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J Sharkey

Publications and source records attributed to J Sharkey.

At least 55 records · Page 3Linked to original sources
PubMed1993

Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat.

In the present study, we describe the effects of perivascular microapplication of the potent vasoconstrictor peptide endothelin-1 (ET-1; (120 pmol in 3 microliters), delivered via a guide cannula stereotaxically positioned above the left cerebral artery (MCA) of the conscious male Sprague-Dawley rat. Ten minutes after the administration of Et-1, mean arterial blood pressure had increased by 20% and profound reductions in local cerebral blood flow (up to 93%) were observed within those brain areas supplied by the MCA. In addition, significant increases in local cerebral blood flow were observed within the globus pallidus (100%), substantia nigra pars reticulata (48%), ventrolateral thalamus (65%), and dorsal hippocampus (74%) ipsilateral to the insult. Twenty-four hours following the insult, the pattern of ischaemic damage was similar to that reported previously following permanent occlusion of the rat MCA. It is suggested that perivascular microapplication of Et-1 may provide a useful model for the study of the functional disturbances associated with focal cerebral ischaemia in the conscious rat.

Animals↗
PubMed1992

Autoradiographic determination of glucose content and estimation of the lumped constant in intracerebral neuronal tissue transplants.

The quasi-steady-state distribution volume of brain glucose was measured using 3-O-[14C]methylglucose quantitative autoradiography in a group of rats (n = 5) which 12-15 weeks previously had undergone unilateral ibotenic acid-induced lesion of the nucleus basalis magnocellularis, followed by implantation into ipsilateral neocortex of primordial basal forebrain cell suspensions. The effects of the lesion and the presence of transplanted tissue in neocortex were visualized by acetylcholinesterase histochemistry. The 3-O-[14C]methylglucose tracer was distributed homogeneously throughout the host brain areas analysed, with no side-to-side differences, despite a marked unilateral depletion of acetylcholinesterase activity ipsilateral to the lesion site. Whilst the transplants were indistinguishable from the homogeneity of surrounding host frontal cortex, there was a 70% increase in the apparent distribution volume of methylglucose localized around the ibotenate injection site and associated needle tract. Brain glucose content is an important experimental variable affecting the lumped constant of the 2-deoxyglucose technique. There was no evidence of any significant difference in the lumped constant between transplant and host tissue which might compromise the validity of the 2-deoxyglucose technique when used together with intracerebral implantation of fetal neuronal cell suspensions.

3-O-Methylglucose↗
PubMed1991

Cerebrovascular and functional consequences of 5-HT1A receptor activation.

Cerebral glucose utilization and blood flow were measured in rats using 2-deoxy-D-[14C]glucose and [14C]iodoantipyrine quantitative autoradiography, respectively, following treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). In control and 8-OH-DPAT-treated animals blood flow and glucose use were similarly correlated, but the ratio was increased following 8-OH-DPAT treatment. Since 5-HT1A receptor activation is known to reduce neuronal 5-HT release, these results are consistent with a vasoconstrictor role for endogenous serotonin.

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

Acute cocaine administration: effects on local cerebral blood flow and metabolic demand in the rat.

Local cerebral blood flow and glucose utilisation were measured in both saline (n = 10) and cocaine (10 mg/kg; n = 10) treated rats using [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiography respectively. In control animals, the ratio of flow to metabolism was 1.40 (r = 0.92) for the 40 brain regions examined. Cocaine treatment altered neither the correlation (r = 0.83) nor the ratio (1.49). Thus, the fundamental relationship between CBF and metabolism remains intact following acute cocaine exposure.

Animals↗
PubMed1991

Cerebrovascular responsiveness to hypercapnia in intracerebral tissue transplants.

