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R H Roth

Publications and source records attributed to R H Roth.

At least 217 records · Page 12Linked to original sources
PubMed1983

Plasma homovanillic acid as an index of brain dopamine metabolism: enhancement with debrisoquin.

Plasma levels of the dopamine (DA) metabolite homovanillic acid (HVA) may be a useful measure of brain HVA production by central DA systems. Even though there is a significant peripheral contribution to plasma HVA, experimental manipulations that alter brain HVA produce parallel changes in plasma HVA levels. This study was designed to assess whether the ability of plasma HVA to reflect haloperidol induced increases in brain HVA could be strengthened by reducing the contribution to plasma HVA from peripheral sources. Debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain, was given in a low dose schedule to rats and lowered the peripheral contribution to plasma HVA by between 42 and 68%, resulting in a situation where between 62 and 87% of plasma HVA derived from brain. Using this dose schedule, rats pretreated with debrisoquin displayed a significant increase in plasma HVA following a lower dose of haloperidol than that required in the vehicle pretreated rats. In the debrisoquin pretreated group, a 71% increase in brain HVA was accompanied by a significant 60% increase in plasma HVA, whereas the vehicle pretreated group required a 136% increase in brain HVA to display a significant 50% increase in plasma. These findings indicate that debrisoquin pretreatment improves the reliability of plasma HVA to reflect changes in brain DA metabolism. Plasma HVA samples obtained from humans following debrisoquin may provide a clinically applicable method for assessing brain DA systems in neurologic and psychiatric illness.

Animals↗
PubMed1983

Panic-induced elevation of plasma MHPG levels in phobic-anxious patients. Effects of clonidine and imipramine.

Six subjects with the phobic-anxiety syndrome were treated in a controlled, crossover trial of clonidine hydrochloride v imipramine hydrochloride for periods of four weeks each. During each drug trial and during baseline placebo treatment, each patient exposed himself or herself to a situation that previously elicited panic attacks. Self-rated anxiety and plasma levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured to study the effect of the drug treatments on noradrenergic activity and anxiety. Plasma MHPG level correlated highly with rated anxiety under all conditions, and was consistent with significant symptom reduction by clonidine or imipramine. Diminished suppression of plasma MHPG concentrations in two subjects was associated with the continued emergence of panic symptoms in response to phobic stimuli.

Adult↗
PubMed1983

Relative importance of 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol as norepinephrine metabolites in rat, monkey, and humans.

A gas chromatographic-mass spectrometric assay, which allowed simultaneous measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), was used to show that the concentration of MHPG in primate CNS far exceeded that of DHPG and that both metabolites were mainly in the unconjugated form. In rat brain, DHPG concentration was generally higher than that of MHPG, and both existed predominantly as conjugates. Rat and primate plasma contained more MHPG than DHPG. In plasma of primates but not of rats, higher proportions of the metabolites were conjugated, compared to those in brain. Significant correlations existed between MHPG and DHPG in rat brain, monkey brain, human plasma, and both monkey CSF and plasma. In monkeys, a significant CSF-plasma correlation was found for MHPG, but not for DHPG. Acute administration of piperoxane raised rat brain MHPG and DHPG concentration; desipramine prevented this rise in DHPG, but not in MHPG. Desipramine alone decreased DHPG, but not MHPG, concentration. Piperoxane increased monkey brain MHPG, but not DHPG, concentration. These data suggest that DHPG is a valuable metabolite to measure when assessing norepinephrine metabolism in the rat. Under certain conditions, measurement of rat brain MHPG and DHPG may provide information concerning the site of norepinephrine metabolism. However, in primates the importance of monitoring DHPG, in addition to MHPG, is uncertain.

Animals↗
PubMed1983

Clonidine prevents methylxanthine stimulation of norepinephrine metabolism in rat brain.

