lobster antennular epithelium: rate of genesis of olfactory receptor neurons is dependent on molt stage.

Olfactory systems undergo continuous growth and turnover in many animals. Many decapod crustaceans, such as lobsters and crayfish, have indeterminate growth, and in these animals, turnover of both peripheral and central components of the olfactory system occurs continuously throughout life. In this study, we examine the dynamics of olfactory receptor neuron (ORN) proliferation in the antennule of the Caribbean spiny lobster, Panulirus argus, using in vivo incorporation of the cell proliferation marker BrdU. We show that addition of ORNs occurs in a "proximal proliferation zone" (PPZ), which exists on the proximo-lateral margin of the existing ORN population. The PPZ is spatially and temporally dynamic in that it travels as a wave in the proximal and lateral directions in the antennule. This wave results in continuous addition of ORNs throughout the molt cycle. The rate of proliferation, as measured by the size and shape of the PPZ, changes depending on the animal's molt stage. The rate is highest during premolt and lowest during intermolt. ORNs are the most prominent cell-type produced in the PPZ, but other cell types, including glia, are also produced. Patches of proliferating epithelial cells occur immediately proximal to the PPZ, suggesting that neuronal and glial precursors reside in this region. Possible mechanisms for peripheral and central modulation of ORN development are discussed.

Animals↗
PubMed2001

Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia.

The occurrence of human cerebellar serotonin 5-HT(2A) receptors (5-HT(2A)R) is equivocal and their status in schizophrenia unknown. Using a range of techniques, we investigated cerebellar 5-HT(2A)R expression in 16 healthy subjects and 16 subjects with schizophrenia. Immunocytochemistry with a monoclonal antibody showed labelling of Purkinje cell bodies and dendrites, as well as putative astrocytes. Western blots showed a major band at approximately 45 kDa. Receptor autoradiography and homogenate binding with [(3)H]ketanserin revealed cerebellar 5-HT(2A)R binding sites present at levels approximately a third of that in prefrontal cortex. 5-HT(2A)R mRNA was detected by reverse transcriptase-polymerase chain reaction, with higher relative levels in men than women. Several aspects of 5-HT(2A)R expression were altered in schizophrenia. 5-HT(2A)R immunoreactivity in Purkinje cells was partially redistributed from soma to dendrites and was increased in white matter. 5-HT(2A)R mRNA was decreased in the male patients. 5-HT(2A)R measured by dot blots and [(3)H]ketanserin binding (B(max) and K(d)) were not significantly altered in schizophrenia. These data show that 5-HT(2A)R gene products (mRNA, protein, binding sites) are expressed in the human cerebellum at nonnegligible levels; this bears upon 5-HT(2A)R imaging studies which use the cerebellum as a reference region. 5-HT(2A)R expression is altered in schizophrenia; the shift of 5-HT(2A)R from soma to dendrites is noteworthy since atypical antipsychotics have the opposite effect. Finally, the results emphasise that expression of a receptor gene is a mutifaceted process. Measurement of multiple parameters is necessary to give a clear picture of the normal situation and to show the profile of alterations in a disease.

Adult↗
PubMed2001

Cerebellar synaptic protein expression in schizophrenia.

A cortico-subcortico-cerebellar neural circuit has been postulated to be important in the pathophysiology of schizophrenia. This study investigated whether there are synaptic changes in the cerebellum to accompany its putative involvement in the disorder. We measured the expression of three synaptic proteins (synaptophysin, complexin I and complexin II) in the cerebellar cortex of 16 subjects with schizophrenia and 16 controls using in situ hybridisation histochemistry and immunoautoradiography. Complexin I and II are expressed predominantly by inhibitory and excitatory neurones respectively. In schizophrenia, synaptophysin mRNA was decreased, as was complexin II and its mRNA. Complexin I mRNA and protein levels were unaltered. Expression of the mRNAs in the rat cerebellum was unaffected by 2 weeks administration of antipsychotic drugs (haloperidol, chlorpromazine, risperidone, olanzapine or clozapine). We conclude that there is synaptic pathology in the cerebellum in schizophrenia. By disrupting neural circuits, the alterations may contribute to the cerebellar dysfunction thought to occur in the disorder.

