Social value framing of physical activity in European Member State policies: a content analysis.

Background: Engagement in physical activity (PA) benefits physical and mental health as well as many other areas of society. In Europe however, 1/3 adults do not meet minimum PA recommendations. Social value, and its quantification through social return on investment (SROI) evidence, may be a useful framing to enhance PA promotion. This study aimed to assess the current use of social value framing of PA in European Union (EU) policies. Methods: Content analysis of 45 EU member state policies which contain reference to PA was conducted to evaluate the presence of five social value domains and SROI evidence. Data was analysed using manual inductive coding, supported by DeepL translation and NVivo tools. Results: Social value framing was present to a certain extent in existing policies, with improved health being the most commonly referenced benefit of PA, followed by reference to social and community and then environmental benefits. Acknowledgement of the positive impacts of PA on wellbeing and education was the least present. Reference to SROI evidence was also limited. Generally, policies lacked holistic recognition of the social value of PA. Policies from the health sector were particularly limited in recognising the wider benefits of PA, whilst those from the environmental sector acknowledged the widest range of co-benefits. Conclusion: Adopting social value framing could be a useful approach for enhancing PA promotion. Whilst it is present to a certain extent in existing policy, this could be increased in terms of comprehensiveness to increase issue salience and multisectoral policy action.

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.

Inhibition of neuronal nitric oxide synthase by 7-nitroindazole: effects upon local cerebral blood flow and glucose use in the rat.

The novel nitric oxide synthase inhibitor 7-nitroindazole (7-NI) is relatively specific for the neuronal isoform of the enzyme and in this study we have used this compound to investigate the physiological role of perivascular nitric oxide-containing nerves in the cerebrovascular bed. Following injection of 7-NI (25 or 50 mg/kg, i.p.), cerebral blood flow and glucose utilization were measured in the conscious rat using the fully quantitative [14C]iodoantipyrine and 2-[14C]deoxyglucose techniques, respectively. Neither dose of the drug produced any change in arterial blood pressure, confirming a lack of effect upon the endothelial isoform of the enzyme, although there was a pronounced decrease in heart rate (-28% by 10 min postinjection). Throughout the brain 25 mg/kg 7-NI i.p. resulted in decreases in blood flow of between -20% in the hippocampus and -58% in the substantia nigra. Increasing the dose to 50 mg/kg resulted in a further generalized decrease, to almost -60% in parts of the thalamus and hippocampus, but in every animal this higher dose of 7-NI also produced randomly distributed areas of relative hyperaemia, which were most commonly found in those areas where the most intense hypoperfusion was otherwise in evidence. Despite these changes in blood flow, in all but a very few areas of the brain no significant decrease in glucose use was measured at either of the two doses of 7-NI. Thus despite the greater specificity of 7-NI for neuronal nitric oxide synthase, the cerebrovascular effects of the drug in vivo are very similar to that reported for the arginine analogues. However, these data do suggest that nitric oxide-releasing neurones in the brain may have an important role to play in the regulation of cerebral blood flow.

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)

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.

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)

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".

Intracerebral fetal raphé implants normalize hippocampal function but not cerebrovascular control in serotonin-depleted adult rat brain.

The effects of hypercapnia upon local cerebral blood flow and local cerebral glucose utilization were measured by quantitative autoradiography in parallel groups of rats (six per group) which 14-16 weeks previously had been treated with the serotonergic neurotoxin, methylenedioxymethamphetamine, followed by implantation of fetal raphé or basal forebrain tissues. Following the experiments, transplants were visualized by acetylcholinesterase histochemistry, and serotonergic reinnervation assessed using [3H]paroxetine binding to serotonin reuptake sites. In methylenedioxymethamphetamine-treated rats, contralateral to the implants, [3H]paroxetine binding was reduced by between 50 and 90% in the neocortex and hippocampus. Hippocampal glucose utilization was significantly increased in these rats, and the normal increase in flow which accompanies hypercapnia was also significantly enhanced. High levels of [3H]paroxetine binding were found within the raphé transplants (308 +/- 13 fmol/mg tissue). In host brain adjacent to the implant, binding levels were normalized, and in these same areas glucose utilization was also normalized. Basal forebrain implants had no effect upon either [3H]paroxetine binding or glucose utilization. Raphé transplants did not, however, alter the enhanced cerebrovascular response to hypercapnia induced by methylenedioxymethamphetamine, even in those areas where there was evidence of serotonergic reinnervation. The transplants also showed the same enhanced response. In conclusion, intracerebral fetal raphé implants normalize hippocampal function but not cerebrovascular control in serotonin-depleted adult rat brain, and despite not sharing the serotonergic deficit, blood flow in the implants follows that of the dysfunctional host.

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.

