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R H Roth

Publications and source records attributed to R H Roth.

At least 127 records · Page 7Linked to original sources
PubMed1991

D1 dopamine receptors of NS20Y neuroblastoma cells are functionally similar to rat striatal D1 receptors.

Dopamine or agonists with D1 receptor potency stimulated cyclic AMP (cAMP) accumulation in whole cell preparations of NS20Y neuroblastoma cells. The accumulation of cAMP after D1 stimulation was rapid and linear for 3 min. Both dopamine and the novel D1 receptor agonist dihydrexidine stimulated cAMP accumulation two- to three-fold over baseline. The pseudo-Km for dopamine was approximately 2 microM, whereas for dihydrexidine it was approximately 30 nM. The effects of both drugs were blocked by either the D1-selective antagonist SCH23390 (Ki, 0.3 nM) or the nonselective antagonist (+)-butaclamol (Ki, 5 nM). Both (-)-butaclamol and the D2-selective antagonist (-)-sulpiride were ineffective (Ki greater than 3 microM). Forskolin (10 microM), prostaglandin E1 (1 microM), and adenosine (10 microM) also stimulated cAMP accumulation, but none were antagonized by SCH23390 (1 microM). Finally, muscarinic receptor stimulation (100 microM carbachol) inhibited both D1- and forskolin-stimulated increases in cAMP accumulation by 80%. The present results indicate that NS20Y neuroblastoma cells have D1 receptors that are coupled to adenylate cyclase, and that these receptors have a pharmacological profile similar to that of the D1 receptor(s) found in rat striatum.

Benzazepines↗
PubMed1991

D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey.

Previous studies have revealed the involvement of a dopaminergic link in the regulation of spontaneous eye blink rate in primates. Based on the effect of dopamine D2 receptor-selective drugs and the anecdotal failure of the partial D1 agonist, SKF 38393, to alter blink rate in monkeys, it was assumed that D1 dopamine receptors did not control blink rate. The recent availability of dihydrexidine, a full D1 agonist, prompted us to reevaluate the role of D1 and D2 receptors in the regulation of blink rate. African green monkeys (n = 5) were used in all studies. Dihydrexidine produced a rapid and dose-dependent (up to 1 mg/kg, i.m.) increase in blink rate. The elevation in blink rate elicited by 0.3 mg/kg dihydrexidine was completely reversed by prior administration of a specific D1 antagonist, SCH 23390 (0.01 mg/kg, i.m.), but was unaffected by prior administration of a specific D2 antagonist, remoxipride (1 mg/kg, i.m.). Treatment with the specific D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine, led to a rapid and dose-dependent (up to 0.01 mg/kg, i.m.) increase in blink rate. The raised blink rate produced by (+)-4-propyl-9-hydroxynaphthoxazine (0.001 mg/kg) was abolished by pretreatment with remoxipride, but was not influenced by pretreatment with SCH 23390. These data indicate that spontaneous blink rate in the primate can be regulated by both D1 and D2 dopamine receptors. Furthermore, the receptor subtypes appear to affect blink rate in the same direction, yet function independently. Measurement of blink rate may provide a noninvasive method to assess the potency and selectivity of dopamine agonists and antagonists in primates.

Animals↗
PubMed1991

Extracellular dopamine and neurotensin in rat prefrontal cortex in vivo: effects of median forebrain bundle stimulation frequency, stimulation pattern, and dopamine autoreceptors.

In vivo microdialysis coupled with HPLC and radioimmuno-assay techniques were used to analyze dopamine (DA) and neurotensin (NT) in prefrontal cortical extracellular fluid following electrical stimulation of mesocortical axons. The release (overflow into the extracellular fluid) of both DA and NT increased with increasing number of impulses and with frequency. At the lowest frequency tested (2.5 Hz), DA release was significantly increased, while there was no significant increase in the release of NT. As the frequency of stimulation was increased from 2.5 to 20 Hz, the ratio of extracellular DA:NT decreased exponentially. Stimulation in a burst pattern produced greater release of both DA and NT than tonic stimulation when the number of impulses per second and the total number of impulses were held constant. Furthermore, blockade of DA autoreceptors with sulpiride stereoselectively increased the release of DA while decreasing the release of NT. These data suggest that the release of coexistent molecules (DA and NT) from mesocortical neurons can be influenced by physiological and pharmacological factors such that under certain conditions simultaneous or differential release may occur.