Methylxanthines can produce behavior resembling opiate withdrawal in rats. Since previous studies have demonstrated the involvement of central noradrenergic systems during naloxone-precipitated withdrawal, the effects of 3-isobutyl-1-methylxanthine (IBMX) on norepinephrine metabolism in rat brain were studied. It was found that administration of IBMX elevated levels of the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in areas innervated by the locus coeruleus. The increases in MHPG was noted 1 h after administration and was maximal (270% of control) after 3 h. Levels of another norepinephrine metabolite, 3,4-dihydroxyphenylglycol, followed a similar pattern and time course. Coadministration of naloxone with IBMX did not affect the IBMX-induced elevation in MHPG. Administration of the alpha-agonist clonidine, however, antagonized the effects of IBMX on MHPG levels. The effects of IBMX and clonidine were dose dependent; the lowest dose of IBMX needed to elevate MHPG was 30 mumol/kg (i.p.), and clonidine (180 nmol/kg) reduced the effect of IBMX (100 mumol/kg) by 50%. The data, discussed in terms of a methylxanthine-noradrenergic interaction, suggest that withdrawal behaviors in general may be subserved by hyperactive noradrenergic neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Pharmacology of mesocortical dopamine neurons.

The current information on the pharmacology and function of the DA innervation to the prefrontal cortex is a synthesis of data from several initially distinct areas of research. Some possible functions of the mesocortical DA system are suggested from the extensive studies conducted on the role of the prefrontal cortex in behavior, and also from the data on prefrontal cortical modulation of the output of subcortical DA systems. Meanwhile, anatomical, behavioral, biochemical, and electrophysiological studies on mesocortical DA neurons have largely resulted from interest in determining the site(s) and mechanism(s) of action of various psychotropic drugs, and particularly the antipsychotic drugs (DA antagonists). An interrelated field of study has investigated the functional role of DA autoreceptors. The mesocortical DA system possesses many unique characteristics compared to the nigrostriatal/mesolimbic DA systems, including 1) a higher DA turnover rate, 2) a higher rate and different pattern of neuronal discharge, 3) a greatly diminished responsiveness to DA agonists and antagonists, 4) a lack of tolerance to the effect of chronically administered DA antagonists, and 5) a selective activation by footshock stress. These characteristics may be due to the fact that the DA cells projecting to the prefrontal cortex lack DA autoreceptors, an important site for the physiological and pharmacological modulation of subcortical DA systems. This contention is further supported by recent studies on two distinct DA systems innervating, respectively, the anterior cingulate and piriform cortices: the former system, which lacks DA autoreceptors, responds much like the prefrontal cortical DA sy stem; the latter system, which possesses functional DA autoreceptors, manifests a pharmacological responsiveness similar to the nigrostriatal/mesolimbic DA systems (11, 14, 118, 119, 38). Autoreceptors may be an important target for future rational drug design. For example, DA agonists more selective for DA autoreceptors (65, 72) may be useful agents in the treatment of schizophrenia. If, however, these drugs prove ineffective in schizophrenic patients, it might help to explain the equivocal results obtained to date in the treatment of schizophrenia with low (autoreceptor-specific) doses of less selective DA agonists (for a review, see Ref. 97). A lack of clinical efficacy of DA autoreceptor agonists might also suggest that if a DA system is indirectly involved in schizophrenia the site of therapeutic action of antipsychotic drugs is a DA system (such as that innervating the prefrontal cortex) that lacks autoreceptors.

Adenylyl Cyclases↗
PubMed1983

Noradrenergic modulation of serotonin synthesis and metabolism. II. Stimulation by 3-isobutyl-1-methylxanthine.

The hypothesis that norepinephrine neurons facilitate serotonin metabolism was tested by employing the adenosine antagonist 3-isobutyl-1-methylxanthine (IBMX) as a pharmacological probe to enhance central noradrenergic metabolism. IBMX elevated brain concentrations of 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid and increased the accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan. Maximal effects were observed 3 hr after drug administration, with 14 mg/kg of IBMX. The effects of IBMX on serotonin metabolism were observed in cortex, striatum and hippocampus, antagonized by clonidine and propranolol and prazosin and absent in animals whose norepinephrine neurons had been destroyed with 6-hydroxydopamine. The data are discussed in terms of a noradrenergic facilitation of serotonin turnover.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Neuropharmacology of 3-isobutylmethylxanthine: effects on central noradrenergic systems in vivo.