Cerebrovascular autoregulation in response to hypertension induced by NG-nitro-L-arginine methyl ester.

Local neocortical blood flow and glucose utilization were measured in conscious rats using [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiography, respectively, following intravenous injection of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (30 mg/kg). The dose of NG-nitro-L-arginine methyl ester was chosen so as to produce a level of hypertension equivalent to that produced in a parallel group of rats by the infusion of angiotensin-II (5 micrograms/ml at 0.5-2.0 ml/h). In those animals in which angiotensin-induced hypertension did not exceed 150 mmHg (mean arterial blood pressure), there were no significant effects upon cortical blood flow when compared to controls, but at higher pressures (157 +/- 1 mmHg), blood flow was significantly increased in circumscribed areas of cortex, most notably in parietal (from 204 +/- 10 to 780 +/- 44 ml/100 g per min) and occipital cortex (from 175 +/- 5 to 600 +/- 46 ml/100 g per min), whilst other cortical areas (e.g. temporal and frontal areas) were unchanged. Despite the fact that NG-nitro-L-arginine methyl ester increased blood pressure to levels (164 +/- 1 mmHg) which were in excess of the highest produced by angiotensin, there was no evidence of focal hyperaemia; indeed blood flow was significantly reduced in every cortical region except parietal area 1. No significant differences in glucose use were evident between any of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular localization of the uptake of 5-hydroxytryptamine in the area postrema of the rabbit after injection into a lateral ventricle.

1. The cellular localization of 5-hydroxytryptamine (5-HT) was investigated in the area postrema of the rabbit after intraventricular injection under different experimental conditions.2. 5-HT was found to be accumulated in different parts in and near to the area postrema, e.g. in glial cells, dorsal surface of the area postrema and ependyma of the central canal.3. The concentrations of 5-HT and 5-hydroxy indol-3-yl acetic acid (5-HIAA) were measured in different parts of the brain and CSF in control and in 5-HT treated animals with and without pargyline pretreatment. Intraventricular injection of 5-HT increased the concentration of 5-HT and 5-HIAA in the brain and in the CSF; pretreatment with pargyline further increased the concentrations of 5-HT but decreased the concentration of 5-HIAA.

Cerebrovascular consequences of repeated exposure to NG-nitro-L-arginine methyl ester.

1. Acute treatment with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produces cerebral oligaemia. The effects of repeated exposure to L-NAME upon cerebral blood flow were examined to determine whether the enhanced NOS inhibition reported following chronic treatment might reduce cerebral perfusion to ischaemic levels. 2. Rats were treated with L-NAME (75 mg kg-1, i.p.) once daily for 10 days. Local cerebral blood flow and glucose utilization were measured by [14C]-iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography respectively, either 1 h or 15 h after the last injection. A second group of rats was injected (i.p.) only once with L-NAME, either 1 h or 15 h prior to the measurement procedures. 3. Mean arterial blood pressure (MABP) was significantly increased (+35%) 1 h after a single injection of L-NAME. Although the hypertension was reduced 15 h after the injection (+13%), MABP remained significantly higher than control. 4. Local cerebral blood flow was significantly decreased 1 h after a single injection of L-NAME (ranging from -45% to -54%), and remained so even after 15 h (-39% to -48%). At neither time-point was there any change in glucose utilization. 5. At 15 h after the final injection of the chronic L-NAME treatment protocol, MABP was significantly elevated from control (+58%) and was also significantly higher than at 1 h following a single injection (+20%). There was no effect upon the established hypertension when rats treated chronically with L-NAME were challenged with a further injection of the drug and MABP was measured 1 h later, suggesting saturation of NOS inhibition. 6. Although reduced, cerebral blood flow was not significantly different from control when measured 15 h after the last injection of the chronic L-NAME treatment. When rats treated chronically with L-NAME were subjected to a further challenge with the drug, cerebral blood flow was reduced when measured 1 h after the acute injection (ranging from -34% to -41%). There was however evidence of some attenuation in the response when compared to that measured 1 h after a single injection of L-NAME (ranging from -45% to -54%). Thus, the cerebral circulation shows no evidence of either sustained L-NAME-induced vasoconstriction or saturated NOS inhibition following 10 daily injections of L-NAME. Chronic L-NAME treatment had no effect upon cerebral glucose use. 7. The trend towards re-establishment of cerebrovascular dilator tone and the normalization of cerebral flow-metabolism relationships could explain the lack of any ischaemic damage found in chronically treated rats, but the loss of an extended autoregulatory range afforded by acute L-NAME treatment may be responsible for an increased incidence of stroke.

Arterial chemoreceptor involvement in salicylate-induced hyperventilation in rats.