Cerebral blood flow was measured using [14C]iodoantipyrine quantitative autoradiography in rats which had previously undergone unilateral ibotenate-induced nucleus basalis lesion followed by intracortical implantation of foetal basal forebrain cell suspensions. Transplants had no effect upon host cortical blood flow, although within the transplant itself, blood flow was significantly lower than the contralateral site. Both the transplant and host cortex exhibited a similar degree of hyperaemia in response to hypercapnia.

Animals↗
PubMed1991

Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography.

The widely abused "designer" drug MDMA (3,4-methylenedioxymethamphetamine) has been shown to cause marked and long-lasting changes in brain serotonergic systems. The present study uses quantitative in vitro autoradiography of 3H-paroxetine labeled 5-HT uptake sites to assess the time-dependent effects of MDMA on 5-HT neurons in specific neuroanatomic loci. Following treatment with MDMA (20 mg/kg, b.i.d. for 4 days), marked decreases in 5-HT uptake sites were observed in a number of brain regions known to receive projections of 5-HT neurons. These regions included cerebral cortex, caudate nucleus, hippocampus, nucleus accumbens, olfactory tubercle, superior and inferior colliculi, geniculate nuclei, and most thalamic nuclei. In contrast, other areas such as the septal nuclei and some thalamic nuclei which also receive 5-HT projections were not substantially affected by this drug. In most regions, decreases in 5-HT uptake sites occurred within 24 hours of the last dose of MDMA and persisted at the 2 week time point. Some regions such as dorsal striatum exhibited a time-dependent reduction with greater reductions occurring at 2 weeks rather than immediately following the MDMA treatment regimen. The density of 5-HT uptake sites in other regions such as endopiriform nucleus and substantia nigra at the 2 week versus 18 hour time point indicated some degree of region-specific recovery. Regions which demonstrated no significant reduction in 5-HT uptake sites included the dorsal and median raphe nuclei, ventral tegmental area, central grey, interpeduncular nucleus, locus coerulus, pontine reticular formation and cerebellum. Likewise, regions containing 5-HT axons of passage (e.g., indusium griseum and lateral hypothalamus) appeared to be insensitive to the neurotoxic effects of MDMA on 5-HT neurons. Furthermore, the neurotoxic effects of MDMA showed specificity in that the catecholamine neurons labeled by 3H-mazindol were unaffected by the treatment regimen. These data indicate that the preferential degeneration of serotonergic neurons by MDMA is mediated primarily at 5-HT terminal regions, whereas regions containing 5-HT perikarya and axons of passage remain relatively unaffected. In addition, the observed time-dependent reductions and recovery of 5-HT uptake sites which were detected within 2 weeks of the treatment regimen in certain brain regions suggest region-specific differences in recovery of 5-HT systems from MDMA-induced lesion.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Alterations in hippocampal function following repeated exposure to the amphetamine derivative methylenedioxymethamphetamine ("Ecstasy").

The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), upon integrated cerebral function was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen days after the final administration, [3H]-paroxetine binding to 5HT uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex. In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within neocortex (0-92%) and hippocampus (30-95%). Despite these profound reductions in 5-HT uptake sites no significant alterations were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25-35%). This study provides direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Normal cerebrovascular regulatory mechanisms are present in intracerebral neuronal transplants.