Acidosis↗
PubMed2001

RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia.

5-HT(2C) receptor (5HT(2C)R, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT(2C)R RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT(2C)R gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT(2C-MNI) and 5-HT(2C-VDI). Screening of the 5-HT(2C)R gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT(2C-INI) is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT(2C)R-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.

Animals↗
PubMed2001

Schizophrenia and the frontal lobes: post-mortem stereological study of tissue volume.

BACKGROUND: It has been suggested that there is frontal lobe involvement in schizophrenia, and that it may be lateralised and gender-specific. AIMS: To clarify the structure of the frontal lobes in schizophrenia in a post-mortem series. METHOD: The volume of white matter and cortical components of the frontal lobes was measured in brains of controls and patients with schizophrenia using planimetry and the Cavalieri principle. The components measured were: superior frontal gyrus, middle frontal gyrus, a composite of inferior frontal gyrus and orbito-frontal cortex, as well as total frontal lobe cortex and white matter. In addition, the anterior cingulate gyrus was measured. RESULTS: No diagnosis, gender, diagnosis x side, diagnosis x gender or diagnosis x gender x side interactions were observed in the volume of any of the components, the grey matter as a whole or the white matter. No evidence for volumetric inter-group differences was found for the anterior cingulate gyrus. CONCLUSIONS: Such structural abnormalities as are present in the frontal lobes are more subtle than straightforward alterations in tissue volume; they may include changes in shape and the pattern of gyral folding.

Adult↗
PubMed2000

Sulcogyral variation in NMDA receptor 2A/B subunit immunoreactivity in human brain.

NMDA receptors (NR) are important in many neurological processes. Using a large series of human brain tissue, we show that the distribution of NR2A/B immunoreactivity varies according to position along a gyrus. For pyramidal neurons in laminae II and III, immunoreactivity is most marked at gyral crown and gyral lips, diminishes along sulcal wall, and is barely detectable in sulcal floor cortex. In contrast, in some cases, immunoreactivity in laminae V and VI pyramidal neurons shows the reverse pattern. Neurofilament and calretinin immunoreactivity do not show this phenomenon. The findings suggest novel functional regionalization at the sulcogyral level in normal human brain.

Adolescent↗
PubMed2000

Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain.

Complexin (cx) I and II are homologous synaptic protein genes which are differentially expressed in mouse and human brain and differentially affected in schizophrenia. We characterized the distribution of cx I and II mRNAs in rat forebrain and examined whether their abundance, or the transcript of the synaptic marker synaptophysin, is affected by 14 days' administration of antipsychotic drugs (haloperidol, chlorpromazine, risperidone, olanzapine, or clozapine). Cx I mRNA predominated in medial habenula, medial septum-diagonal band complex, and thalamus, whereas cx II mRNA was more abundant in most other regions, including isocortex and hippocampus. Within the hippocampus, cx I mRNA was primarily expressed by interneurons and cx II mRNA by granule cells and pyramidal neurons. Localized cx II mRNA signal was seen in the dentate gyrus molecular layer, suggestive of its transport into granule cell dendrites. Antipsychotic treatment produced selective, modest effects on cx mRNA expression. Cx I mRNA was elevated by olanzapine in dorsolateral striatum and frontoparietal cortex, while the abundance of cx II mRNA relative to cx I mRNA was decreased in both areas by olanzapine and haloperidol. Chlorpromazine increased cx II mRNA in frontoparietal cortex and synaptophysin mRNA in dorsolateral striatum. In summary, the data have implications both for understanding the effects of antipsychotic medication on synaptic organization, and for synaptic protein expression studies in patients treated with the drugs.

Adaptor Proteins, Vesicular Transport↗