1. The extent to which peripheral arterial chemoreceptors are involved in the respiratory stimulant action of salicylates has been investigated in rats. 2. Injection of sodium salicylate (200 mg kg-1, single dose i.v.) caused a rapid transient hyperventilation that was not obtained when the carotid chemoreceptors were denervated by section of the carotid sinus nerves. A delayed (10 min) increase in respiration occurred regardless of whether or not the carotid nerves were sectioned. 3. Intravenous infusions of sodium salicylate (0.5 or 4 mg kg-1 min-1) caused hyperventilation in barbiturate-anaesthetized rats. The threshold dose for respiratory stimulation was significantly lower when the carotid sinus nerves were intact than when they were bilaterally sectioned, and the same pattern was observed following intravenous injections of sodium salicylate (cumulative doses) in anaesthetized and conscious rats. 4. Bilateral sectioning of the vagosympathetic nerve trunks did not significantly affect hyperventilation evoked by salicylate, suggesting that this response does not involve actions of salicylate on sensory receptors innervated by these nerves. 5. Administration of salicylate close-arterial to a carotid body, by local perfusion or cross-perfusion of a carotid sinus, led to an increase in respiration when the ipsilateral carotid nerve was intact, but not when it was sectioned. 6. Neuropharmacological studies on anaesthetized rats showed that chemosensory discharge, recorded from a sectioned carotid nerve, increased in response to salicylate injections with a similar dose-response pattern to the hyperventilation. Salicylate had no effect on baroreceptor discharge. 7. We conclude from our experiments that arterial chemoreceptors do contribute to salicylate-induced hyperventilation, and are almost exclusively responsible for the initial phase of the response in rats. Later increases in breathing are independent of reflexes from arterial chemoreceptors and result from actions at other sites, including the CNS. The therapeutic implications of our results are discussed.

Cerebrovascular effects of nitric oxide manipulation in spontaneously hypertensive rats.

1. Evidence that nitric oxide (NO) bioactivity is altered in chronic hypertension is conflicting, possibly as a result of heterogeneity in both the nature of the dysfunction and in the disease process itself. The brain is particularly vulnerable to the vascular complications of chronic hypertension, and the aim of this study was to assess whether differences in the cerebrovascular responsiveness to the NO synthase (NOS) inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), and to the NO donor 3-morpholinosydnonimine (SIN-1) might indicate one possible source of these complications. 2. Conscious spontaneously hypertensive (SHR) and WKY rats, were treated with L-NAME (30 mg kg-1, i.v.), 7-NI (25 mg kg-1, i.p.), (0.54 or 1.8 mg kg-1 h-1, continuous i.v. infusion) or saline (i.v.), 20 min before the measurement of local cerebral blood flow (LCBF) by the fully quantitative [14C]-iodoantipyrine autoradiographic technique. 3. With the exception of mean arterial blood pressure (MABP), there were no significant differences in physiological parameters between SHR and WKY rats within any of the treatment groups, or between treatment groups. L-NAME treatment increased MABP by 27% in WKY and 18% in SHR groups, whilst 7-NI had no significant effect in either group. Following the lower dose of SIN-1 infusion, MABP was decreased to a similar extent in both groups (around -20%). There was no significant difference in MABP between groups following the higher dose of SIN-1, but this represented a decrease of -41% in SHR and -21% in WKY rats. 4. With the exception of one brain region (nucleus accumbens), there were no significant differences in basal LCBF between WKY and SHR. L-NAME produced similar decreases in LCBF in both groups, ranging between -10 and -40%. The effect of 7-NI upon LCBF was more pronounced in the SHR (ranging from -34 to -57%) compared with the WKY (ranging from -14 to -43%), and in seven out of the thirteen brain areas examined there were significant differences in LCBF. 5. Following the lower dose of SIN-1, in the WKY 8 out of the 13 brain areas examined showed significant increases in blood flow compared to the saline treated animals. In contrast, only 2 brain areas showed significant increases in flow in the SHR. In the rest of the brain areas examined the effects of SIN-1 upon LCBF were less marked than in the WKY. 6. Infusion of the higher dose of SIN-1 resulted in further significant increases in LCBF in the WKY group (ranging between +30% and +74% compared to saline-treated animals), but no significant effects upon LCBF were found in the SHR. As a result, there were significant differences in LCBF between SIN-1-treated WKY and SHR in six brain areas. In most brain areas examined, cerebral blood flow in SHR following the higher dose of SIN-1 was less than that measured with the lower dose of SIN-1. 7. Despite comparable reductions in MABP (approximately 20%) in both groups, calculated cerebrovascular resistance (CVR) confirmed that the vasodilator effects of the lower dose of SIN-1 were significantly more pronounced throughout the brain in the WKY (ranging between -3% and -50%; median = -38%) when compared to the SHR (ranging between -10% and -36%; median = -26%). In the animals treated with the higher dose of SIN-1, CVR changes were broadly similar in both groups (median = -45% in WKY and -42% in SHR), but with the reduction in MABP in SHR being twice that found in WKY, this is in keeping with an attenuated blood flow response to SIN-1 in the SHR. 8. The results of this study indicate that NO-dependent vasodilator capacity is reduced in the cerebrovasculature of SHR. In addition, the equal responsiveness to a non-specific NOS inhibitor but an enhanced effectiveness of a specific neuronal NO inhibitor upon LCBF in the SHR could be consistent with an upregulation of the neuronal NO system.