We have previously shown that administration of 3-isobutyl-1-methylxanthine (IBMX) to rats causes an increase in levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) by a clonidine-reversible mechanism (J. Neurochem. 40: 246-251, 1983). Further investigations have revealed that IBMX administration (100 mumol/kg i.p.) stimulates noradrenergic tyrosine hydroxylation in vivo (measured after decarboxylase inhibition), an effect also reversed by the alpha-2 agonist clonidine. Consistent with previous electrophysiological data, IBMX also accelerates the disappearance of NE after inhibition of tyrosine-3-monooxygenase. When axons of the NE-dorsal bundle are mechanically severed, the effect of IBMX on MHPG is not attenuated, in contrast to the effects of the alpha-2 antagonist yohimbine which are blocked by axotomy. Administration of the adenosine agonist, 2-chloroadenosine (8 or 17 mumol/kg i.p.) or diazepam (35 mumol/kg) did not prevent the increase in MHPG caused by IBMX. The data, discussed in terms of enhanced noradrenergic activity, adenosine antagonism and phosphodiesterase inhibition, show that administration of methylxanthines (compounds known to produce anxiety and opiate withdrawal-like behaviors) results in increased biochemical activity of noradrenergic neurons in the rat.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Brain catecholamine metabolites and behavior in morphine withdrawal.

Morphine withdrawal behavior, brain and plasma catecholamine metabolites, and brain beta-noradrenergic receptor binding were examined after acute treatment with naloxone in rats treated with morphine pellets or a sham pelleting procedure. Increases in brain 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), a norepinephrine metabolite, occurred in parallel with rated withdrawal behavior. Withdrawal behavior correlated significantly with brain, and, more modestly, with plasma levels of MHPG but did not correlate with beta-receptor binding or HVA. The effectiveness of debrisoquin sulfate was variable, but the reductions in withdrawal signs and cerebral cortex MHPG were strongly correlated. These data support a direct relationship between presynaptic noradrenergic hyperactivity and opiate withdrawal behavior.

Animals↗
PubMed1982

Striatal dopamine autoreceptors uninfluenced by chronic administration of antidepressants.

Dopamine (DA) receptor sensitivity to apomorphine (APO) was assessed in the rat nigrostriatal system following chronic antidepressant treatment. Imipramine (IMI), iprindole (IPR) or vehicle was administered to rats for 10 days (10 mg/kg i.p., b.i.d.). Two and a half days after the last injection 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured in rat striata following injection of APO (50 or 100 micrograms/kg s.c.) or vehicle. In contrast with rats receiving chronic vehicle injections, rats chronically treated with IMI or IPR failed to exhibit a significant APO-induced fall in striatal DOPAC levels. Antidepressant-treated animals, however, exhibited significantly lower basal DOPAC levels than vehicle-treated rats. In an effort to localize the diminished APO response, DA autoreceptor sensitivity to APO was assessed in drug- and vehicle-treated animals. Employing gamma-butyrolactone (GBL) and a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor to elevate striatal DOPA, the APO-induced reversal of DOPA elevation was used as an index of DA autoreceptor sensitivity. This GBL-stimulated in vivo tyrosine hydroxylation was similarly reversed by APO (125, 250 or 500 micrograms/kg i.p.) in IMI-, IPR- and vehicle-treated animals. In view of these findings, we propose that the blunted biochemical response to APO observed in animals pretreated with antidepressants does not originate as a result of alterations in the sensitivity of DA autoreceptors located on the striatal presynaptic nerve terminal.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Influence of dopamine agonists on plasma and brain levels of homovanillic acid.

