Response to the Roth appliance treatment reply.
Explore the source record for details and available documents.
Dental Occlusion, Centric↗
Biomedical subjects
R H Roth
Publications and source records attributed to R H Roth.
Preexposure to, but not cotreatment with, the neurotensin antagonist SR 48692 delays the development of cocaine sensitization.
This study examined the role of neurotensin (NT) in the development of cocaine sensitization using the novel nonpeptide NT antagonist SR 48692. Male Sprague-Dawley rats received five daily administrations of SR 48692 (80 micrograms/kg, IP or PO) or vehicle. Following a 7 day drug-free period, cocaine-induced (15 mg/kg, IP) locomotor activity was assessed. Subsequent cocaine tests occurred every other day. No differences were observed between groups during the first day of cocaine testing. Sensitization to the locomotor activating effects of cocaine occurred rapidly in the controls reaching peak effects by the third cocaine challenge injection. By contrast, subjects preexposed to SR 48692 IP were delayed in the development of cocaine sensitization maintaining significantly lower cocaine-induced activity counts relative to controls until the sixth cocaine challenge injection. Preexposure to SR 48692 PO also produced an attenuating effect on the development of cocaine sensitization. The decreased cocaine-induced activity in SR 48692-preexposed subjects did not appear to be the result of a locomotor deficit as SR 48692-preexposed subjects exhibited increased activity rates following a high dose (30 mg/kg, IP) cocaine challenge injection. In an additional experiment, the effect of cotreatment with SR 48692 on the development of cocaine sensitization was assessed. Subjects were cotreated with SR 48692 (80 micrograms/kg, IP) or vehicle 60 minutes prior to each of two cocaine (15 mg/kg, IP) or saline preexposure injections. Following a drug-free day, subjects were tested for cocaine-induced (15 mg/kg, IP) locomotor activation. SR 48692 cotreatment had no effect on the development of sensitization to cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Postmortem stability of monoamines, their metabolites, and receptor binding in rat brain regions.
The effects of postmortem delay, time of storage, and freezing, thawing, and refreezing tissue samples were studied in postmortem rat brain using conditions that reflect the handling of postmortem human brain before neurochemical analysis. The levels of monoamines and metabolites in the striatum and cingulate and occipital cortex were measured using alumina extraction and HPLC methods. Binding of raclopride to dopamine D2, SCH-23390 to dopamine D1, ketanserin to serotonin 5-HT2, 8-hydroxy-2-(di-n-propylamino)tetralin to serotonin 5-HT1A, and cholecystokinin (CCK)-8 to CCK-B sites was measured in tissue homogenates from the striatum or fronto-parietal cortex. An 18-h postmortem delay before dissection and storage resulted in region-specific changes in monoamine and metabolite levels. Binding to striatal D1 and frontoparietal cortex CCK-B sites was reduced over the course of a 27-h postmortem delay. Binding to D2 and 5-HT sites was relatively stable. Storage of tissue for up to 8 months also resulted in region-specific changes in monoamine and metabolite levels. No changes in receptor binding were seen after long-term storage. Freezing, thawing, and refreezing tissue samples resulted in increased levels of striatal 3,4-dihydroxyphenylacetic acid and decreased binding to striatal D2 sites. These results demonstrate time-, temperature-, and storage-dependent regional differences in the stability of monoamines and their metabolites and in binding to various receptor sites. These differences in stability and binding should be accounted for to interpret accurately the effects of neurological disorders on neurotransmitter dynamics in postmortem human brain tissue.
3,4-Dihydroxyphenylacetic Acid↗
The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat.