Animals↗
PubMed1990

3-Acetylpyridine results in degeneration of the extrapyramidal and cerebellar motor systems: loss of the dorsolateral striatal dopamine innervation.

3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.

Animals↗
PubMed1990

MPTP reduces dopamine and norepinephrine concentrations in the supplementary motor area and cingulate cortex of the primate.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to primates produces many of the biochemical, morphological and behavioral changes that occur in Parkinson's disease. MPTP-induced degeneration of the mesostriatal dopamine innervation has been well documented. In the present study, concentrations of dopamine and norepinephrine in cortical regions surrounding the cingulate sulcus were assessed, and were found to be markedly decreased in symptomatic MPTP-treated vervet monkeys; these results parallel the cortical involvement in Parkinson's disease. Dopamine and norepinephrine levels were not reduced in a group of asymptomatic MPTP-treated monkeys that suffered large losses of striatal dopamine concentration. If therefore appears that the dopaminergic innervations of the supplementary motor area and cingulate cortex are susceptible to MPTP-induced degeneration, but are less vulnerable than the striatal dopamine innervation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Prefrontal cortical dopamine depletion enhances the responsiveness of mesolimbic dopamine neurons to stress.

Mild footshock stress results in the metabolic activation of the prefrontal cortical dopamine (DA) innervation, but does not augment DA utilization in mesolimbic areas (such as the nucleus accumbens septi, NAS) or the striatum. However, increases in either the intensity or duration of footshock stress increase DA utilization in the subcortical sites. DA afferents to the prefrontal cortex (PFC) hold corticofugal projection neurons under tonic inhibition. Previous data suggest that removal of these corticofugal glutamatergic neurons from tonic DA inhibition results in a transsynaptic alteration in the NAS, such that the DA innervation of the NAS is rendered hyperresponsive to certain perturbations. We therefore examined the effects of stress on subcortical DA systems in rats previously subjected to 6-hydroxydopamine lesions of the PFC DA innervation. Mild footshock stress resulted in an increase in concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the PFC, but not NAS or striatum, of sham-lesioned animals. Footshock resulted in a significant increase in the concentration of DOPAC in the nucleus accumbens of animals sustaining PFC lesions two weeks previously. The PFC lesion did not result in a stress-induced increase in DA release in the striatum. These results suggest that disruption of the PFC DA innervation results in an enhanced responsiveness of the mesolimbic DA innervation to stress. These data may help explain the stress-elicited exacerbation of the psychotic process in schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies.

Microdialysis and in vivo voltammetry combined with K(+)-selective microelectrodes were utilized to study the effect of L-glutamate (GLU) on the in vivo release of dopamine (DA) from the rat striatum. Perfusion of 500 nM-5 mM GLU through the microdialysis probe was without an effect on DA outflow whereas 10 mM GLU resulted in a significant (295%) increase in the basal level of DA. This increase was blocked in the presence of 2-amino-5-phosphonopentanoic acid, an N-Methyl-D-aspartate (NMDA) receptor antagonist. Repetitive local applications of 10 mM GLU were also required to observe an increase in extracellular DA measured by in vivo voltammetry. These signals were accompanied with a massive increase in extracellular K+ and a large negative shift in the field potential resembling the ionic changes seen after the phenomenon spreading depression. These studies suggest that high concentrations of GLU are required to enhance the extracellular concentration of DA in vivo. Further, pathophysiological conditions such as spreading depression may be responsible for the observed increase in extracellular DA concentration.

Animals↗
PubMed1990

Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam.

Alterations in a low affinity form of the GABAA receptor were examined with [3H]bicuculline methylchloride in the adult rat following perinatal exposure to diazepam. Perinatal exposure resulted in a significant reduction in [3H]bicuculline binding in the cingulate cortex. A significant decrease in the ability of GABA to displace bound [3H]bicuculline was observed only in the hypothalamus. The results suggest that the effects of perinatal exposure to diazepam are regionally specific and that benzodiazepine receptors and low affinity GABAA receptors are functionally linked during the perinatal period.

