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Biomedical subjects

J Sharkey

Publications and source records attributed to J Sharkey.

At least 37 records · Page 2Linked to original sources
PubMed1998

Outpatient ultrasound-guided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: a preliminary report of 434 patients.

OBJECTIVES: To assess the effectiveness of palladium 103 (Pd-103) brachytherapy in Stage T1 and T2 adenocarcinoma of the prostate. METHODS: Charts of 474 patients treated between 1991 and 1996 with transperineal real-time ultrasound-guided Pd-103 implants were reviewed to assess post-treatment prostate-specific antigen (PSA) levels and follow-up biopsy results. Of 474 patients, 434 had sufficient data for this report. The implant technique used allows precise placement of seeds and accurate dose delivery of the entire prostate. Preoperative neoadjuvant leuprolide (Lupron) and flutamide (Eulexin) were given selectively to reduce prostate size greater than 50 cc and for Gleason grade lesions greater than 7. RESULTS: Of 434 patients, successful cancer control was demonstrated in 81% of patients by a decrease in PSA levels to less than 1.5 ng/mL at 1 year. Biopsies were negative in 88% of patients 1 year after the procedure and in 89% at 2 years. Analysis of the data suggests that patients with pretreatment PSA levels less than 10 ng/mL had the best outcomes. There were no disease-related deaths; the predominant morbidity was short-term bladder and bowel irritation without permanent sequelae. Incontinence occurred in less than 5% of patients who had undergone prior transurethral resection of the prostate. Impotence occurred in less than 15% of patients. CONCLUSIONS: The technique used in this study proved effective in reducing PSA levels to less than 1.5 ng/mL and in producing negative biopsies 1 and 2 years postoperatively. Results are comparable to external-beam radiation therapy, demonstrating a significant reduction in morbidity.

Adenocarcinoma↗
PubMed1998

Pharmacological characterization of a simple behavioral response mediated selectively by central adenosine A1 receptors, using in vivo and in vitro techniques.

The behavioral profile of a range of adenosine receptor ligands was examined in rats using a locomotor activity model. Adenosine receptor agonists, including the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the A2A agonist, 2-[(2-aminoethylamino)carbonylethyl-phenylethylamino]- 5'-ethylcarboxa midoadenosine (APEC), reduced spontaneous motor activity in a dose-dependent manner. CPA-induced locomotor depression was attenuated by adenosine A1 receptor selective antagonists, such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-2-piperidine ethanol (FK453), and (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-piperidin-2-yl acetic acid (FK352), but not by the A2A receptor antagonist, (E)-1,3-dipropyl-8-(3, 4-dimethoxystyryl)-7-methylxanthine (KF17837). By contrast, APEC-induced hypolocomotion was attenuated by KF17837 but not by DPCPX, confirming that adenosine A1 and A2A receptor activation mediates locomotor output independently. It was found that two peripheral adenosine receptor antagonists, 8-(p-sulphophenyl)-1, 3-dipropylxanthine (DPSPX) and 8-(p-sulphophenyl)-1, 3-dimethylxanthine (8-PST), did not alter CPA-induced hypolocomotion. This confirmed that pharmacological reversal of the adenosine A1 receptor-mediated response involved a central site of drug action. The relationship between occupancy of central adenosine A1 receptors and behavioral effect was therefore assessed. Regression analysis on log transformed data confirmed associations between antagonist affinity for brain [3H]DPCPX binding sites and, in order of increasing significance, the equivalent behavioral dose (EBD) for reversal of CPA-induced hypolocomotion (r2 = 0.32), the serum concentration of drug (r2 = 0.65), and most significantly with the brain concentration of drug detected 20 min after administration of the (EBD) (r2 = 0.95). These data suggest that competition between agonists and antagonists, for occupancy of central adenosine A1 receptors, is intrinsic to the pharmacological reversal of CPA-induced hypolocomotion. The validity of the model as a simple predictive screen for the blood/brain barrier permeability of adenosine A1 receptor antagonists was thereby confirmed.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed1997

Detection of adenosine receptor antagonists in rat brain using a modified radioreceptor assay.