Local cerebral blood flow and local cerebral glucose utilization were measured using quantitative autoradiography in parallel groups of rats (n = 5-7) which 12-15 weeks previously had undergone limited unilateral ibotenate-induced lesion of the nucleus basalis magnocellularis, followed by implantation into ipsilateral neocortex of primordial basal forebrain cell suspensions. Surviving transplants were visualized by acetylcholinesterase histochemistry. Neither lesion alone nor the presence of a transplant produced significant side-to-side differences in either blood flow or glucose use in any of the 20 brain areas measured. Glucose use within the transplant was independent of the site of implantation. When sited in neocortex, glucose use in the transplant (66 +/- 4 mumol/100 g per min) was significantly lower than in the corresponding contralateral site (113 +/- 3 mumol/100 g per min), whereas when sited in subcortical white matter, glucose use (53 +/- 3 mumol/100 g per min) was significantly higher than in the contralateral side (29 +/- 4 mumol/100 g per min). In the host brain as a whole, the ratio of blood flow to glucose use ipsilateral to the transplant (m = 1.27, r = 0.88) was not significantly different from that of the contralateral side (m = 1.30, r = 0.94). This relationship was also observed within the transplanted tissue itself despite the fact that alkaline phosphatase histochemistry revealed a relative hypervascularization associated with the implantation site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Glycyrrhetinic acid, an inhibitor of 11 beta-hydroxysteroid dehydrogenase, alters local cerebral glucose utilization in vivo.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes corticosterone (B) to inactive 11-dehydrocorticosterone and thus protects the non-specific renal mineralocorticoid receptor from exposure to B in vivo. There is regional 11 beta-OHSD mRNA expression and bioactivity in brain in vitro, but any in vivo function is unknown. We used the [14C]2-deoxyglucose technique in conscious rats to investigate whether 11 beta-OHSD inhibition with glycyrrhetinic acid alters local cerebral metabolic activity. We found increased glucose use in subregions of the hypothalamus, hippocampus, neocortex and subthalamus. Thus, 11 beta-OHSD may play a role in regulating the effects of B in the brain, in vivo.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Evidence for a possible role for serotonergic systems in the control of cerebral blood flow.

Cerebral blood flow and glucose utilisation were measured in rats using [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiography respectively following repeated exposure to the serotonergic neurotoxin methylenedioxyamphetamine. In both control and treated animals blood flow and glucose use were similarly correlated but the ratio was increased following lesion. Some focal increases in flow were greatly in excess of metabolic demand. These results are consistent with a cerebrovascular vasoconstrictor role for serotonin.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Chronic effects of the selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon cerebral function.

The amphetamine derivative methylenedioxyamphetamine selectively destroys serotoninergic terminals in the brain. We have studied the effects of this toxin upon resting cerebral function, as reflected in rates of glucose utilization. Rats were injected subcutaneously with either 1 ml/kg saline (n = 5) or 20 mg/kg methylenedioxyamphetamine (n = 5) twice daily for four days. Local cerebral glucose utilization was measured between six and nine weeks after treatment using [14C]2-deoxyglucose quantitative autoradiography. Samples of frontal cortex taken from these animals for in vitro [3H]paroxetine binding showed a 64% reduction in 5-hydroxytryptamine uptake sites. In the majority of the 31 functionally diverse brain areas analysed, no significant changes were measured, but significant (P less than 0.05) increases in glucose use were found in neocortical regions e.g. anterior cingulate cortex (+16%) and sensorimotor cortex (+21%). However, the most profound increases were found in globus pallidus (+30%) and hippocampus molecular layer (+34%). It would appear, therefore, that treatment with methylenedioxyamphetamine results in long-lasting alterations in cerebral functional activity.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Dopamine transporter: solubilization from dog caudate nucleus.

3H-GBR 12935 was used to label the digitonin-solubilized dopamine transporter from dog caudate nucleus. Specific binding to soluble fractions was observed in dog caudate but was absent in rat cerebellum. Binding to the solubilized transporter sites was saturable and of high affinity (Bmax = 2.57 +/- 0.60 pmol/mg protein, KD = 23.42 +/- 2.24 nM, n = 4). Heating or addition of trypsin abolished specific binding in the soluble fractions. In competition studies, soluble 3H-GBR 12935 binding was inhibited by mazindol, GBR 12909, nomifensine, dimethocaine, dopamine, (-) cocaine, and (+) cocaine in a manner typical of binding to the dopamine transporter. As expected, tomoxetine and citalopram, inhibitors of norepinephrine and serotonin uptake, respectively, were weak competitors of 3H-GBR 12935 binding.

Animals↗
PubMed1989

Alterations in local cerebral glucose utilization following central administration of corticotropin-releasing factor in rats.