Animals↗
PubMed1990

MPTP-induced parkinsonism: relative changes in dopamine concentration in subregions of substantia nigra, ventral tegmental area and retrorubral field of symptomatic and asymptomatic vervet monkeys.

Dopamine (DA) and homovanillic acid (HVA) concentrations were measured in subregions of substantia nigra, ventral tegmental area and retrorubral field in vervet monkeys 1 to 2 months after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Identical MPTP treatment regimens produced animals with different degrees of parkinsonism. In asymptomatic monkeys, changes in DA and HVA concentrations in the midbrain DA regions were relatively small and involved central substantia nigra and dorsomedial ventral tegmental area. In contrast, changes in symptomatic monkeys were more severe and widespread, significantly affecting all examined subregions of substantia nigra (greater than 75% DA depletion), both dorsomedial and ventromedial ventral tegmental area and lateral, but not medial, retrorubral field. The data indicate that DA neurons in subregions of substantia nigra, ventral tegmental area and retrorubral field are not equally susceptible to MPTP toxicity. The pattern of MPTP-induced DA and HVA losses in the vervet monkey mesostriatal dopaminergic system may resemble postencephalitic Parkinson's disease more closely than idiopathic Parkinson's disease.

Animals↗
PubMed1990

3,4-Methylenedioxymethamphetamine-induced release of serotonin and inhibition of dorsal raphe cell firing: potentiation by L-tryptophan.

The effects of the serotonin (5-HT) precursor L-tryptophan on MDMA (3,4-methylenedioxymethamphetamine)-induced inhibition of dorsal raphe neuronal firing were characterized using extracellular single-unit recording and microdialysis techniques in the in vitro midbrain slice preparation. Pretreatment with L-tryptophan (100 microM) lowered the doses of MDMA required to inhibit unit activity. Based upon IC50 values, L-tryptophan increased the potency of MDMA by approximately 3-fold. In a parallel series of experiments, microdialysis probes resting on the brain slice surface provided a means to estimate 5-HT release from the dorsal raphe nucleus. Pretreatment with L-tryptophan increased MDMA-induced 5-HT release in a manner consistent with the suppression of dorsal raphe cell firing: compared to untreated preparations, peak 5-HT release, total release and the duration of release were all increased. Taken together, these data suggest that the enhancement by L-tryptophan of MDMA-induced 5-HT release and inhibition of dorsal raphe neuronal firing is due to an increase in the amount of 5-HT available for release. The question is raised as to what effect L-tryptophan may have on the psychotropic and neurotoxic actions of MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Interaction of [3H]GBR 12935 and GBR 12909 with the dopamine uptake complex in nucleus accumbens.

Although some behavioral effects of cocaine are hypothesized to be due to blockade of dopamine uptake in nucleus accumbens, it has been reported that in nucleus accumbens there are no specific cocaine binding sites and that cocaine is a weak inhibitor of dopamine uptake. [3H]GBR 12935 and an unlabelled analog, GBR 12909, are ligands that bind with great affinity and specificity to a site on dopamine uptake complex in striatum. We therefore investigated the interaction of these GBR compounds with the dopamine uptake complex in nucleus accumbens. We found specific high affinity [3H]GBR 12935 binding and a significant correlation between displacement of [3H]GBR 12935 binding by a series of compounds in striatum and nucleus accumbens. GBR 12909 inhibited dopamine uptake with equal potency in nucleus accumbens and striatum. Thus, there appear to be some aspects of the dopamine uptake complex in nucleus accumbens and striatum that are similar.

Animals↗
PubMed1990

Effects of dopamine autoreceptor stimulation on the release of colocalized transmitters: in vivo release of dopamine and neurotensin from rat prefrontal cortex.

