Comment on condylar movement and mandibular rotation during jaw opening.
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Cephalometry↗
Biomedical subjects
R H Roth
Publications and source records attributed to R H Roth.
Blockade of FG 7142-induced increased dopamine utilization by the glycine/NMDA receptor antagonist (+)-HA 966.
Systemic administration of the anxiogenic benzodiazepine inverse agonist FG 7142 has been shown to increase selectively dopamine utilization in the medial prefrontal cortex and the shell, but not core, subregion of the nucleus accumbens. In the present study, we examined the functional interaction between benzodiazepine and N-methyl-D-aspartate receptor influences on dopamine utilization in these areas. Male Sprague-Dawley rats were pretreated with the glycine receptor antagonist (+)-HA 966 (15 mg/kg, i.p.) or saline 15 min before FG 7142 (20 mg/kg, i.p.) or vehicle administration. Subjects were killed 30 min later and assayed for tissue concentrations of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid in the core and shell subdivisions of the nucleus accumbens and the media prefrontal cortex. (+)-HA 966 administration blocked FG 7142-induced increased dopamine utilization in both the medial prefrontal cortex and the shell subdivision of the nucleus accumbens. Results are discussed in terms of N-methyl-D-aspartate receptor influences on the response of mesoaccumbal dopamine neurons to stress.
3,4-Dihydroxyphenylacetic Acid↗
Alcohol plus cocaine: the whole is more than the sum of its parts.
Cocaethylene, an active metabolite that arises through hepatic transesterification of cocaine when cocaine and ethanol are used together, shares many neurochemical and pharmacological properties with cocaine. Cocaethylene is similar to cocaine in its properties as an indirect dopamine agonist, and human subjects cannot distinguish its effects from those of cocaine. Cocaethylene, and especially its isopropyl analog, are more selective indirect dopamine agonists than cocaine, with relatively weak potency at the serotonin transporter. Cocaethylene may contribute to the manifestations and consequences of combined cocaine and ethanol use, although its relative importance remains unclear.
Central Nervous System Depressants↗
The role of mesoprefrontal dopamine neurons in stress.
While several catecholaminergic systems are activated by stressful stimuli, the mesoprefrontal dopamine (DA) system appears to be particularly vulnerable to stress. Low intensity stressors that do not produce detectable effects in most ascending catecholaminergic systems activate mesoprefrontal DA neurons. Mesoprefrontal DA neurons are unique in that they lack or have decreased densities of specific autoreceptors affecting autoregulatory capabilities, which could contribute to the fact that mesoprefrontal DA neurons exhibit increased rates of burst firing and DA turnover relative to other midbrain dopaminergic projections. In addition, mesoprefrontal DA neurons are uniquely modulated by a number of chemically distinct afferent influences including gamma-aminobutyric acid (GABA), serotonin, excitatory amino acid, substance P, opiate, and noradrenergic systems. Any or all of these factors could contribute to the selective activation of mesoprefrontal DA neurons following exposure to low intensity stressors. The present review summarizes the possible mechanisms by which mesoprefrontal DA neurons are preferentially activated by stress. The operational significance of this unique neurochemical response to stress is discussed in terms of a possible coping versus anxiety function. Also discussed are the ramifications of a dysfunction of this system with respect to stress-related or exacerbated disorders such as post-traumatic stress disorder and schizophrenia.
Animals↗
Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.
This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.
Adult↗
R-(+)-HA-966, an antagonist for the glycine/NMDA receptor, prevents locomotor sensitization to repeated cocaine exposures.
Repeated administration of cocaine results in a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. In this study, we examined the effect of an antagonist for the strychinine-insensitive glycine receptor of the NMDA receptor complex, R-(+)-HA-966, on the development of locomotor sensitization to cocaine. Co-administration of R-(+)-HA-966 with repeated cocaine prevented locomotor sensitization to a subsequent challenge dose of cocaine. However, R-(+)-HA-966 (15 mg/kg i.p.) did not attenuate locomotor activation to an acute dose of cocaine (15 mg/kg). These results indicate that the glycine/NMDA receptor is involved in locomotor sensitization to repeated cocaine administration but not in the locomotor activation to the acute stimulant effects of cocaine administration.
Animals↗
General cognitive ability following unilateral and bilateral fetal ventral mesencephalic tissue transplantation for treatment of Parkinson's disease.