We have examined the effects of intracerebroventricular administration of corticotropin-releasing factor (CRF) (5.25 nmol in 10 microliters of saline) on glucose utilization, an index of cerebral function, in 65 anatomically discrete regions of rat brain by using the 14C-2-deoxyglucose quantitative autoradiographic technique. CRF administration increased plasma glucose concentrations with a temporal onset and magnitude of response similar to those previously reported. CRF differentially affected glucose utilization (GU) in discrete regions of rat brain. Consonant with the hypophysiotropic role for CRF, pronounced increases in GU were seen in median eminence and lateral nucleus of the hypothalamus. CRF also increased GU in brain regions implicated in mediating responses to stress including locus coeruleus and median raphe nucleus. In contrast, reductions in GU were observed in prefrontal cortex and nucleus accumbens. Punctate increases in GU were noted in the cerebellar cortex. Furthermore, large increases in GU occurred in vermis, inferior olive, and red nucleus substantiating a neurotransmitter role for CRF in the olivocerebellar pathway. Additional brain areas showing significant alterations in GU in response to CRF included anteroventral, anterior pretectal, and posterolateral nuclei of the thalamus, fornix, dorsal tegmental nucleus, spinal trigeminal nucleus, and cuneate nucleus. These data demonstrating regional changes in GU in response to CRF administration further elucidate the neuroanatomical substrates underlying the actions of CRF in brain and support the role of this neuropeptide in coordinating responses to stress.

Animals↗
PubMed1989

[125]I-spectramide: a novel benzamide displaying potent and selective effects at the D2 dopamine receptor.

The new substituted benzamide Spectramide, (N-[2-[4-iodobenzyl-N-methylamino]-2-methoxy-4-ethyl]-5-chloro- methylamine] benzamide) labelled with 125I was used as a potent and highly selective dopamine-D2 receptor antagonist in rat striatal homogenates for in vitro receptor binding. Kinetic experiments demonstrated the reversibility of the binding and the estimated Kd from saturation analysis was 25 pM, with a Bmax of 20 pmol/g of tissue. Competition studies showed that spectramide did not interact potently with the D1 or dopamine-uptake site. Drugs known to interact with other receptor systems were weak competitors of the binding, while binding was potently inhibited by other D2 antagonists, such as spiperone and eticlopride. These data indicate that Spectramide binds selectively and with high affinity to the dopamine D2 receptors, and may prove to be a useful tool for the study of these receptors in vivo using PET or SPECT.

Animals↗
PubMed1988

Cocaine binding at sigma receptors.

Cocaine and some related psychostimulants interact with sigma receptors in binding assays. Their Ki values are compatible with blood concentrations reported to produce psychosis in human volunteers. It is proposed that the psychotomimetic effects of some psychostimulants may derive, at least in part, from their interaction with sigma receptors.

Animals↗
PubMed1988

Cocaine inhibits muscarinic cholinergic receptors in heart and brain.

(-)-Cocaine inhibits M2 muscarinic cholinergic binding measured with [3H]quinuclidinyl benzilate in heart and brain with a Ki of 18.8 microM. The cyclic nucleotide 5'-guanylylimidodiphosphate does not shift the competition curve, suggesting that (-)-cocaine is an antagonist. (-)-Cocaine also reverses the methacholine-induced inhibition of guinea pig atrial contractions at a similar concentration. Although (+)-cocaine is about 8-fold more potent than (-)-cocaine, (+)-cocaine is not present in extracts of the coca plant. Of the many compounds tested, only (-)-cocaine and lidocaine have a higher affinity at M2 muscarinic receptors than at M1 receptors; other compounds such as (+)-cocaine, norcocaine, procaine and dimethocaine are equipotent at the M1 and M2 subtypes. These results indicate that cocaine can act as an antimuscarinic agent, particularly at higher, toxic doses.

Animals↗