Browsing by Author "Davson, Hugh (7003995718)"

The brain vascular perfusion method, with a multiple-time brain uptake analysis, has been employed to study the effects of chronic amphetamine intoxication on the kinetics of entry of 2 inert polar molecules, d-[14C]mannitol (mol.wt. 180) and [3H]polyethylene glycol (PEG, mol.wt. 4000) into the forebrain of the guinea pig. The unidirectional transfer constants, Kin, determined from graphic analysis 14 and 20 days after chronic amphetamine treatment (5 mg/kg daily, i.p.) showed a marked time-dependent progressive enhancement of transfer for both molecules. The kinetic features of this entry suggest the opening up of pathways through the blood-brain barrier (BBB) which allows mannitol and PEG to pass into the brain at rates which are irrespective of their molecular size and/or lipophilia and these changes cannot be attributed to simple mechanical factors such as hypertension. This opening of the BBB was associated with changes in behaviour (increased locomotor activity, stereotypy, hypervigilance, social withdrawal, and loss of weight) seen in 14- and 20-day amphetamine-treated animals. At 7 and 28 days after the withdrawal of the amphetamine treatment, the behavioural manifestations were absent, and the Kin values for both molecules were not significantly different from those measured in normal control animals which had been treated with placebo injections. The present results suggest a reversible dysfunction of the BBB as a consequence of the chronic amphetamine intoxication which correlates with the behavioural syndrome induced in the guinea pig. © 1989.

The brain vascular perfusion method, with a multiple-time brain uptake analysis, has been employed to study the effects of chronic amphetamine intoxication on the kinetics of entry of 2 inert polar molecules, d-[14C]mannitol (mol.wt. 180) and [3H]polyethylene glycol (PEG, mol.wt. 4000) into the forebrain of the guinea pig. The unidirectional transfer constants, Kin, determined from graphic analysis 14 and 20 days after chronic amphetamine treatment (5 mg/kg daily, i.p.) showed a marked time-dependent progressive enhancement of transfer for both molecules. The kinetic features of this entry suggest the opening up of pathways through the blood-brain barrier (BBB) which allows mannitol and PEG to pass into the brain at rates which are irrespective of their molecular size and/or lipophilia and these changes cannot be attributed to simple mechanical factors such as hypertension. This opening of the BBB was associated with changes in behaviour (increased locomotor activity, stereotypy, hypervigilance, social withdrawal, and loss of weight) seen in 14- and 20-day amphetamine-treated animals. At 7 and 28 days after the withdrawal of the amphetamine treatment, the behavioural manifestations were absent, and the Kin values for both molecules were not significantly different from those measured in normal control animals which had been treated with placebo injections. The present results suggest a reversible dysfunction of the BBB as a consequence of the chronic amphetamine intoxication which correlates with the behavioural syndrome induced in the guinea pig. © 1989.

The permeability of the blood-cerebrospinal fluid (CSF) barrier to 3H-labelled thyrotropin-releasing hormone (TRH), was studied at the blood-tissue interface of the isolated perfused choroid plexus of the sheep, using a rapid (if< 30 s), single circulation paired-tracer dilution technique, in which d-[14C]mannitol serves as an extracellular marker. Arterio-venous loss of 14C radioactivity reflects the percentage of the d-mannitol dose that crosses the blood-CSF barrier using a non-specific pathway. This loss suggests that the choroidal epithelium is moderately leaky. Cellular uptake of TRH, estimated by directly comparing venous dilution profiles of [3H]TRH and d-[14C]mannitol was independent of this leakiness. The unidirectional transport of TRH could not be saturated with unlabelled TRH at a concentration as high as 10 mM, but was markedly reduced by 10 mM proline and by inhibitor of amidase and aminopeptidase activity, bacitracin (2 mM). Permeability of the blood-brain barrier to [3H]TRH was studied in the adult rat, employing the intracarotid injection technique of Oldendorf25 in which [14C]butanol served as an 'internal standard'. Brain-uptake of 3H radioactivity corrected for residual vascular space indicated a low extraction from the blood of TRH during a 15 s period of exposure to the peptide. Self-inhibition of [3H]TRH uptake by unlabelled TRH (10 mM) could not be demonstrated, but l-proline (10 mM) and bacitracin (2 mM) strongly inhibited this uptake. It is concluded that similar mechanisms at the blood-CSF and blood-brain barriers tend to prevent TRH penetration into the brain; namely the absence of significant transport systems or binding at the barrier and peptide degradation by the barrier or by plasma enzymes. However, in the presence of bacitracin, which prevents deamidation and hydrolysis of TRH, there is still an arterio-venous loss of 3H radioactivity during a single capillary passage through the choroid plexus of the same order as that of d-[14C]mannitol. It is suggested that there may be a passage of some intact TRH by a non-specific pathway through the choroid plexus into the CSF. This passage from blood via the CSF followed by diffusion in the extracellular space of nervous structures adjacent to the ventricles may represent a route of entry for TRH into the brain. © 1985.

The permeability of the blood-cerebrospinal fluid (CSF) barrier to 3H-labelled thyrotropin-releasing hormone (TRH), was studied at the blood-tissue interface of the isolated perfused choroid plexus of the sheep, using a rapid (if< 30 s), single circulation paired-tracer dilution technique, in which d-[14C]mannitol serves as an extracellular marker. Arterio-venous loss of 14C radioactivity reflects the percentage of the d-mannitol dose that crosses the blood-CSF barrier using a non-specific pathway. This loss suggests that the choroidal epithelium is moderately leaky. Cellular uptake of TRH, estimated by directly comparing venous dilution profiles of [3H]TRH and d-[14C]mannitol was independent of this leakiness. The unidirectional transport of TRH could not be saturated with unlabelled TRH at a concentration as high as 10 mM, but was markedly reduced by 10 mM proline and by inhibitor of amidase and aminopeptidase activity, bacitracin (2 mM). Permeability of the blood-brain barrier to [3H]TRH was studied in the adult rat, employing the intracarotid injection technique of Oldendorf25 in which [14C]butanol served as an 'internal standard'. Brain-uptake of 3H radioactivity corrected for residual vascular space indicated a low extraction from the blood of TRH during a 15 s period of exposure to the peptide. Self-inhibition of [3H]TRH uptake by unlabelled TRH (10 mM) could not be demonstrated, but l-proline (10 mM) and bacitracin (2 mM) strongly inhibited this uptake. It is concluded that similar mechanisms at the blood-CSF and blood-brain barriers tend to prevent TRH penetration into the brain; namely the absence of significant transport systems or binding at the barrier and peptide degradation by the barrier or by plasma enzymes. However, in the presence of bacitracin, which prevents deamidation and hydrolysis of TRH, there is still an arterio-venous loss of 3H radioactivity during a single capillary passage through the choroid plexus of the same order as that of d-[14C]mannitol. It is suggested that there may be a passage of some intact TRH by a non-specific pathway through the choroid plexus into the CSF. This passage from blood via the CSF followed by diffusion in the extracellular space of nervous structures adjacent to the ventricles may represent a route of entry for TRH into the brain. © 1985.