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A J Friedhoff

Publications and source records attributed to A J Friedhoff.

At least 37 records · Page 2Linked to original sources
PubMed1992

Site-directed mutagenesis of tyrosine hydroxylase. Role of serine 40 in catalysis.

We have investigated the role of serine 40 (Ser-40) in tyrosine hydroxylase (TH) catalysis of basal and activated enzymes by protein kinase A (PKA)-mediated phosphorylation. Wild type and mutant TH were transiently and stably expressed in AtT-20 cells, and the enzymatic activities of the recombinant enzymes were analyzed. The specific enzymatic activity of transiently expressed TH mutants Ser-40-->leucine or-->tyrosine (Leu-40m or Tyr-40m) was higher than that of the wild type enzyme or of other mutants in which Ser-8, -19, and -31 were replaced by leucine. The kinetic studies carried out with the stably expressed TH show that the Km for the cofactor 6-methyltetrahydropterine is lower and the Ki for dopamine is higher when the enzymatic hydroxylation is catalyzed by the Leu-40m or Tyr-40m than by the wild type enzyme. The kinetic parameters and the pH profile of the enzymatic hydroxylation catalyzed by the Leu-40m or Tyr-40m are similar to the enzyme activated by PKA-mediated phosphorylation. We suggest that Ser-40 in TH exerts an inhibitory influence on the enzymatic activity, and its replacement with another amino acid by site-directed mutagenesis or its modification by phosphorylation leads to a change in conformation with an increased enzymatic activity. The importance of Ser-40 in the activation of TH by PKA-mediated phosphorylation was investigated by comparing the activation of the wild type enzyme with that of Leu-40m or Tyr-40m. The findings that the enzymatic activity is increased by PKA-mediated phosphorylation of the wild type enzyme, but not of the Leu-40m or Tyr-40m, demonstrate that phosphorylation at Ser-40 is essential for activation of TH by PKA. The findings that addition of ATP plus cAMP to homogenates from transfected AtT-20 cells stimulates the recombinant wild type TH activity indicate that these cells contain endogenous cAMP-dependent protein kinase.

Amino Acid Sequence↗
PubMed1992

Tonic inhibition of striatal dopamine transmission: effects of benzodiazepine and GABAA receptor antagonists on extracellular dopamine levels.

At present, it is unclear whether ligands which bind at the benzodiazepine/GABA receptor complex play a tonic modulatory role with regard to striatal dopamine (DA) transmission. The present study was designed to examine the effects of Ro15-1788, a benzodiazepine (BZ) receptor antagonist, and SR 95531, a GABAA receptor antagonist, on striatal extracellular DA (DA[e]) concentrations in anesthetized and awake rats using the technique of in vivo microdialysis. Local administration of Ro15-1788 resulted in a dose-dependent increase in DA[e] in both anesthetized and awake animals. The Ro15-1788-induced increase in DA[e] was blocked by coadministration of the BZ agonist diazepam, as well as GABA. Local administration of SR 95531 also resulted in a dose-dependent alteration in striatal DA levels in both anesthetized and awake animals. The SR 95531-induced increase in DA was blocked by coadministration of GABA. The results suggest that GABA may play a tonic inhibitory role with regard to striatal DA transmission.

Animals↗
PubMed1991

Receptor reserve for D2 dopaminergic inhibition of prolactin release in vivo and in vitro.