The present study describes a modified radioreceptor binding assay using brain homogenate or serum from drug treated animals as the 'competing drug' in a conventional in vitro radioligand binding assay. Method validation involved measurement of the brain and serum concentration of three adenosine receptor antagonists following systemic administration, using a [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) binding assay. The intrinsic [3H]DPCPX binding capacity of test samples was abolished by protein denaturation (80 degrees C, 15 min) and, endogenous ligand was depleted enzymatically, prior to determination of drug concentration. Brain and serum concentrations of the adenosine A1 receptor antagonist, DPCPX increased in a dose related manner when measured 20 min after intraperitoneal injection. Estimated brain concentrations were 13.8, 87.7 and 288 nM following injection of 0.01, 0.1 and 1.0 mg/kg DPCPX, and serum concentrations were 26.5, 195 and 1370 nM respectively. A time dependent decrease in both brain and serum concentration was noted 20-180 min following injection of 1.0 mg/kg DPCPX. The peripheral adenosine receptor antagonists, 1,3-dipropyl-8-p-sulphophenylxanthine (DPSPX; 5.6 mg/kg) and 8-(p-sulphophenyl)theophylline (8-PST; 20 mg/kg), were not detected in brain tissue 20 min after intraperitoneal injection, despite serum concentrations of 56 and 52 microM respectively. This assay provides a useful and versatile method for determining the central penetration of neuroactive drugs.

Animals↗
PubMed1997

Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism.

The cellular mechanisms underlying the neuroprotective action of the immunosuppressant FK506 in experimental stroke remain uncertain, although in vitro studies have implicated an antiexcitotoxic action involving nitric oxide and calcineurin. The present in vivo study demonstrates that intraperitoneal pretreatment with 1 and 10 mg/kg FK506, doses that reduced the volume of ischemic cortical damage by 56-58%, did not decrease excitotoxic damage induced by quinolinate, NMDA, and AMPA. Similarly, intravenous FK506 did not reduce the volume of striatal quinolinate lesions at a dose (1 mg/kg) that decreased ischemic cortical damage by 63%. The temporal window for FK506 neuroprotection was defined in studies demonstrating efficacy using intravenous administration at 120 min, but not 180 min, after middle cerebral artery occlusion. The noncompetitive NMDA receptor antagonist MK801 reduced both ischemic and excitotoxic damage. Histopathological data concerning striatal quinolinate lesions were replicated in neurochemical experiments. MK801, but not FK506, attenuated the loss of glutamate decarboxylase and choline acetyltransferase activity induced by intrastriatal injection of quinolinate. The contrasting efficacy of FK506 in ischemic and excitotoxic lesion models cannot be explained by drug pharmacokinetics, because brain FK506 content rose rapidly using both treatment protocols and was sustained at a neuroprotective level for 3 d. Although these data indicate that an antiexcitotoxic mechanism is unlikely to mediate the neuroprotective action of FK506 in focal cerebral ischemia, the finding that intravenous cyclosporin A (20 mg/kg) reduced ischemic cortical damage is consistent with the proposed role of calcineurin.

Animals↗
PubMed1997

Assessment of sensorimotor neglect after occlusion of the middle cerebral artery in the rat.

Evaluating the efficacy of neuroprotective drugs in rat models of focal cerebral ischemia has involved histological and behavioral batteries to examine treatment outcome. However, the behavioral tests used to date provide little insight into the nature of the neurological impairments. To provide an analysis of a possible "neglect" syndrome after occlusion of the middle cerebral artery, M. I. Posner's (1980) visual attentional paradigm was adapted for use in the rat. A paw-reaching task and a test of somatosensory "neglect" also were used to assess forelimb sensorimotor function. The lesion group displayed unilateral deficits; however, there was no evidence of attentional dysfunction. Results are consistent with the conclusion that the behavioral deficits identified arise from a somatosensory deficit rather than hemineglect due to dysfunctional spatial attention.

Animals↗
PubMed1996

Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists.

