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Biomedical subjects

J J Warsh

Publications and source records attributed to J J Warsh.

At least 73 records · Page 4Linked to original sources
PubMed1988

In vitro and ex vivo effects of antidepressants on rat brain membrane-bound phosphatidylinositol synthetase activity.

The in vitro and ex vivo effects of antidepressant drugs on membrane-bound phosphatidylinositol (PI) synthetase and PI: myo-inositol exchange enzyme activities were examined. In rat brain subcellular fractions, PI synthetase occurred exclusively in the microsomes. In comparison, the activity of CDP-diglyceride independent PI:myo-inositol exchange enzyme was low (3%). Of the various CDP-diglycerides tested for the activation of PI synthetase, CDP-dipalmitin was the most active. Addition of 1 mM of desipramine, amitriptyline, imipramine, iprindole, clomipramine and mianserin in vitro significantly inhibited (30-60%) PI synthetase activity, whereas the same concentration of zimelidine and fluoxetine had no effect. At low liponucleotide concentrations, PI synthetase activity was significantly enhanced by imipramine (1 mM), whereas the enzyme activity was inhibited at higher liponucleotide concentrations (greater than 0.3 mM). In contrast, imipramine had no effect on the PI: myo-inositol exchange enzyme activity. No significant alteration in the PI synthetase activity was found following either acute (2 h) or chronic (21 d) treatment of rats with imipramine. The above results indicate that the de novo synthesis of PI is inhibited in vitro but not ex vivo by some antidepressant drugs. However, in view of the high concentration of the drugs required, the pharmacological significance of this inhibitory action with respect to their therapeutic effects is doubtful.

Animals↗
PubMed1988

Assessment of rat brain alpha 1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment.

Chronic (21 days) treatment of rats with imipramine (10 mg/kg) did not change the density or affinity of alpha 1-adrenoceptors as measured by the specific binding of [3H]prazosin in rat cortical membranes, but produced the expected significant decrease in the density of beta-adrenoceptors labeled by [125I]iodocyanopindolol. The functional status of brain alpha 1-adrenoceptors was also assessed by measuring the noradrenaline (NA)-induced accumulation of [3H]inositol 1-phosphate (IP1) in brain slices from these animals. No apparent change was observed in the concentration-response relationship between NA and [3H]IP1 accumulation in rat cerebral cortex after chronic treatment with imipramine. At concentrations higher than 1 microM in vitro, imipramine and its metabolite, desipramine, produced a concentration-dependent decrease in the [3H]IP1 accumulation elicited by NA. This inhibitory effect is likely mediated by direct blockade of alpha 1-adrenoceptors by these drugs. As the endogenous drug concentration would not reach 1 microM in our preparation, the lack of changes in alpha 1-adrenoceptor response following chronic imipramine treatment are not likely attributable to residual imipramine or desipramine retained in the tissues. In conclusion, the above findings do not support previous suggestions that brain alpha 1-adrenoceptors are upregulated following chronic imipramine administration.

Animals↗
PubMed1988

Pharmacologic characterization of cirazoline-activated inositol phospholipid hydrolysis in rat brain cortical slices.

Interaction of cirazoline, an imidazoline derivative, with alpha 1-adrenoceptor coupled inositol phospholipid hydrolysis was characterized in rat brain cortical slices. Norepinephrine, a full alpha 1-agonist, and phenylephrine, a partial alpha 1-agonist, on inositol phospholipid hydrolysis were included for comparison. Norepinephrine produced a fourfold stimulation of inositol phospholipid hydrolysis, whereas cirazoline and phenylephrine caused only submaximal responses (40-60%) when compared with norepinephrine. The stimulation of inositol phospholipid hydrolysis by cirazoline was completely blocked by the alpha 1-adrenoceptor antagonist prazosin, but not by selective alpha 2- or beta-adrenoceptor antagonists. Furthermore, the norepinephrine dose-response curve was shifted to the right in the presence of cirazoline, without affecting the maximal response. These results suggest that cirazoline behaves as a partial agonist at brain alpha 1-adrenoceptors linked to inositol phospholipid hydrolysis.

Animals↗
PubMed1988

A trial of isocarboxazid in the treatment of bulimia nervosa.

Eighteen women completed a double-blind, placebo-controlled crossover study designed to investigate the effects of isocarboxazid in the treatment of bulimia nervosa. There was a significant reduction in binge eating and vomiting during isocarboxazid treatment. Response was not influenced by either the presence or absence of current major depression or personality disorder. There were no serious adverse effects from this monoamine oxidase inhibitor therapy, although over 50% of patients elected to discontinue isocarboxazid 1 year after the study.