The full dopamine agonist R-(-)-N-n-propylnorapomorphine (NPA) completely suppressed (ED50 0.12 micrograms/kg) serum prolactin (PRL) levels elevated by pretreatment with gamma-butyrolactone (750 mg/kg). Pretreatment with the receptor-inactivating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 and 2 x 6 mg/kg) progressively shifted the dose-response curve for NPA to the right, but PRL secretion was still maximally inhibited. Receptor inactivation elicited smaller (2-fold) dextral shifts in the ED50 for the partial agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine. These results are consistent with the presence of a sizable receptor reserve at the D2 receptor regulating PRL release in the anterior pituitary. Analogous results were obtained in vitro utilizing primary cultures of anterior pituitary cells. NPA potently inhibited basal PRL release in culture (ED50 0.06 nM, maximal inhibition 83%). Receptor alkylation with phenoxybenzamine (1 microM, 1 hr) did not affect basal PRL release but right-shifted the ED50 for NPA more than 6-fold and attenuated maximal inhibition (to 68%); both effects were significant (P less than .01). The extracellular accumulation of cyclic AMP (cAMP) stimulated by a combination of forskolin (1 microM) and 3-isobutyl-1-methyl xanthine (100 microM) required higher concentrations of NPA (ED50 0.36 nM), and the maximal effect was much smaller (46%). Phenoxybenzamine treatment did not alter either basal or forskolin-stimulated cAMP accumulation, but it reduced the maximal inhibitory response to NPA (to 13%) without shifting the ED50. Plots of receptor occupancy vs. response demonstrated a 60% receptor reserve for NPA inhibition of PRL release, but none for inhibition of cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1990

Interleukin-1 stimulates the beta-amyloid precursor protein promoter.

1. Amyloid plaques found in the brains of Alzheimer's diseased patients are composed of the 42 amino acid beta-amyloid peptide (BAP) which is processed out of the larger amyloid precursor protein (APP). 2. To study the regulation of the APP gene expression, we have isolated the promoter region of this angle of this single-copy gene and produced a reporter gene system to determine if the promoter is responsive to agents that may cause the overproduction of APP leading to the abnormal accumulation of plaques in AD. 3. The promoter contains sequences homologous to heat shock elements, AP-1 binding sites, and phorbol ester-inducible sequences as well as GG-rich regions found in other constitutively expressed genes. 4. We show here that this promoter is inducible in cultured cells by interleukin-1 (IL-1) in a transient assay system and that the HSE and AP-1 binding site are required for this inducibility. 5. This induction of transcription from the APP promoter implies that this gene is responsive to tropic and/or trophic agents which may be present in the diseased brain.

Alzheimer Disease↗
PubMed1990

The effect of hyperthyroidism on opiate receptor binding and pain sensitivity.

This study was conducted to determine the effect of thyroid hormone on opiate receptor ligand-binding and pain sensitivity. Specific opiate receptor-binding was performed on brain homogenates of Swiss-Webster mice. There was a significant increase in 3H-naloxone-binding in thyroxine-fed subjects (hyperthyroid). Scatchard analysis revealed that the number of opiate receptors was increased in hyperthyroid mice (Bmax = 0.238 nM for hyperthyroid samples vs. 0.174 nM for controls). Binding affinity was unaffected (Kd = 1.54 nM for hyperthyroid and 1.58 nM for control samples). When mice were subjected to hotplate stimulation, the hyperthyroid mice were noted to be more sensitive as judged by pain aversion response latencies which were half that of control animals. After morphine administration, the hyperthyroid animals demonstrated a shorter duration of analgesia. These findings demonstrate that thyroxine increases opiate receptor number and native pain sensitivity but decreases the duration of analgesia from morphine.

Animals↗
PubMed1990

Antihypertensive therapy and quality of life: a comparison of atenolol, captopril, enalapril and propranolol.

This randomized, double-blind parallel study compared the effects of atenolol, captopril, enalapril and propranolol in 360 men with mild-to-moderate essential hypertension. Patients were titrated until diastolic blood pressure (Korotkoff phase V) decreased by at least 10 mmHg or to 90 mmHg or less. Quality of life assessments, based on validated psychometric questionnaires and objective measurements of cognitive function, occurred after three study phases: placebo run-in (3-5 weeks), titration (1-4 weeks), and maintenance (4 weeks). After four weeks of maintenance therapy, atenolol, captopril and enalapril generally had equivalent effects on quality of life, as measured by psychometric questionnaires, whereas propranolol consistently evidenced worsening or less improvement. Global scores of distressing psychological symptoms differed as a function of specific treatment (P = 0.01), with improvements significantly better for the atenolol, captopril and enalapril groups as compared with the propranolol group. There were no statistically significant differences among treatments for changes in cognitive function at maintenance. Thus, the quality of life questionnaires differentiated among drugs of the same class, indicating that selection among antihypertensive drugs should be based on their specific qualities, not on general class characteristics.