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [14C]2-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1-3 mg/kg i.v.; n = 20), dizocilpine (0.03-0.3 mg/kg; n = 15), CGS19755 (1-30 mg/kg; n = 15) or saline (2 ml/kg; n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively unaffected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the f statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional f values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).

Animals↗
PubMed1996

The pattern of alcohol consumption of a general hospital population in north Belfast.

This study aimed to examine the pattern of alcohol use among those attending a General Hospital and to explore the perception of safe drinking. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire was given for self-completion to all inpatients and outpatients on separate days and to all adults attending the Accident and Emergency Department (A&E) on both a midweek and a weekend period. Additional questions to determine attitudes to, and intake of, alcohol were also given. Of the 464 people approached, 82% completed the questionnaire. Twenty-nine per cent of outpatients, 37.5% of inpatients and 20% of those attending A&E were leetotal. Fifteen per cent of outpatients, 16% of inpatients and 38.5% of those attending A&E scored as misusers of alcohol according to the AUDIT questionnaire. Males were three times more likely to misuse alcohol than females. Younger women were much more likely to misuse alcohol than older women. An unexpectedly large number of those attending the gynaecological clinic reported alcohol misuse. Of the inpatient alcohol misusers identified by AUDIT, only 50% were independently detected by either nursing or medical staff, the lower misuse scores being more frequently missed. We conclude that there continues to be a significant identifiable proportion of alcohol misuse that goes undetected. These individuals attend throughout the hospital and a simple self-completion questionnaire would considerably aid their detection.

Adult↗
PubMed1996

Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: Tacrolimus (FK506) is a potent immunosuppressant that is presently in clinical use for prevention of allograft rejection. Recently, animal studies reporting significant reductions in the volume of tissue damage associated with cardiac, hepatic, and cerebral ischemia suggest that tacrolimus may also be of use in the clinical management of stroke. In the present study, we examine whether the neuroprotective effects of tacrolimus, as assessed by histological outcome, are accompanied by an amelioration of the skilled motor deficits induced in the rat by middle cerebral artery occlusion (MCAO). METHODS: Animals were trained to perform a skilled paw-reaching task before MCAO by perivascular microinjections of endothelin-1. Tacrolimus (1 mg/kg, n = 6) or vehicle (n = 6) was administered by intravenous infusion 1 minute after MCAO. After a 5-day postoperative recovery period, the rats were retested for skilled paw-reaching ability for an additional 9 days. RESULTS: In vehicle-treated rats, MCAO resulted in a profound bilateral impairment in skilled paw use. Rats treated with tacrolimus, although still impaired, performed significantly better than those treated with vehicle alone (P < .01). Histological analysis, 14 days after occlusion, confirmed the neuroprotective efficacy of tacrolimus with a 66% reduction in the volume of hemispheric brain damage produced by MCAO (P < .01). CONCLUSIONS: The present studies show that tacrolimus not only protects neural tissue from focal cerebral ischemia but also significantly ameliorates the deficits in skilled motor ability produced by this lesion. These data provide further support for the view that tacrolimus may be of use in the treatment of stroke.

Animals↗
PubMed1995

Behavioural assessment of endothelin-1 induced middle cerebral artery occlusion in the rat.

The behavioural effects of unilateral middle cerebral artery occlusion (MCAO) induced by perivascular injection of endothelin, and a unilateral excitotoxic lesion of the striatum, were explored using the staircase test of skilled paw-reaching in the rat. A profound bilateral impairment in pellet recovery, with a concomitant increase in pellet displacement, was observed in the MCAO group. By contrast the striatal lesion group exhibited a primarily contralateral impairment. The findings provide both further insight into the control of unilateral motor function and a reliable behavioural endpoint for the assessment of experimental stroke.

Animals↗
PubMed1995

Characterisation of an experimental model of stroke produced by intracerebral microinjection of endothelin-1 adjacent to the rat middle cerebral artery.

