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Biomedical subjects

K W Perry

Publications and source records attributed to K W Perry.

At least 73 records · Page 4Linked to original sources
PubMed1984

Tropolone antagonism of the L-dopa-induced elevation of S-adenosylhomocysteine: S-adenosylmethionine ratio but not depletion of adrenaline in rat hypothalamus.

Tropolone, an inhibitor of catechol O-methyl transferase, largely prevented the increase in SAH : SAMe ratio in rat hypothalamus following L-dopa injection. Tropolone did not prevent but instead enhanced the decrease produced by L-dopa of adrenaline concentration in rat hypothalamus. The results imply that the decrease in hypothalamic adrenaline concentration following L-dopa injection was not caused by the increase in SAH : SAMe ratio.

Animals↗
PubMed1983

Effect of a stereospecific D2-dopamine agonist on acetylcholine concentration in corpus striatum of rat brain.

The enantiomers of LY141865, trans(+/-)-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo[3,4-g]qu inoline, were compared as dopamine D2 agonists by determining their abilities to elevate acetylcholine concentrations in rat corpus striatum. The levorotatory isomer, LY156258, increased striatal acetylcholine concentration at doses of 0.1-1 mg/kg i.p., whereas the dextrorotatory isomer had no effect even at doses as high as 30 mg/kg. The levorotatory isomer also decreased striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, but did not significantly alter dopamine or 5-hydroxyindoleacetic acid concentration. The dextrorotatory isomer had no effect on any of these substances alone and did not alter the effects of the levorotatory isomer. The elevation of striatal acetylcholine levels by LY156258 was mimicked by pergolide, a dopamine agonist, and was totally prevented by pretreatment with haloperidol, a dopamine antagonist. The elevation of striatal acetylcholine concentration by LY157258 was maximal at 0.5 hour and declined thereafter, following a time course similar to that of pergolide. Neither LY141865 nor LY156258 shared with peroglide and dopamine the ability to activate striatal adenylate cyclase in vitro, an effect mediated by D1 receptors. LY141865 and LY156258 (but not the dextrorotatory isomer) inhibited the binding of tritiated apomorphine and spiperone to striatal membrane receptors, but were not as potent as pergolide, they also had less effect, or no effect, on the binding of other tritiated ligands (dopamine, WB4101, clonidine, dihydroalprenolol, pyrilamine or quinuclidinyl benzilate) to their membrane receptors. These results indicate that LY156258 stereospecifically activates dopamine D2 receptors and the studies are the first evidence of sterospecificity of dopamine receptors mediating an increase in striatal acetylcholine concentration.

Acetylcholine↗
PubMed1983

Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine.

Repeated administration of large doses of d-methamphetamine produce long-lasting depletion of brain dopamine (DA) and serotonin (5-HT), as well as persistent decreases in the activity of their respective biosynthetic enzymes, tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH). The present results indicate that the inhibitor of 5-HT uptake fluoxetine, prevented the long-term depletion of 5-HT produced by large doses of methamphetamine (15 mg/kg X 5, 6 hr apart) in the neostriatum and hippocampus, while simultaneously augmenting the depletion of DA produced by this drug in the neostriatum. Fluoxetine also enhanced the prolonged neostriatal depletion of DA produced by a comparable regimen of d-amphetamine. In these doses (15 mg/kg X 5,6 hr apart), d-amphetamine did not produce long-lasting depletion of 5-HT in either the neostriatum or hippocampus. Larger depletion of DA after the amphetamines had been administered in the fluoxetine pretreated animal were associated with a transient increase in the brain levels of methamphetamine and amphetamine. This suggests that fluoxetine may inhibit the metabolism of amphetamines.

Animals↗
PubMed1982

Dopamine accumulation after dopamine beta-hydroxylase inhibition in rat heart as an index of norepinephrine turnover.