Adult↗
PubMed1986

Further characterization of brain 3,4-dihydroxyphenylethyleneglycol (DHPG) formation: dependence on noradrenergic activity and site of formation.

The dependence of brain and plasma 3,4-dihydroxyphenylethyleneglycol (DHPG) formation upon CNS noradrenergic neutronal activity was evaluated following manipulations that are known to alter the firing rate of the locus coeruleus (LC) neurons and as a consequence, noradrenaline (NA) release and turnover. In addition, the relative degree of intraneuronal formation of brain DHPG was assessed by studying the metabolism of released NA during uptake inhibition. Electrical stimulation of the LC for 20 min induced an increase in rat cortical (40-42%), hypothalamic (22-29%) and plasma (68-79%) total DHPG and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels. Two hours following administration of the alpha-2 adrenoceptor antagonist yohimbine (10 mg/kg, i.p.), rat brain cortical conjugated DHPG and MHPG as well as free MHPG concentrations were increased whereas cortical free DHPG levels remained unchanged. The same treatment also increased plasma total DHPG and MHPG levels. In mice given the NA uptake inhibitor desipramine (10 mg/kg, i.p.) 2 h prior to sacrifice, brain free DHPG and MHPG concentrations were significantly reduced by 30 and 40%, respectively, whereas yohimbine (1-20 mg/kg, i.p.) induced a dose-dependent increase in brain DHPG (60-80%) and MHPG (60-220%) concentrations. Pretreatment with desipramine (10 mg/kg, i.p.) 30 min prior to yohimbine reduced, in rat, or abolished, in mice, the yohimbine-induced elevation of brain DHPG levels. In contrast, desipramine augmented the effect of yohimbine on brain MHPG levels resulting in a shift to the left of the dose response curves. These findings indicate that brain and plasma DHPG levels are sensitive to changes in brain noradrenergic neuronal impulse flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Unchanged norepinephrine turnover and concentrations in amygdala-kindled rat brain regions 2 months postseizure.

Norepinephrine turnover and concentrations were examined in eight brain regions of amygdala-kindled and yoked control rats. The subjects were killed 2 months after the kindled subjects had exhibited their sixth "stage 4-5" generalized seizure. No significant differences were found in norepinephrine turnover or concentrations between kindled and yoked control rats in any of the brain regions examined. Dopamine turnover and concentrations in brain regions were also unchanged in kindled rats compared with their yoked controls. The data suggest that amygdala kindling does not produce any long-lasting alterations in brain regional catecholamine turnover or concentrations.

Amygdala↗
PubMed1985

Neurotransmitter metabolites and endocrine responses in depression.

Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 less than p less than .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.

Adult↗
PubMed1985

Elevated 3,4-dihydroxyphenylethyleneglycol (DHPG) excretion in dexamethasone resistant depressed patients.

Urinary and plasma DHPG and MHPG were estimated in patients with MADD and showing DST non-suppression as compared to those with normal suppression. Day and night 12h urine collections and morning plasma samples were analyzed by GC-MS for total MHPG and DHPG and free MHPG levels. Urinary DHPG excretion was significantly elevated in DST non-suppressors compared to suppressors, but no differences were found in urinary MHPG or plasma glycol levels. Elevated DHPG excretion in DST non-suppressors suggests that increased peripheral sympathetic NE activity occurs in association with dexamethasone resistance in MADD.

Adult↗
PubMed1985

Studies on the utility of urinary 3,4-dihydroxyphenylethylene-glycol (DHPG) measurement.

The utility of urinary DHPG measurement as an index of NE function was evaluated in an animal model by determining its excretion following pharmacological manipulations that are known to alter noradrenergic activity. Acute desipramine (DMI) administration (10 mg/kg, i.p., b.i.d.) significantly reduced urinary DHPG (-26%) but not MHPG (-18%) excretion. Acute yohimbine administration (5 mg/kg, i.p., b.i.d.) significantly increased urinary DHPG and MHPG levels to a similar extent (+46%). These findings suggest that urinary DHPG levels also provide a sensitive indicator reflecting changes in NE neuronal activity. Further, DHPG may be a better measure of NE metabolism than MHPG to assess the efficiency of the NE neuronal uptake system.

Animals↗
PubMed1984

Seasonal variation in platelet 3H-imipramine binding: comparable values in control and depressed populations.

Recent findings of reduced 3H-imipramine binding in platelets of depressed patients compared to healthy controls have been proposed as a biological marker of depression. However, these studies failed to consider the possible occurrence of seasonal variation in the binding characteristics. Our results show a highly significant seasonal variation in platelet 3H-imipramine binding which occurs in both normal and depressed populations. Furthermore, when annual rhythms are taken into account, there is no difference in the binding parameters in the two populations.