Cerebrovascular responsiveness to NG-nitro-L-arginine methyl ester in spontaneously diabetic rats.

1. There is evidence that endothelial dysfunction is associated with diabetes mellitus. The purpose of the present study was to assess local cerebral blood flow (LCBF) and cerebrovascular responsiveness to the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in spontaneously diabetic insulin-dependent BioBred (BB) rats. 2. Diabetic rats, and non-diabetic controls, were treated with L-NAME (30 mg kg-1, i.v.) or saline, 20 min prior to the measurement of LCBF by the fully quantitative [14C]-iodoantipyrine autoradiographic technique. 3. There were no significant differences in physiological parameters (blood pH, PCO2, and PO2, rectal temperature, arterial blood pressure, or plasma glucose) between any of the groups of rats, and no difference in either the extent or the temporal characteristics of the hypertensive response to L-NAME between diabetic and non-diabetic rats. 4. In diabetic rats, a global reduction in basal LCBF was observed, although significant reductions (between -20 and -30%) were found in only 5 (mainly subcortical) out of the 13 brain regions measured. Following L-NAME injection, significant reductions in LCBF (between -20 and -40%) were found in the non-diabetic animals. In diabetic animals treated with L-NAME, a significant reduction in LCBF was measured only in the hypothalamus (-33%). 5. The cerebrovascular response to acute L-NAME is attenuated in spontaneously diabetic insulin-dependent BB rats. This would be consistent with the endothelial dysfunction in cerebral vessels, known to be associated with diabetes mellitus and it is possible that a loss of NO-induced dilator tone, amongst other factors, may underlie the observed reductions of basal LCBF in these animals.

A comparison of D and L-tryptophan on the cerebral metabolism of 5-hydroxytryptamine and dopamine in the dog.

1 After D and L-tryptophan (50 mg/kg) were given intravenously in the dog, the concentration of the amino acid was increased in ventricular cerebrospinal fluid (CSF) during the subsequent 4 h or sampling, although the concentrations were significantly lower following the administration of the D-isomer. 2 There was no evidence that D-tryptophan increased the synthesis of 5-hydroxytryptamine (5-HT) in dog brain as judged by the failure to cause a change in 5-hydroxyindoleacetic acid (5-HIAA) concentrations in ventricular CSF different from that seen with controls. 3 There was no appreciable conversion of D-tryptophan to L-tryptophan in the dog. 4 D-tryptophan was cleared more rapidly from plasma than L-tryptophan. 5 No difference in plasma binding between D and L-tryptophan was detected.

Cerebrovascular permeability in intracerebral implants of foetal basal forebrain cell suspensions.

Blood-brain barrier permeability was measured using [14C]-labelled a-aminoisobutyric acid (AIB) quantitative auto-radiography in rats which had previously received unilateral ibotenate-induced lesions of the nucleus basalis followed by intracortical implantation of foetal basal forebrain cell suspensions. The permeability characteristics of intracortical transplants were found to be dependent upon the site of implantation. Superficial transplants were invariably associated with AIB transfer constants (Ki) 3- to 4-fold higher than those in corresponding contralateral host cortex. In transplants sited deep in host neocortex, Ki values were not significantly different from those measured in surrounding host brain tissue.

Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma.

C6 glioma strongly express nitric oxide synthase. Rats bearing C6 tumours were pre-treated with i.v. Ng-nitro-L-arginine methyl ester (L-NAME), 3-morpholinosydnonimine (SIN-1) or saline before local cerebral blood flow (LCBF) or tumour capillary permeability (TCP) was measured by the [14C]iodoantipyrine autoradiographic or [14C]alpha-amino-isobutyric acid techniques. L-NAME and SIN-1 caused significant TBF alterations (-44% and +136%, respectively) with less marked (-15% and +33%) alterations in normal brain. Calculated cerebrovascular resistance changes within tumour were indeed selective. Baseline TCP was increased compared with normal brain (20-fold). L-NAME and SIN-1 administration did not alter TCP. These effects have significant implications for human malignant glioma management. Selective i.v. manipulation of LCBF, without significant changes in TCP, could increase the efficacy of chemotherapy, radiotherapy or provide better peritumoural oedema control.

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.

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.