Animals confronting threatening stimuli respond with a coordinated set of autonomic, neuroendocrine, neurochemical, and behavioral responses that constitute the stress response. The role of the NMDA receptor and its glycine modulatory site was investigated in a rat conditioned stress model. Behavioral, neuroendocrine, and neurochemical analyses were conducted. Regional dopamine (DA) and serotonin (5-HT) utilization was assessed by postmortem tissue measurements of metabolite-to-parent neurotransmitter ratios. Rats were conditioned to fear a tone previously paired with footshock. The following day, rats were systemically administered saline or the NMDA glycine site antagonist (+)-HA-966 before exposure to thirty minutes of conditioned stress. Conditioned stress resulted in a selective increase in medial prefrontal cortical DA and 5-HT utilization, elevation in serum corticosterone, and freezing behavior in control animals. The conditioned stress-induced increase in DA utilization in control animals was also detected in the lateral prefrontal cortex and nucleus accumbens, whereas DA utilization was not affected in the perirhinal or cingulate cortices, lateral-basolateral amygdaloid complex, anterior ventromedial caudatoputamen, or posterior dorsolateral caudatoputamen. Pretreatment with (+)-HA-966 at 15 mg/kg completely abolished the conditioned stress-induced increase in DA utilization in the medial and lateral prefrontal cortices. This effect was regionally specific since (+)-HA-966 pretreatment did not block increased DA utilization in the nucleus accumbens. This effect was also neurochemically specific since the stress-induced increase in 5-HT utilization in the medial prefrontal cortex was not affected by (+)-HA-966 pretreatment. Pretreatment with (+)-HA-966 did not affect stress-induced serum corticosterone elevation but did attenuate the freezing response. Control experiments demonstrated that (+)-HA-966 pretreatment did not (1) induce sedation, (2) interfere with habituation to a novel environment, (3) alter basal DA, 5-HT, or serum corticosterone levels, or (4) block acquisition of aversive memories. These data suggest that the NMDA receptor complex and associated glycine modulatory site may play an important role in the afferent control of the mesoprefrontal cortical DA system during conditioned stress. The relevance of these findings to schizophrenia and human anxiety disorders such as post-traumatic stress disorder are discussed.
Animals↗
Neural transplantation for neurodegenerative diseases: past, present, and future.
After almost 100 years of sporadic, and marginally successful, studies of neural transplantation in animals, we are now on the threshold of a clinical treatment of the damaged brain. The initial studies of neural transplantation have focused on Parkinson's disease, primarily as a model for a more general strategy of "repair by cellular replacement." Parkinson's is known to result from the loss of a small population of cells that produce the essential neuromodulator, dopamine, for much of the brain. Further, the disease is improved significantly, during the early part of its course, by chemical augmentation of dopamine activity through drug therapies, such as L-dopa. Finally, the disease is often fatal in spite of the best medical treatments, therefore justifying more radical therapeutic experiments. If transplantation of brain cells can be accomplished successfully in humans, as it has been in animals, then replacement of a small population of dopamine-producing cells in Parkinson's disease should have important functional effects and possibly reverse the course and symptoms of the disease. Other useful applications will surely follow for conditions affecting millions of people for whom medicine now has only palliative and ineffective treatments. Just as Parkinson's disease is a model clinical condition for testing cellular replacements, fetal neural tissue transplants are also a first step for a broader strategy of molecular and cellular therapies. Fetal cells are, in many respects, the best replacements one could imagine, since precursor cells have the capacity to develop into every cell found in the adult. So, the best replacement for a dopamine neuron would likely be a precursor dopamine neuron or "neuroblast." Animal research through 1985 had demonstrated the unique properties of such fetal cells, but survivability after transplantation had not been attained with primate or human neural tissue. Our programs developed techniques to transplant monkey fetal neural tissue, to cryopreserve it, and to reverse functional effects of the neurotoxin, MPTP, in monkeys. This technique was applied to the collection and preservation of human tissue, and preliminary successful results have been obtained in patients with idiopathic Parkinson's disease. Others have reported success with different techniques in two MPTP-Parkinsonian patients and a small number of patients with idiopathic disease. If the most dramatic improvements can be replicated consistently and the benefits last for a reasonable period without complications, a clinical treatment might develop using "random-source" fetal cadaver cells.
Animals↗
Stress activation of mesocorticolimbic dopamine neurons: effects of a glycine/NMDA receptor antagonist.
Restraint of brief duration causes a metabolic activation of mesocortical and some mesolimbic dopaminergic systems with little effect on the nigrostriatal system. We have examined the ability of an antagonist of the allosteric glycine site of the N-methyl-D-aspartate receptor complex to block the stress-induced response in dopamine utilization. Thirty minutes of restraint stress elevated dopamine metabolism, as measured by the ratio between 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine, in both the medial prefrontal cortex and nucleus accumbens. An antagonist for the glycine/N-methyl-D-aspartate receptor complex, 1-hydroxy-3-aminopyrrolidone-2 ((+)-HA-966), given systemically or injected into the ventral tegmental area, prevents the stress-induced increase in dopamine metabolism in the prefrontal cortex without altering the response in the nucleus accumbens. Similarly, systemic administration of the non-competitive antagonist for the N-methyl-D-aspartate receptor, dizocilpine ((+)-MK-801), blocked the stress-induced rise in dopamine metabolism in the medial prefrontal cortex but not the nucleus accumbens. The negative enantiomer of HA-966 did not produce a selective antagonism of the stress-induced dopamine metabolism in the medial prefrontal cortex. These results support previous work which suggest the mesocortical and mesoaccumbens dopamine neurons respond to excitatory input through different glutamate receptor mechanisms. Additionally, the specific blockade of the stress-induced change in dopamine metabolism in the medial prefrontal cortex by a glycine antagonist implies a role for such an antagonist in treatment of disease states which may involve disruptions of N-methyl-D-aspartate receptor function.