A novel experimental model of stroke has been developed using the powerful vasoconstrictor peptide, endothelin-1, to occlude the middle cerebral artery (MCA) of anaesthetised rats. Intracerebral microinjections of endothelin-1 were administered under stereotaxic guidance adjacent to the MCA, and after 3 days rats were perfusion fixed for histopathological determination of ischaemic brain damage. The pattern of brain damage noted using this model was similar to that reported following permanent surgical occlusion of the MCA. Brain damage was apparent in the dorsal and lateral neocortex (98 +/- 12 mm3) and striatum (32 +/- 3 mm3) ipsilateral to the insult. Rats anaesthetised with halothane and barbiturate exhibited a similar volume of brain damage. However, infarct volume increased when the duration of halothane anaesthesia was extended from 5 to 180 min post-occlusion. Neuroprotection studies demonstrated that dizocilpine (5 mg/kg, i.p.), administered 30 min prior to MCA occlusion, reduced the volume of cortical brain damage by 51% (P < 0.05) but did not alter the volume of striatal brain damage. The present results demonstrate that microinjections of endothelin-1 adjacent to the rat MCA result in a reproducible pattern of focal cerebral infarction which is sensitive to the duration of anaesthesia and can be reduced by dizocilpine.

Anesthesia↗
PubMed1995

Enhanced cerebrovascular responsiveness to hypercapnia following depletion of central serotonergic terminals.

Serotonin-containing nerve fibres innervate cerebral blood vessels, but the source of this innervation and the physiological effects of perivascular serotonin release remain controversial. The purpose of the present study was to examine the effects of central serotonergic depletion upon the relationship between CBF and glucose utilization under both normo- and hypercapnic conditions. To induce the loss of serotonergic terminals, rats were injected twice daily for 4 consecutive days with 20 mg/kg of the specific serotonergic neurotoxin methylenedioxyamphetamine (MDA). Between 4 and 6 weeks later, local CBF and glucose utilization were measured using the fully quantitative [14C]iodoantipyrine and [14C]2-deoxyglucose autoradiographic techniques, respectively, and the efficacy of the lesioning protocol was assessed using [3H]paroxetine radioligand binding analysis. In all animals treated with MDA, there was a significant decrease in serotonin uptake sites throughout the brain, falling from 223 +/- 20 to 40 +/- 16 fmol/mg tissue in parietal cortex, for example, although the raphe nuclei themselves were unaffected (300 +/- 20 fmol/mg tissue in controls and 291 +/- 18 in MDA-treated rats). In normocapnic rats, the effects of MDA pretreatment upon blood flow and glucose use were slight and focally concentrated. However, when the animals were rendered hypercapnic, CBF was significantly higher in MDA-treated rats than in normal controls, for example, increasing from 356 +/- 22 ml 100 g-1 min-1 in frontal cortex of hypercapnic controls to 700 +/- 81 ml 100 g-1 min-1 in MDA-pretreated rats with similar levels of hypercapnia. In some brain areas of hypercapnic MDA-pretreated rats, blood flows were too high (> 800 ml 100 g-1 min-1) to be accurately quantified.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1994

Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia.

The immunosuppressive action of the drug FK506 involves inhibition of calcineurin in T-lymphocytes by a complex of FK506 and an FK506 binding protein, FKBP12, a member of the immunophilin protein family. The functional role of brain immunophilins is, however, unclear. We show here that FK506 is a powerful neuroprotective agent in an in vivo model of focal cerebral ischaemia when administered up to 60 min post-occlusion. The minimum effective neuroprotective dose is comparable with the immunosuppressant dose in humans, suggesting that FK506 may have clinical potential for the treatment of stroke. Although the related immunosuppressants rapamycin and cyclosporin failed to reduce brain damage, the finding that rapamycin pretreatment blocked the effect of FK506 confirms a role for immunophilins in the neuroprotective mechanism.

Animals↗
PubMed1994

Differential effects of competitive (CGS19755) and non-competitive (MK 801) NMDA receptor antagonists upon local cerebral blood flow and local cerebral glucose utilisation in the rat.