The response of the plasma dopamine (DA) metabolite, homovanillic acid (HVA), to two DA agonists was investigated in the rat. Apomorphine administered i.p. (2 mg/kg) produced, within one hour, a significant decrease in plasma HVA. The response of plasma HVA to apomorphine was also investigated after pretreatment with debrisoquin, a drug which selectively blocks peripheral HVA production by inhibition of MAO. Pretreatment with debrisoquin did not significantly alter the decrement in plasma HVA produced by apomorphine indicating that a substantial portion of the plasma HVA response to apomorphine is due to the drug's action on brain. Bromocriptine (2 mg/kg) was also found to produce a significant decrease in plasma HVA. Since the response of brain HVA to DA agonists reflects the sensitivity of the DA receptor, the plasma HVA response to DA agonists might be a practical method of assessing brain DA receptor sensitivity in humans.

Animals↗
PubMed1982

Plasma and cerebrospinal fluid 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) as indices of brain norepinephrine metabolism in primates.

The relationship between MHPG concentration in several brain areas, cisternal CSF and plasma was examined in 26 vervet monkeys. Free MHPG was measured by gas chromatography-mass spectrometry using deuterated MHPG as internal standard. In animals with or without treatment with drugs that alter norepinephrine metabolism, highly significant correlations were found in concentrations of MHPG between the various brain areas, between plasma and CSF, between plasma and brain areas and between CSF and brain areas. The concentration of MHPG in CSF was higher than in plasma and with the exception of occipital cortex, all brain regions contained a higher concentration of MHPG than CSF. This study supports the notion that free MHPG concentrations in plasma and cisternal CSF are useful indices of central noradrenergic activity.

Animals↗
PubMed1982

Acceleration by stress of dopamine synthesis and metabolism in prefrontal cortex: antagonism by diazepam.

Using liquid chromatography and electrochemical detection (LCEC), we have measured the accumulation of 3,4-dihydroxyphenylalanine (DOPA) (after L-aromatic amino acid decarboxylase inhibition), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the frontal cortex and in the corpus striatum of the rat. Mild-footshock stress increased frontal cortex DOPA accumulation, as well as DA and DOPAC, without changing the concentration of these substances in the corpus striatum. The increases in cortical DA synthesis and metabolism were antagonized by diazepam which, given alone, tended to decrease DOPA accumulation to a small degree. In addition, we have measured the indoles serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the noradrenergic metabolite MHPG, none of which were altered by stress. The accumulation of 5-hydroxytryptophan (5-HTP) was also unaffected by stress but, like DOPA accumulation, was reduced to a small degree by diazepam. This study directly demonstrates a selective activation of frontal cortex catechol synthesis (in vivo tyrosine hydroxylation) by a mild stress, which did not significantly alter cortical noradrenergic or serotonergic metabolism.

Animals↗
PubMed1982

Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: biochemical studies in rodents and primates.

In rodents, naloxone-precipitated withdrawal of morphine-dependent animals causes an increase in NE turnover and MHPG accumulation in certain regions of the brain. This increase in NE turnover and MHPG accumulation is suppressed by clonidine to a dose-dependent degree via a naloxone-insensitive mechanism. In general, drugs which have been shown by electrophysiological studies to cause changes in the activity of NE neurons in the locus coeruleus also alter the brain levels of MHPG. These studies suggest that the brain levels of MHPG may be used as a biochemical measure of alterations of impulse flow in NE neurons of the locus coeruleus. In morphine-dependent vervet monkeys, administration of naloxone or naltrexone causes an increase in the brain levels of MHPG. The increase in MHPG observed during withdrawal is suppressed by clonidine. Brain levels of MHPG measured in both drug-treated and control monkeys correlate significantly with plasma and CSF measures of MHPG. These observations suggest that under controlled conditions plasma MHPG can provide a reasonable measure of brain NE metabolism in primates. Pilot data from clinical studies taken together with the more direct observations made in non-human primates are consistent with the hypothesis that in humans brain NE systems become hyperactive during opiate withdrawal and that this hyperactivity of NE systems is suppressed by clonidine.

Animals↗