Dopamine concentration in rat heart is normally very low, only a few percent of the concentration of norepinephrine. After treatment of rats with a dopamine beta-hydroxylase inhibitor, 1-cyclohexyl-2-mercapto-imidazole (CHMI), there was a rapid increase in dopamine concentration even before norepinephrine concentration had decreased perceptibility. This accumulation of dopamine was readily measured by liquid chromatography with electrochemical detection. Since the percentage change in dopamine was much greater than the percentage change in norepinephrine, especially at early times, measurement of dopamine accumulation rather than norepinephrine decline was considered as a useful measure of norepinephrine turnover. Drugs that act on noradrenergic receptors and are known to alter norepinephrine turnover were found to alter the rate of dopamine accumulation. Clonidine and guanabenz decreased dopamine accumulation after CHMI, whereas piperoxan (but not prazosin) increased dopamine accumulation after CHMI. Pergolide, a dopamine agonist whose lowering of blood pressure and cardiac rate has been suggested to be due to suppression of neurogenic release or norepinephrine, also decreased dopamine accumulation after CHMI. The results suggest that measuring dopamine accumulation may have advantages over measuring norepinephrine disappearance after dopamine beta-hydroxylase inhibition as an indicator of norepinephrine turnover in heart.

Animals↗
PubMed1982

Depletion of epinephrine in rat hypothalamus by a dopamine agonist, pergolide.

The i.p. injection of pergolide mesylate, a dopamine agonist, at doses of 0.3-0.6 mg/kg led to a decrease in epinephrine concentration in rat hypothalamus. After a 0.6 mg/kg dose of pergolide mesylate, epinephrine concentration in hypothalamus decreased within 2 hr, reached a minimum concentration at about 8 hrs, and then returned toward control values. Norepinephrine N-methyltransferase activity was not decreased after pergolide injection in vivo nor was it inhibited by pergolide added in vitro at concentrations as high as 10(-3) M. Higher i.p. doses of less potent dopamine agonists, apomorphine (10 mg/kg) and lergotrile (3 mg/kg), also decreased epinephrine concentration in hypothalamus. The pergolide-induced decrease in hypothalamic epinephrine concentration was prevented by pretreatment with haloperidol or spiperone, antagonists of dopamine receptors. Activation of dopamine receptors appears to result in a decrease in epinephrine concentration in rat brain, possibly due to enhanced release of epinephrine.

Animals↗
PubMed1982

Dopamine deficiency in the weaver mutant mouse.

The dopamine system in weaver mutant mice (B6CBA-Aw-J/A background) was studied. Dopamine was 27% lower in the olfactory tubercle, 77% lower in the frontal cortex, and 75% lower in the striatum of 6-month-old weaver mice compared to control mice of the same age. Norepinephrine and serotonin were not lower in these brain areas. Tyrosine hydroxylase activity in the striatum was measured with a radiometric assay and was 70% lower in weaver mice. Examination of mice from 11 to 180 days of age revealed that the dopamine system failed to develop in weaver mice. Motor activity in individual animals was assessed using circular photocell activity cages with minimal illumination. Apomorphine and pergolide, direct dopamine agonists, increased activity more in weaver mice than in normal littermates. Amphetamine, which releases endogenous stores of dopamine, was less active in mutant mice. These findings provide suggestive evidence that postsynaptic dopamine receptors in weaver mutants might have become supersensitive as a result of lower levels of dopamine in motor areas of the brain. Anatomical evidence of dopamine system abnormalities was found in weaver mice by examination of serial sections cut from the midbrain of mutant and normal mice. The pars compacta of the substantia nigra in weaver mice appeared hypocellular when compared with the corresponding sections from controls. Fewer large neurons were seen in the affected animals. This study illustrates that weaver mice have specific deficiencies in the dopamine system. The weaver mouse might provide a way of examining the biochemical and behavioral effects of long term dopamine deficiency and a way to examine drugs to treat dopamine-deficient states in vivo.

Animals↗
PubMed1982

Effects of L-dopa on epinephrine concentration in rat brain: possible role of inhibition of norepinephrine N-methyltransferase by S-adenosylhomocysteine.