Adult↗
PubMed1984

The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma.

Plasma levels of desipramine (DMI) and the unconjugated form of its principal metabolite 2-hydroxydesipramine (OH-D) were measured under steady-state conditions in nine depressed inpatients during treatment with 75 mg DMI every 12 hr and after at least 1 wk of an increased dose of DMI (after steady state). When DMI dosage was raised after an initial steady state had been reached, the rise in plasma DMI level was proportionately greater than the increase in dosage, suggesting saturation of DMI elimination pathways. Levels of OH-D rose in proportion to dose, suggesting saturation of DMI elimination by 2-hydroxylation could not explain DMI plasma level changes. In contrast, there were no dose-dependent effects on the disposition of amitriptyline or its metabolite nortriptyline in subjects receiving the same amitriptyline dose.

Administration, Oral↗
PubMed1984

Formation and clearance of norepinephrine glycol metabolites in mouse brain.

To determine the degree of conversion of 3,4-dihydroxyphenylethyleneglycol (DHPG) to 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the amount of DHPG eliminated unchanged from the brain, we have examined the kinetics of formation and disappearance of mouse brain MHPG and DHPG following clorgyline (10 mg/kg, i.p.) and/or tropolone (75 mg/kg, i.p.) treatment. During the first 10 min after tropolone, brain DHPG levels accumulated linearly at a rate of 1,300 pmol/g/h, whereas MHPG disappeared exponentially at a rate of 411 pmol/g/h. Following clorgyline administration, brain DHPG declined exponentially at a rate of 1,240 pmol/g/h. In contrast, the elimination of MHPG became a first-order process only when catechol-O-methyltransferase (COMT) was also inhibited in addition to monoamine oxidase. Thus, combined clorgyline and tropolone treatment resulted in an exponential decline of MHPG levels at a rate of 524 pmol/g/h, whereas DHPG levels were slightly but significantly elevated compared to control values. When the animals were treated with pargyline (75 mg/kg, i.p.) in combination with clorgyline and tropolone, brain DHPG and MHPG disappeared at rates of 40 and 660 pmol/g/h, respectively. The above observations suggest that mouse brain DHPG is cleared primarily through O-methylation with minimal direct elimination from brain. Assuming the disposition and clearance of norepinephrine metabolites are similar in mouse and human brain, peripherally measured DHPG in humans is likely derived principally from extracerebral sources and reflects peripheral sympathetic function.

Animals↗
PubMed1984

Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.

We have identified a generalized deficiency of monoamine neurotransmitters in a patient with a defect in biopterin synthesis. Neurotransmitter precursors (L-3,4-dihydroxyphenylalanine [L-dopa]; 5-hydroxytryptophan [5-HTP] and a tetrahydropterin [6-methyltetrahydropterin (6MPH4)] were investigated for their ability to normalize monoamine neurotransmitter metabolism. Before treatment, the concentrations of dopamine (DA), norepinephrine, epinephrine, and six monoamine metabolites were very low or undetectable in plasma, cerebrospinal fluid, or urine. L-Dopa and 5-HTP replacement was begun at age 7 mo. This therapy generally corrected the deficiency of monoamines and their metabolites, and improved neurological development until the age of 25 mo. Despite these benefits, the intermittent administration of L-dopa could not produce a stable improvement of acute neurological function or DA metabolism. In the 3 h after L-dopa administration, plasma DA and the motor activity and alertness of the patient rose and fell in parallel. Doses of L-dopa that were clinically optimal produced normal plasma levels of norepinephrine and epinephrine, but excessive concentrations of DA and its metabolites. Furthermore, the clinical and biochemical effects of L-dopa were inhibited by phenylalanine and 5-HTP, respectively, demonstrating that these amino acids have antagonistic pharmacological effects. Physiological correction of the monoamine deficit and the hyperphenylalaninemia of this disorder was attempted at age 35 mo using high doses (8-38 mg/kg per d) of 6MPH4. 6MPH4, a synthetic analogue of tetrahydrobiopterin, controlled the hyperphenylalaninemia. Significant concentrations of 6MPH4 were obtained in the cerebrospinal fluid; no neurological improvement or stimulation of monoamine synthesis in the central nervous system was detected. These findings indicate the complexity in replacement therapy with L-dopa and 5-HTP, but suggest that this treatment may be partially effective in biopterin-deficient patients who are unresponsive to high doses of tetrahydropterins.

5-Hydroxytryptophan↗
PubMed1983

Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction.