Adult↗
PubMed1989

Persistence of cyclicity of the plasma dopamine metabolite, homovanillic acid, in neuroleptic treated schizophrenic patients.

The dopamine metabolite, homovanillic acid, decreases in concentration in plasma between 8:30 A.M. and 12:30 P.M. In patients with schizophrenia this cyclic change is attenuated by chronic neuroleptic treatment; however, if the 8 A.M. dose of neuroleptic is omitted, the decrease in level occurs. Presuming that neuroleptics attenuate the decline through a receptor mediated compensatory increase in dopamine release, it would appear that receptors are not fully occupied by neuroleptics even at therapeutically effective doses. The usual morning decrease in plasma cortisol levels was unaffected by neuroleptics.

Adolescent↗
PubMed1989

A full repetitive jaw movement response after 70% depletion of caudate D1 receptors.

Repetitive jaw movements (RJM in the rat can be produced in a dose-dependent manner with the selective D1 agonist, SKF 38393. Administration of the protein coupling agent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats pretreated with a D2 receptor blocker resulted in a 70-30% reduction of D1 dopamine receptors, but only a 10% reduction of D2 receptors in the rat caudate. Twenty-four hours following EEDQ, the RJM response to SKF 38393 was assessed. The massive selective reduction of the D1 receptor density was found not to modify the rate of RJM induced by SKF 38393 in that dose response curves in control and EEDQ-treated rats were essentially identical. These data provide evidence to indicate that there is a functional D1 receptor reserve for D1-mediated RJM behavior.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Plasma homovanillic acid as a predictor of response to neuroleptics.

Fourteen schizophrenic subjects were evaluated for degree of psychosis before and after treatment with the antipsychotic drug haloperidol and for plasma homovanillic acid concentration after four and 28 days of treatment. A significant correlation was found between an increase in homovanillic acid concentration on day 4 or a decrease from day 4 to day 28 and the degree of improvement after four weeks of treatment. Thus, those patients who had the greatest change in plasma homovanillic acid in response to neuroleptic blockade showed the greatest improvement. These and other observations have led us to propose that the central dopaminergic system, through adaptive changes in activity, serves as a physiologic buffer system protecting against destabilization of mental function from diverse biologic or psychologic insults.

Adult↗
PubMed1988

Diminished D2 dopamine receptor function and the emergence of repetitive jaw movements.

Oral movements in rats, repetitive jaw movements (RJM), can be induced in a dose dependent manner by a specific D1 agonist, SKF 38393, and decreased by D2 receptor stimulation with a specific D2 agonist, LY 141865. Irreversible D1 receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline severely reduced oral responses induced by SKF 38393, whereas such blockade of D2 receptors greatly augmented the D1 mediated behavior. Further, we found that chronic prolonged D2 receptor blockade following administration of fluphenazine decanoate facilitated repetitive jaw movements.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Effects of prenatal exposure to neuroleptic drugs on children's growth.

The effect of prenatal exposure to neuroleptic drugs on height and weight from birth to 7 years was examined in children of psychiatrically normal parents and of parents with a history of psychiatric treatment, using data from the Collaborative Perinatal Project of the National Institute of Neurological Diseases, Communicative Disorders, and Stroke. Analysis of covariance was used to control for potential confounding factors. We found that prenatal exposure to dopamine receptor-blocking neuroleptic drugs was associated with increased height in one or more of our groups at 4 months, 1 year, and 7 years and less consistently with increased weight. Seven-year-old children who had been exposed to these drugs for more than 2 months during gestation were approximately 3 cm taller than unexposed controls (p less than 0.05). Prenatal exposure to dopamine-depleting agents was associated with decreased height at 4 months but not later. Possible mechanisms for these effects, including a permanent decrease in the number of brain dopamine receptors and effects on various hormones, are discussed.

Antipsychotic Agents↗