L-Dopa injected at 200 mg/kg i.p. into rats caused a slight reduction in hypothalamic concentration of epinephrine and completely prevented the accumulation of epinephrine after monoamine oxidase inhibition. The lowering of epinephrine concentration was greater with L-dopa than with D-dopa, was dose-related over a dosage range of 50 to 200 mg/kg of L-dopa and was not prevented by a dopamine receptor antagonist. Hypothalamic norepinephrine N-methyltransferase activity measured in vitro was not altered in rats treated with L-dopa. L-Dopa injection decreased S-adenosylmethionine (SAMe) concentration and increased S-adenosylhomocysteine (SAH) concentration in hypothalamus, probably a result of extensive O-methylation of L-dopa and its metabolites. The decrease in SAMe and epinephrine concentration and the increase in SAH concentration occurred at lower doses of L-dopa in carbidopa-pretreated rats than in control rats. Norepinephrine N-Methyl-transferase activity assayed in vitro was markedly inhibited by SAH; the inhibition was competitive with SAMe as the variable substrate and the Ki for SAH was 1.9 x 10(-5) M. Increasing the SAH/SAMe ratio in in vitro experiments sharply reduced norepinephrine N-methyltransferase activity. The apparent inhibition of hypothalamic epinephrine synthesis in vivo after L-dopa injection is suggested to be a consequence of the increased SAH/SAMe ratio.

Animals↗
PubMed1981

Ionophore (A23187)-induced efflux of [3H]norepinephrine and endogenous norepinephrine in the rat vas deferens.

The calcium ionophore, A23187, produced a concentration-dependent increase in the release of norepinephrine from nerves in the rat vas deferens. Maximum response to A23187 (10(-6) - 10(-5) M) was delayed in onset, occurring 60-80 min after initiation of continuous superfusion with A23187. In fact. after tissue exposure to A23187 (10(-5) M) for only 5 min with subsequent superfusion in A23187-free buffer, a significant but delayed increase in norepinephrine efflux occurred. The A23187-induced increase in efflux of norepinephrine was not altered when neuronal sodium conductance was blocked with tetrodotoxin (3.1 X 10(-7) M) or when Na+, K+ -stimulated ATPase was blocked with ouabain (10(-4) M). Release of norepinephrine by A23187 was calcium-dependent since A23187-induced efflux of norepinephrine was diminished (approximately 50%), although not abolished, in calcium-free buffer. Thus, one component of A23187 action was calcium independent. A23187 caused an increased efflux of both norepinephrine formed endogenously and [3H]norepinephrine taken up into neuronal stores. However, the effects of A23187, both on rate and maximum amount of release were greater for [3H]norepinephrine than for endogenous norepinephrine. The present studies demonstrate that neurotransmitter efflux can be induced by carboxylic ionophores in a calcium-dependent process, and this approach may prove useful in studies evaluating factors that modulate neurotransmitter release processes.

Animals↗
PubMed1981

Comparative effects of amantadine and amfonelic acid on dopamine metabolism in rat brain.

Amantadine (50 and 100 mg/kg IP) did not change basal levels of DOPAC (3,4-dihydroxyphenylacetic acid) or HVA (homovanillic acid) in rat brain and did not alter the increase in DOPAC levels resulting from dopamine receptor blockade by spiperone. The increase in HVA levels produced by spiperone was significantly, but only slightly, enhanced by amantadine at these doses. In contrast, amfonelic acid at a dose of 5 mg/kg increased DOPAC and HVA levels and enhanced several-fold the spiperone-induced elevation of DOPAC and HVA levels. Amfonelic acid at at 2.5 mg/kg dose enhanced the turnover of dopamine (measured by the decline in dopamine concentration after inhibition of tyrosine hydroxylation with alpha-methylytyrosine) in spiperone-treated rats, whereas amantadine (100 mg/kg) had a smaller and not statistically significant effect. Neither compound affected significantly dopamine levels in a alpha-methyltyrosine-treated rats not given spiperone. Although amantadine has been observed by earlier workers to enhance the stimulated release of dopamine, it does not appear to act in a manner similar too amfonelic acid.

3,4-Dihydroxyphenylacetic Acid↗