3,4-Dihydroxyphenylacetic Acid↗
In vivo assessment of basal and drug-induced dopamine release in cortical and subcortical regions of the anesthetized primate.
There is an acute interest in studying the functional characteristics of dopamine systems in the cortex of primates. In particular, the prefrontal cortical dopamine projections have received a great deal of attention. This system is essential for proper functioning of the prefrontal cortex, and dysfunction within the system may be involved in some psychiatric and neurological illnesses. In vivo assessments of cortical dopamine in the primate have been scarce. This has been due, in part, to technical difficulties associated with these studies and with quantifying the relatively low levels of dopamine found in cortical regions. In the present study, intracerebral microdialysis was utilized to assess the extracellular concentration of dopamine in cortical and subcortical areas of the pentobarbital-anesthetized rhesus monkey. Basal extracellular dopamine levels were consistently detected in the medial prefrontal cortex, premotor cortex, and caudate-putamen. The basal extracellular concentration of dopamine in the dorsolateral prefrontal cortex was reliably detected in 1 of 4 animals. Intravenous administration of amphetamine (1 mg/kg) enhanced extracellular dopamine levels in the caudate-putamen area by more than 20-fold. In cortical areas, amphetamine's effect was less profound: An increase of 400-500 percent over basal extracellular dopamine levels was observed in each region. These studies demonstrate the feasibility of microdialysis for detecting extracellular fluxes of dopamine in the cortex of nonhuman primates. They further provide direct evidence that the dopamine released within the prefrontal cortex and the premotor cortex of nonhuman primates responds to pharmacological manipulation.
Amphetamine↗
Tyrosine hydroxylase immunoreactivity and monoamine and metabolite levels in cryopreserved human fetal ventral mesencephalon.
Both fresh and cryopreserved-thawed human fetal ventral mesencephalon have been used for preclinical research and implantation into the brains of patients with Parkinson's disease. Further characterization and an evaluation of the effects of cryopreservation on immunocytochemical and neurochemical markers of monoamine neurons in human fetal ventral mesencephalic tissue are reported here. Fresh and cryopreserved-thawed human fetal mesencephalic tissue of 7-10 weeks fetal age was analyzed for the presence of tyrosine hydroxylase-like immunoreactivity and levels of dopamine (DA), norepinephrine, serotonin, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid. After fixation, cryopreserved-thawed mesencephalic tissue exhibited cellular tyrosine hydroxylase-like immunoreactivity identical to that seen in fresh tissue. The levels of DA, norepinephrine, serotonin, and 5-hydroxyindole acetic acid in the cryopreserved-thawed tissue were the same as the levels in fresh tissue. The levels of DOPAC were higher, and those of HVA were lower, in the cryopreserved-thawed tissue compared to the levels in fresh tissue. The changes in the levels of the DA metabolites, DOPAC and HVA, without corresponding change in the levels of the parent monoamine in cryopreserved-thawed tissue, indicate ongoing metabolic activity in DA-containing neurons. These results further suggest that cryopreservation and subsequent thawing does not have a measurable adverse effect on DA biosynthesis in the human fetal mesencephalon. The presence of the monoamines and their metabolites in the ventral mesencephalon at 7-10 weeks of fetal age coincides well with the early presence of immunocytochemical markers of monoamine neurons and reflects the early function of the nuclear groups containing specific monoamine neurotransmitters.
3,4-Dihydroxyphenylacetic Acid↗
Fetal dopamine cell survival after transplantation is dramatically improved at a critical donor gestational age in nonhuman primates.