The effects of the selective non-competitive NMDA receptor antagonist dizocilpine (MK801) and the competitive NMDA receptor antagonist CGS19755 upon local blood flow (lCBF) and local glucose utilisation (lCGU) were examined in 81 neuroanatomically discrete regions of the conscious rat brain using the [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiographic techniques, respectively. Animals received dizocilpine (0.3 mg/kg), CGS19755 (30 mg/kg) or saline vehicle (2 ml/kg) 10 min prior to the initiation of lCGU studies while blood flow determinations were performed in parallel groups of animals 20 min after drug administration. Dizocilpine significantly increased lCGU in 33 of the 81 regions measured (most notably in cortical and subcortical limbic structures and in the basal ganglia) while reducing glucose use in seven brain areas (frontoparietal and somatosensory cortex, and in areas subserving auditory function). In contrast, CGS19755 significantly reduced lCGU use in 39 of the 81 areas examined while increases were observed in only three areas (anterior piriform cortex, substantia nigra pars reticulata, and posterior thalamic nucleus). Following Dizocilpine administration, there was evidence of widespread (64 of the 81 areas studied) increases in lCBF, while blood flow was reduced in the inferior colliculus. Significant increases in lCBF were also noted in 26 brain areas of CGS19755-treated rats while in one area (flocculus) blood flow was reduced. In saline-treated rats there was a close correlation between lCBF and lCGU. Dizocilpine administration was associated with an increase in the overall lCBF:lCGU ratio from 1.56 ml/mumol (in saline-treated rats) to 2.34 ml/mumol. In some brain areas (CA1 subfield of the dorsal hippocampus, somatosensory cortex and nucleus accumbens) there was evidence of focal disturbances in flow-metabolism relationship. While a similar increase in the overall lCBF-lCGU use ratio was evident in CGS19755 treated animals, there was no evidence of focal uncoupling of the flow metabolism relationship in any of the 81 brain areas examined. These data show that whilst both competitive and non-competitive NMDA receptor antagonists increased cerebral tissue perfusion beyond that required to meet underlying metabolic demand, focal disturbances in the flow metabolism relationship were observed only in dizocilpine-treated rats.

Animals↗
PubMed1994

Endothelin-1 induced middle cerebral artery occlusion: pathological consequences and neuroprotective effects of MK801.

In the present study we utilise the potent vasoconstrictor properties of endothelin-1 (Et-1) in a new model of middle cerebral artery occlusion in the anaesthetized rat. We evaluate the reproducibility of the model and examine the neuroprotective efficacy of the potent anti-ischaemic agent, MK801. Adult male SD rats received MK801 (5 mg/kg, n = 7) or saline vehicle (n = 7) 30 mins prior to the microinjection of Et-1 (60 pmol in 3 microliters) via a 31-g cannula stereotaxically positioned 0.5 mm above the middle cerebral artery. Three days after the injection of Et-1, rats were perfusion fixed, the brain removed, cryostat sectioned and processed for histological staining. Sections at eight predetermined levels were examined by light microscopy and the volume of infarction calculated. Following administration of Et-1, saline-pretreated rats exhibited a pattern of ischaemic damage similar to that previously reported following permanent occlusion of the rat middle cerebral artery. This pattern was characterised by a large volume of infarction covering the dorsal and lateral neocortex (98 +/- 12 mm3) and striatum (32 +/- 3 mm3) ipsilateral to the insult. Power analysis predicted a group size of 7 would be required for a 50% reduction in ischaemic damage to be recorded as statistically significant at the 5% level. Pretreatment with MK801 reduced cortical tissue damage by 51% (P = 0.026) but did not significantly alter either the pattern or volume of infarction (33 +/- 4 mm3; P = 0.95) in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1994

Chronic 3,4-methylenedioxymethamphetamine administration decreases glucocorticoid and mineralocorticoid receptor, but increases 5-hydroxytryptamine1C receptor gene expression in the rat hippocampus.