Amitriptyline has clinically important interactions with ethanol. Five healthy volunteers received 25 mg of amitriptyline orally, preceded by one hour and followed for eight hours by oral ethanol (or juice), dosed to achieve and maintain blood ethanol concentrations of 800 mg/l. In the presence of ethanol, amitriptyline free plasma concentrations were increased by a logarithmic mean of 204%, 186% and 127% at 1.5, 2, and 2.5 h, respectively, and amitriptyline free AUC0-8h was increased by 48% +/- 13% (means +/- SEM) (t = 5.21, p less than 0.01). Nortriptyline total AUC0-8h was increased by 26.6% +/- 12% (means +/- SEM) (t = 2.21, p less than 0.09). At the time of peak amitriptyline plasma concentrations, mean postural sway was increased over baseline by 92% with, and 2% without ethanol; likewise, mean short term memory (word recall) was decreased over baseline by 71% with, and 37% without ethanol. Ethanol increases free amitriptyline plasma concentrations most dramatically during the period of drug absorption; this is due to a decrease in amitriptyline hepatic clearance, resulting in decreased first-pass extraction. Together with the pharmacodynamic interaction, the kinetic changes provide a rationale for the toxicity of this combination and its deleterious effects on psychomotor skills.

Adult↗
PubMed1983

Metabolic fate of 3,4-dihydroxyphenylethyleneglycol (DHPG) in mouse brain.

Mouse brain DHPG and MHPG turnover rates were estimated by determining their initial rates of disappearance or accumulation following MAO and/or COMT inhibition. Similar turnover estimates of brain DHPG were obtained following MAO or COMT inhibition, which were comparable to the estimated NE turnover obtained from its initial accumulation following MAO plus COMT inhibition. It was estimated that negligible amounts of DHPG were eliminated directly from brain, the majority being cleared through O-methylation. These findings indicate that mouse brain NE is primarily cleared through DHPG formation followed by O-methylation, and also suggest that brain DHPG turnover is more indicative of NE turnover.

Animals↗
PubMed1983

Obesity and precursor availability affect urinary catecholamine metabolite production in women.

The effect of obesity and tyrosine (tyr) supplements on catecholamine metabolism in 12 normal weight and nine obese adult women was studied. Protein intake was maintained at 1.4 g protein/kg fat-free mass daily for 4 days with tyr added (0.26 g/kg fat-free mass) to the liquid diet on the last 2 days. In the 12 normal subjects, but not the obese, base-line urinary excretion of the norepinephrine metabolite, 3-methoxy-4-hydroxy phenylethyleneglycol was related to body fat whereas excretion of the norepinephrine metabolite vanilmandelic acid was related to fat-free mass and to total energy intake. Normal subjects responded to tyr with elevations in plasma tyr/neutral amino acid, plasma 3-methoxy-4-hydroxy phenylethyleneglycol, urinary vanilmandelic acid, and homovanillic acid, a dopamine metabolite, but not the norepinephrine metabolite, dihydroxy phenylethyleneglycol. The obese showed no increase in plasma or urinary 3-methoxy-4-hydroxy phenylethyleneglycol during tyr supplementation, although vanilmandelic acid and homovanillic acid increased. We conclude that urinary catecholamine metabolite production is related to body composition and to tyr intake in normal weight women. These relationships however, are altered in the obese, suggesting an association of obesity with abnormal catecholamine metabolism.

Adult↗
PubMed1983

Rat brain norepinephrine metabolism: substantial clearance through 3,4-dihydroxyphenylethyleneglycol formation.

To assess whether the metabolic clearance of rat brain norepinephrine (NE) through 3,4-dihydroxyphenylethyleneglycol (DHPG) formation is quantitatively comparable or greater than through 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) production, we studied the accumulation rates of conjugated DHPG and MHPG following probenecid administration in whole brain as well as in several brain regions. Administration of increasing doses of probenecid (100-500 mg/kg, i.p.) 1.5 h before sacrifice produced a dose-dependent increase of conjugated DHPG and MHPG levels. The maximum increment of these conjugated metabolites occurred at a dose of 300 mg/kg or higher. During the first hour following probenecid administration (300 mg/kg, i.p.), rat brain conjugated DHPG and MHPG levels accumulated linearly at a rate of 646 and 319 pmol/g/h, respectively. With the probenecid technique, the estimated appearance rates of conjugated DHPG significantly exceeded those of conjugated MHPG in hypothalamus, midbrain, brainstem, hippocampus, and cerebral cortex. These results clearly indicate that under resting conditions, formation and efflux of conjugated DHPG is the major route of metabolic clearance of rat brain NE.

Animals↗