Mesencephalic tissue containing newly generated dopamine neurons was collected from brains of embryonic African green monkeys at 44 and 49 days of gestation and stereotaxically implanted into multiple sites in the caudate nucleus of adult monkeys previously treated with the dopamine protoxin, 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine. Ultrasonography was utilized to assess the developmental stage prior to hysterotomy. Brains were removed for combined histochemical and biochemical analyses at 3 1/2 months after grafting to determine the extent of graft survival and growth. The dopamine content of the target nucleus was assessed from microdissected "punches" placed in proximity to grafts identified in unfixed brain slices prior to fixation. Tissue dopamine levels adjacent to the grafts were elevated markedly, reaching 25-50% of control levels at some sites in the caudate nucleus. Morphometric analysis of graft size and dopamine cell numbers was performed with computer-enhanced, video-based imaging. Exceptionally large grafts that far exceeded their initial size at the time of implantation were seen at each placement site. The dopamine cell count was as high as 3500 in a single graft from E44 tissue, but only as high as 550 from the E49 donor. Up to 15,000 tyrosine hydroxylase-positive neurons were stained in the host monkey that received E44 tissue; only 1/10 as many were seen in each of the recipients of E49 day samples. The earlier donor grafts occupied as much as 15% of the caudate nucleus as seen in a single coronal section; summation of all sections that contained grafts at each placement from the E44 donor revealed average areas occupied by the grafts ranging from 3 to 8% of the caudate nucleus. In comparison, grafts produced from an E49 donor averaged between 2.4 and 5.4% of the area of the target. Qualitatively, grafts from each gestational stage showed well-developed dopamine neurons with morphological characteristics equivalent to those of all three ventral mesencephalic dopamine cell groups. The attainment of large, well-differentiated grafts with thousands of dopaminergic neurons from early gestation tissue suggests that optimal cell survival in primates is dependent on the degree of postgerminal development of the dopamine neuron. Neurite extension may be critical in this regard as well as other, at present, undefined factors. Maximal graft development and cell survival may be a critical element in the ability of neural grafts to reverse a neurological disability and to maintain improvement in the event of continued degeneration of host dopamine neurons.
Animals↗
Can graft-derived neurotrophic activity be used to direct axonal outgrowth of grafted dopamine neurons for circuit reconstruction in primates?
Explore the source record for details and available documents.
Animals↗
Cocaine-sensitive and -insensitive dopamine uptake in prefrontal cortex, nucleus accumbens and striatum.
Behavioral studies have indicated that the reinforcing effects of cocaine are dependent on inhibition of dopamine uptake in nucleus accumbens and prefrontal cortex. As it has been suggested that dopamine uptake and cocaine-inhibition of dopamine uptake may differ in nucleus accumbens, prefrontal cortex and striatum, we have further characterized dopamine uptake and its susceptibility to inhibition in these three regions. Dopamine uptake was resolved into two processes, which accounts for some of the apparent reported regional differences in sensitivity of dopamine to inhibition by cocaine. One, which is probably associated with uptake into dopaminergic terminals, was sensitive to 6-hydroxydopamine lesions, cocaine, GBR 12909 or ouabain and was dependent on temperature and sodium ion concentration; this was responsible for most of the observed uptake in tissue from striatum and nucleus accumbens, but not from prefrontal cortex. There appeared to be no regional difference in susceptibility of this mode of dopamine uptake to either cocaine or GBR 12909. The other type of dopamine uptake, which represented a significant proportion of the total in prefrontal cortex, but not in striatum or nucleus accumbens, was relatively insensitive to cocaine, GBR 12909 and ouabain and was dependent on temperature, but not sodium ion concentration. In addition, the cocaine-insensitive dopamine uptake was more sensitive to inhibition by dopamine than serotonin, but did not distinguish between dopamine and norepinephrine. The occurrence of cocaine-sensitive dopamine uptake in all examined regions and its equal sensitivity to cocaine and GBR 12909 is consistent with the involvement of nucleus accumbens and/or prefrontal cortex in the reinforcing effects of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Cocaine and cocaethylene: microdialysis comparison of brain drug levels and effects on dopamine and serotonin.
Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 mumol/kg) and intraperitoneal (44 mumol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to approximately 400% of preinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds.
Animals↗
Cellular replacement of dopamine deficit in Parkinson's disease using human fetal mesencephalic tissue: preliminary results in four patients.
Explore the source record for details and available documents.
Animals↗
Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease.
BACKGROUND: Parkinson's disease is characterized by the loss of midbrain dopamine neurons that innervate the caudate and the putamen. Studies in animals suggest that fetal dopaminergic neurons can survive transplantation and restore neurologic function. This report compares the clinical results in four case patients with severe Parkinson's disease who underwent stereotaxic implantation of human fetal ventral mesencephalic tissue in one caudate nucleus with the results in a control group of similar subjects assigned at random to a one-year delay in surgery. METHODS: Each case patient received cryopreserved tissue from one fetal cadaver (gestational age, 7 to 11 weeks). Before implantation, adjacent midbrain tissue underwent microbiologic, biochemical, and viability testing. Cyclosporine was administered for six months postoperatively. RESULTS: The procedure was well tolerated. Three case patients showed bilateral improvement on motor tasks, as assessed on videotape, and were more functional in the activities of daily living, as assessed by themselves and neurologists, during both optimal drug therapy and "drug holiday" periods. One case patient, who died after four months from continued disease progression, had striatonigral degeneration at autopsy. In the patients who received transplants, optimal control was achieved with a lower dose of antiparkinsonian medications, whereas the controls required more medication. Positron-emission tomography with [18F]fluorodopa before and after surgery in one patient revealed a bilateral restoration of caudate dopamine synthesis to the range of normal controls, but continued bilateral deficits in the putamen. CONCLUSIONS: Although the case patients continued to be disabled by their disease, unilateral intracaudate grafts of fetal tissue containing dopamine diminished the symptoms and signs of parkinsonism during 18 months of evaluation.