Both glucocorticoids and serotonin have been implicated in the regulation of mood and neuroendocrine control. In this study we have examined the effects of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine on corticosteroid and 5-hydroxytryptamine receptor subtype gene expression within the hippocampal formation using in situ hybridization histochemistry. Animals were injected subcutaneously with 3,4-methylenedioxymethamphetamine (20 mg/kg) twice daily for four days. Two weeks following this dosage regimen, shown to markedly reduce 5-hydroxytryptamine terminals, both glucocorticoid receptor and mineralocorticoid receptor messenger RNA expression were significantly decreased (30-47% fall) in the granule cells of the dentate gyrus and pyramidal cells of CA1-CA4 fields of Ammon's horn, but not in parietal cortex neurons. In the same rats, 5-hydroxytryptamine1C receptor messenger RNA expression was significantly increased in CA3 pyramidal neurons (133% rise), but neither 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptor messenger RNA levels were altered in any dorsal hippocampal subfield. 3,4-Methylenedioxymethamphetamine treatment was associated with modest hypersecretion of coricosterone during the diurnal nadir, without other peripheral evidence of chronic glucocorticoid excess (unchanged thymic and adrenal weights and corticosterone-binding globulin levels). These results emphasize the importance of the serotonergic innervation in maintaining hippocampal corticosteroid receptor gene expression. It is suggested that 5-hydroxytryptamine1C receptors may be involved in mediating the effects of serotonin on hippocampal glucocorticoid receptor and mineralocorticoid receptor expression and perhaps mood.

Animals↗
PubMed1994

Alterations in local cerebral blood flow in mature rats following prenatal exposure to cocaine.

Time-mated female Sprague-Dawley rats were injected subcutaneously with either 40 mg/kg cocaine-HCl or saline once daily on gestational days 13 through to 16. Local cerebral blood flow and glucose use were measured in the mature male offspring from these dams using the fully quantitative [14C]2-deoxyglucose and [14C]iodoantipyrine autoradiographic techniques, respectively. The effects of the treatment upon the integrity of central serotonergic terminals was assessed using [3H]paroxetine radioligand binding autoradiography. There were no significant changes in glucose use in any of the 40 brain areas analysed in this study, and although there was a generalized tendency towards increases, these never exceeded +15% of control values. In contrast, significant increases in local cerebral blood flow were measured in more than one-third of the areas examined in cocaine-treated rats, ranging from +20% in dorsal raphe nucleus to +95% in some parts of the neocortex. In all but three brain areas, the ratio of cerebral blood flow to metabolic demand was found to increase following cocaine exposure, resetting the relationship from an overall ratio of 1.6 in controls to 2.5 in treated rats. This relative hyperaemia, which must result from excessive dilatation of the cerebrovascular bed under normal physiological conditions, could not be explained by a direct effect of the treatment on serotonergic constrictor neurons as there was no evidence for any changes in [3H]paroxetine binding. Whatever the underlying cause, we conclude that the effects upon cerebrovascular control mechanisms of prenatal exposure to cocaine identified here, might present a further source of difficulty in the management of "crack babies".

Animals↗
PubMed1993

Acute cocaine alters cerebrovascular autoregulation in the rat neocortex.

Although cocaine abuse has been associated with an increased incidence of cerebrovascular accident, the underlying mechanisms are unknown. In this study we have investigated the effects of cocaine upon the autoregulation of local cortical blood flow (lCBF) during hypertension. Hypertension was induced in conscious rats by intravenous infusion of angiotensin-II (5 micrograms/ml; 0.5-2.5 ml/h), and animals were subsequently injected IV with either cocaine-HCl (5 mg/kg) or saline, prior to the measurement of lCBF of glucose utilization (lCGU) using [14C]-iodoantipyrine or [14C]-2-deoxyglucose quantitative autoradiography, respectively. Hypertension alone (< 155 mmHg) did not significantly alter lCBF in any cortical areas examined. However, at higher mean arterial blood pressure (MABP), lCBF increased focally (+265%) in parietal cortex. Cocaine did not alter lCBF in normotensive animals, but with increasing levels of hypertension (MABP > 145 mmHg), all cocaine-treated rats showed focal increases (200-400%) in lCBF in parietal cortex. Glucose use remained relatively unaffected in all treatment groups. This hyperaemia in cocaine-treated rats at MABP below the normal upper limit of autoregulation may provide a mechanism to explain haemorrhagic stroke in cocaine abusers.

Angiotensin II↗