The in vivo release of dopamine and neurotensin from the rat medial prefrontal cortex was studied using perfusion microdialysis coupled with sensitive radioimmunoassay and HPLC techniques. Following stimulation of dopamine autoreceptors with either apomorphine (30 micrograms/kg, s.c.) or EMD-23448 (10 microM in the perfusion buffer) a decrease in dopamine and an increase in neurotensin release was observed. The release of both substances was measured in the same dialysis sample. These data suggest that activation of dopamine autoreceptors in the prefrontal cortex produces opposing effects on the release of dopamine and neurotensin.

Animals↗
PubMed1990

Mesocortical dopamine neurons: high basal firing frequency predicts tyrosine dependence of dopamine synthesis.

Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25-200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic beta-carboline, FG7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Cryopreservation of human brain tissue.

Tissues from products of conception were examined to determine the feasibility of obtaining viable neural tissue after suction abortion at 9-12 weeks of gestation. The ventral mesencephalon, a prototype region whose maturation can be monitored and which is a potential tissue for transplantation, was identified in 32 of 120 cases. The tissue was then screened for the presence of infectious agents, while being held at -196 degrees C in cryopreservative solutions. Three of 32 specimens were found to be contaminated by normal vaginal bacteria; all other viral, fungal, and mycoplasma testing was negative. Thawed brain fragments retained high viability after storage in liquid nitrogen and when grown in vitro exhibited neuronal morphology, tyrosine hydroxylase immunoreactivity, and dopamine production. We have demonstrated that human fetal brain tissue can be cryopreserved in a manner which not only retains viability but allows normal phenotypic differentiation after thawing.

Brain↗
PubMed1990

Perinatal diazepam exposure: alterations in exploratory behavior and mesolimbic dopamine turnover.

Perinatal exposure to diazepam has been shown to lead to alterations in motor activity and exploratory behavior in neonatal animals. Exploratory and locomotor behavior have been associated with changes in mesotelencephalic dopamine function. We have therefore examined the effects of perinatal diazepam administration on both exploratory behavior and mesotelencephalic dopamine turnover in the adult rat. Animals exposed to the benzodiazepine during the perinatal period engaged in significantly less exploratory behavior than did control subjects. The diazepam-induced alterations in behavior were developmentally specific: decreased exploratory behavior was observed at 90, but not 60, days of age. At 90 days of age, specific changes in dopamine turnover in diazepam-treated animals were restricted to mesolimbic (nucleus accumbens and ventral tegmental area) sites; alterations in dopamine turnover were not seen in other mesotelencephalic sites examined. The findings indicate that perinatal exposure to benzodiazepines leads to behavioral changes that are present in adulthood. These changes in exploratory behavior may be associated with alterations in mesolimbic dopamine function.

Aging↗
PubMed1990

Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum.

Using the technique of perfusion microdialysis combined with a small-bore liquid chromatography system we have measured the basal and drug-induced fluxes of extracellular dopamine in the medial prefrontal cortex of chloral hydrate-anesthetized rats and have compared our findings in the cortex to that observed in the striatum. The results were as follows. (1) At a flow rate of 2 microliter/min, the basal level of dopamine in the medial prefrontal cortex was 0.28 +/- 0.1 (n = 32) fmol/microliter perfusate, which was nearly an order of magnitude less than that obtained from the striatum. (2) alpha-Methyl-para-tyrosine (150 mg/kg i.v.) significantly decreased the extracellular levels of striatal and cortical dopamine. The magnitude and duration of the responses were similar in both regions. (3) Local perfusion with 30 mM K+ had a more profound effect on dopamine release in the striatum than in the medial prefrontal cortex. The K(+)-induced release in both regions was significantly attenuated in the absence of Ca2+. (4) The anxiogenic beta carboline FG 7142 (15 mg/kg, i.p.) enhanced the release of cortical dopamine by about 50% while it was without an effect in the striatum. (5) Amphetamine (1 mg/kg, i.v.) significantly elevated, while reserpine (5 mg/kg, i.p.) rapidly attenuated, the dopamine level in the medial prefrontal cortex. These studies demonstrate that perfusion microdialysis, in conjunction with small-bore liquid chromatography with electrochemical detection, can be used to measure the basal release of dopamine in the rat medial prefrontal cortex and that the dopamine release process in this region, as has been shown in the striatum, is sensitive to stimulation conditions and pharmacological manipulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