Activities of Daily Living↗
Low levels of somatostatin-like immunoreactivity in neocortex resected from presumed seizure foci in epileptic patients.
The concentration of somatostatin-like immunoreactivity (SS-LI) was determined by radioimmunoassay in neocortical tissue resected from 20 patients with pharmacologically intractable complex partial seizures. Most resections included either the anterior temporal pole neocortex (15 cases) or cingulate gyrus neocortex (3 cases). The concentration of SS-LI was lowest in cortical tissue immediately adjacent to cortical tumors. Preoperative electrical recordings suggested that this tissue was the seizure focus. In vitro recordings showed that this tissue also exhibited abnormal hyperexcitable synaptic responses. Higher levels of SS-LI, similar to normal values previously reported in human cortex, were present in non-focal temporal neocortical tissue (resected from patients in whom the seizure focus was in the ipsilateral hippocampus) in which no hyperexcitable synaptic activity was present in vitro. The functional loss of inhibitory transmitters suggested by the low SS-LI levels might provide a theoretical basis for the hyperexcitability observed in vivo and in vitro.
Cerebral Cortex↗
Regulation of excitatory amino acid release by N-methyl-D-aspartate receptors in rat striatum: in vivo microdialysis studies.
The microdialysis technique was utilized to study the effects of N-methyl-D-aspartate (NMDA) receptor ligands on the in vivo release of endogenous glutamate (Glu) and aspartate (Asp) from the rat striatum. Addition of NMDA (250 and 500 microM) to the dialysis perfusion solution resulted in a striking dose-dependent increase in extracellular concentrations of Glu and Asp in the striatum. The NMDA-induced effects were reduced in a dose-related way by prior perfusion with 75 microM dizocilpine (MK-801), a non-competitive NMDA receptor antagonist. MK-801, at 75 microM, produced no changes on basal levels of Glu and Asp. However, 100 microM MK-801 did increase Glu and Asp extracellular concentrations. Local infusion with 500 microM D-serine, an agonist at the glycine site associated to the NMDA receptor, significantly increased basal level of Glu, but not Asp. Such D-serine-induced effects were reduced by 7-Cl-kynurenic acid (200 microM), a selective blocker of the glycine site present in the NMDA receptor. It is proposed that activation of NMDA receptors by endogenous Glu and Asp enhances the subsequent release of these excitatory amino acids in the striatum. Part of these NMDA receptors might be located presynaptically on cortico-striatal nerve endings. In addition, postsynaptic NMDA receptors present in the striatum may also indirectly modulate the release of Glu and Asp, through trans-synaptic mechanism.
Animals↗
Effects of CNS stimulants on the in vivo release of the colocalized transmitters, dopamine and neurotensin, from rat prefrontal cortex.
The effect of CNS stimulant drugs on the in vivo release of the colocalized neurotransmitters dopamine and neurotensin in rat prefrontal cortex was studied using microdialysis. Amphetamine, methylphenidate and nomifensine all increased extracellular fluid (ECF) levels of dopamine; however, their effects of neurotensin varied. Amphetamine increased both ECF dopamine (514 +/- 82% of basal) and neurotensin (350 +/- 49% of basal); however, the neurotensin increase lagged behind the increase in dopamine suggesting a possible trans-synaptic effect. Methylphenidate increased both dopamine and neurotensin (226 +/- 26% and 151 +/- 14% of basal respectively) co-synchronously, suggesting exocytosis of vesicles containing both dopamine and neurotensin. The nomifensine-induced increase in dopamine (202 +/- 23% of basal) was similar to that of methylphenidate, whereas the increase in neurotensin was significantly delayed and of lower magnitude (134 +/- 20% of basal). These data suggest that dopamine and neurotensin in part share a common releaseable pool in the prefrontal cortex. Moreover, dopamine may act presynaptically to increase neurotensin release and the different behavioral profiles of these psychostimulants may in part relate to their different effects on neurotensin release.
Analysis of Variance↗