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M J During

Publications and source records attributed to M J During.

82 records · Page 5Linked to original sources
PubMed1989

Controlled release of dopamine from a polymeric brain implant: in vivo characterization.

Intracerebral microdialysis was used to evaluate the long-term in vivo release of dopamine from ethylene-vinyl acetate (EVAc)-dopamine copolymer matrix discs for up to 65 days following striatal implantation. Dopamine release occurred through a single cavity present on one side of the disc, which was otherwise fully coated with an additional, impermeable layer of EVAc. At 20 days following implantation of the device, extracellular concentrations of dopamine within the striatum reached micromolar levels, over 200-fold greater than control values. Release of dopamine was shown to be stable and maintained for the 2-month duration of the experiment. Histological examination confirmed the biocompatible nature of the implant. There are potential applications of this technology to the treatment of Parkinson's disease and other neurological and psychiatric disorders.

Animals↗
PubMed1989

Controlled release of dopamine from a polymeric brain implant: in vitro characterization.

A biocompatible polymeric matrix system for the long-term controlled release of dopamine has been developed. Solid particles of this bioactive agent were encapsulated in ethylene-vinyl acetate copolymer (EVAc). Following immersion in an aqueous buffer solution, the release rate of dopamine from the polymer matrix was found to depend on the initial concentration of dopamine in the polymer. After coating the matrix devices with an additional impermeable layer of EVAc, constant rates of release were obtained by creating a cavity in this impermeable layer. The observed experiments are consistent with a diffusion-limited model of dopamine release; all the in vitro experimental results were therefore correlated by the effective diffusion coefficient of dopamine through the porous polymer network. These results are discussed in terms of potential design modifications to achieve desired release characteristics for a variety of neuroactive substances, including neurotransmitters or their precursors.

Brain↗
PubMed1989

Stimulation-induced release of coexistent transmitters in the prefrontal cortex: an in vivo microdialysis study of dopamine and neurotensin release.

Extracellular fluid levels of dopamine and neurotensin in the rat prefrontal cortex were measured using in vivo microdialysis. Electrical stimulation of the median forebrain bundle resulted in increased release of both dopamine and neurotensin from the prefrontal cortex. Thus, stimulation of neurons in which dopamine and neurotensin are colocalized can evoke the in vivo release of both substances.

Animals↗
PubMed1989

Dopamine release in rat striatum: physiological coupling to tyrosine supply.

Intracerebral microdialysis was used to monitor dopamine release in rat striatal extracellular fluid following the intraperitoneal administration of dopamine's precursor amino acid, L-tyrosine. Dopamine concentrations in dialysates increased transiently after tyrosine (50-100 mg/kg) administration. Pretreatment with haloperidol or the partial lesioning of nigrostriatal neurons enhanced the effect of tyrosine on dopamine release, and haloperidol also prolonged this effect. These data suggest that nigrostriatal dopaminergic neurons are responsive to changes in precursor availability under basal conditions, but that receptor-mediated feedback mechanisms limit the magnitude and duration of this effect.

Animals↗
PubMed1989

Effects of dopamine depletion on striatal neurotensin: biochemical and immunohistochemical studies.

Interactions between striatal dopamine (DA) and neurotensin (NT) have been suggested by anatomical, behavioral, and biochemical studies. Nigrostriatal DA neurons, in contrast to mesocorticolimbic DA neurons, do not appear to contain NT. Thus, distinct neuronal elements subserve interactions between DA and NT within the striatum. We have previously demonstrated that reserpine-induced depletion of striatal DA is accompanied by a dose- and time-dependent increase in striatal NT concentrations. In order to further characterize the effects of reserpine and to define the mechanism by which reserpine acts to increase striatal NT concentrations, we have used immunohistochemical and biochemical approaches. Immunohistochemical examination of rats pretreated with reserpine revealed marked increases in the density of NT-like immunoreactive (NT-li) perikarya and fibers, and the development of NT-li patches. Pretreatment with reserpine had no apparent effect on NT synthesis, as assessed by examination of cycloheximide-induced inhibition of protein synthesis. However, reserpine administration resulted in a significant decrease in the release of both DA and NT into the striatal extracellular fluid, as measured by in vivo microdialysis. These data suggest that the increase in striatal NT concentrations observed after reserpine treatment results from decreased release, rather than increased synthesis of the peptide.

Animals↗
PubMed1988

Phenylalanine administration influences dopamine release in the rat's corpus striatum.

We used intracerebral dialysis to monitor extracellular levels of dopamine and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. Levels of these compounds were determined after intraperitoneal administration of phenylalanine (200, 500 and 1000 mg/kg). A dose of 200 mg/kg phenylalanine increased basal dopamine release by 59%, peaking at 75 min. There was no change in basal dopamine release after the 500 mg dose, whereas the 1000 mg/kg dose significantly reduced (26%) dopamine release. No significant changes were observed in the concentrations of DOPAC and HVA with any of the treatments, indicating that changes in brain phenylalanine and tyrosine levels may selectively affect production of the dopamine molecules that are preferentially released into synapses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens.

Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

Animals↗
PubMed1988

Tyrosine: effects on catecholamine release.

Tyrosine administration elevates striatal levels of dopamine metabolites in animals given treatments that accelerate nigrostriatal firing, but not in untreated rats. We examined the possibility that the amino acid might actually enhance dopamine release in untreated animals, but that the technique of measuring striatal dopamine metabolism was too insensitive to demonstrate such an effect. Dopamine release was assessed directly, using brain microdialysis of striatal extracellular fluid. Tyrosine administration (50-200 mg/kg IP) did indeed cause a dose related increase in extracellular fluid dopamine levels with minor elevations in levels of DOPAC and HVA, its major metabolites, which were not dose-related. The rise in dopamine was short-lived, suggesting that receptor-mediated feedback mechanisms responded to the increased dopamine release by diminishing neuronal firing or sensitivity to tyrosine. These observations indicate that measurement of changes in striatal DOPAC and HVA, if negative, need not rule out increases in nigrostriatal dopamine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Adeno-associated virus vectors for gene therapy of neurodegenerative disorders.

Adeno-associated virus (AAV) shows significant potential as a gene delivery system. Although it is ubiquitous in its distribution, with approximately 85% of the adult population in the United States seropositive for the virus, it has never been associated with clinical disease. Not only is AAV non-pathogenic, but it can infect with high efficiency both dividing and terminally-differentiated cells, moreover the wild-type virus integrates into a specific chromosomal site. It also has a broad host range and the virus is extremely resistant to environmental extremes. These characteristics make it particularly attractive as a gene delivery vehicle. As the enthusiasm driving the proliferation of clinical gene transfer protocols has dampened recently due to the lack of clinical success often reflecting immunogenicity and inefficiency of the gene transfer methods used in these trials, AAV with minimal (if any) toxicity and high efficiency in a wide range of cells and tissues, may become the vector-of-choice for many applications. There have been a number of comprehensive recent reviews of AAV biology and this article specifically discusses recent advances in the use of AAV vectors with particular emphasis on AAV vector-mediated in vivo gene transfer in the mammalian central nervous system.

Animals↗