OBJECTIVE: To contrast the neuropsychological profiles of Parkinsonian patients, before and after fetal ventral mesencephalic tissue transplantation. DESIGN: Case series of personally examined patients. SETTING: Patients were evaluated by neurologists, neurosurgeons, and neuropsychologists as outpatients at a university hospital. PATIENTS: Fetal mesencephalic tissue was implanted in the right caudate nucleus of three patients and both nuclei of one patient. These patients were evaluated prior to surgery and at 12, 24, and 26 months postoperatively. RESULTS: Factor analysis of the test battery identified four statistically orthogonal test clusters. No statistically significant changes were identified postoperatively for clusters assessing verbal cognitive ability, nonverbal cognitive ability, and information-processing speed. An improvement of verbal memory cluster index was observed 12 months after surgery, and the improvement reached the level of statistical significance at 24 months after surgery. However, the verbal memory of all patients declined between 24 and 36 months after surgery. CONCLUSIONS: Fetal tissue transplantation to one or both caudate nuclei did not permanently arrest cognitive dysfunction. Although there is some evidence of improved cognitive ability after transplantation, it is improbable that normal cognitive function can be restored by this procedure because the impairments of cognitive ability associated with Parkinson's disease do not appear to originate solely from dopamine deficiency.
Adult↗
Changes in extracellular levels of glutamate and aspartate in rat substantia nigra induced by dopamine receptor ligands: in vivo microdialysis studies.
The microdialysis technique was utilized to study the local effects of D1 and D2 family type dopamine (DA) receptor (R) ligands on the in vivo release of endogenous glutamate (GLU) and aspartate (ASP) from rat substantia nigra (SN). Addition to the dialysis perfusion solution of either D1-R and D2-R agonists, such as SKF-38393 (50 and 100 microM) and Quinpirole (5 and 10 microM), resulted in dose-dependent increases in extracellular concentrations of GLU and ASP, respectively. The SKF-38393 and Quinpirole-induced effects were reduced by SCH-23390 (0.5 microM), a D1-R antagonist, and by Spiperone (1.0 microM), a D2-R antagonist, respectively. However, SCH-23390 and Spiperone did increase GLU and ASP extracellular concentrations. Local infusion with Tetrodotoxin (TTX) (1.0 microM), a blocker of voltage-dependent Na+ channels, increased basal extracellular levels of GLU. In addition, co-infusion of TTX and SKF-38393 evoked increases in extracellular GLU levels higher than those observed after SKF-38393 alone. Finally, chemical lesions of nigral DA cells with 6-OH-DA increased the basal extracellular levels of GLU. It is proposed that the release of GLU and ASP from SN may be regulated by D1- and D2-receptors present in this basal ganglia structure. In addition, part of the D1 receptors present in SN might be located presynaptically on GLU-containing nerve endings.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Prior exposure to cocaine diminishes behavioral and biochemical responses to aversive conditioning: reversal by glycine/N-methyl-D-aspartate antagonist co-treatment.
Animals will respond with stress-like behavioral and biochemical changes when exposed to a neutral stimulus that had previously been paired with a stressful stimulus. This phenomenon is generally known as aversive conditioning or conditioned fear. We tested the effect of prior exposure to cocaine on rats subjected to an aversive conditioning paradigm. Rats were given repeated doses of cocaine to develop a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. We blocked this sensitization to cocaine in one cocaine-exposed group by co-administering an antagonist of the strychinine-insensitive glycine site of the N-methyl-D-aspartate receptor complex, R-(+)-HA-966, which prevented the development of locomotor sensitization to cocaine. After about three weeks, we examined the effect of cocaine sensitization and the prevention of sensitization by R-(+)-HA-966 on aversive conditioning. Rats were exposed to 10 tones (neutral stimuli) paired with footshock (stressful stimuli) over 30 min for the conditioning session. The following day, rts were returned to the cages, received 10 tones only over 30 min and were killed. No drugs were given to any rat before either session and control rats received the tones without footshock in both sessions. Prior exposure to cocaine caused an attenuation of the behavioral effects of aversive conditioning, namely the amount of time spent immobilized and the number of fecal boli expelled. Additionally, the elevated metabolic activity of dopamine in the medial prefrontal cortex, nucleus accumbens and ventral tegmental area associated with aversive conditioning was diminished in rats pre-exposed to cocaine. The behavioral and biochemical effects of pre-exposure to cocaine were reversed in rats that receive R-(+)-HA-966 co-treatment with the five day cocaine sensitization regimen. These data suggest that prior behavioral sensitization to cocaine diminishes the stressful effect of conditioned fear and that these effects are reversed when sensitization is prevented with R-(+)-HA-966.
Animals↗
Chronic imipramine administration alters the activity and phosphorylation state of tyrosine hydroxylase in dopaminergic regions of rat brain.
In the present study the influence of imipramine, a tricyclic antidepressant, on the expression and function of tyrosine hydroxylase (TH) in dopaminergic rat brain regions was examined. Chronic administration of imipramine (18 days) decreased levels of TH enzyme activity in ventral tegmental area (VTA) and substantia nigra (SN), dopaminergic cell body regions, as well as in caudate-putamen (CP), nucleus accumbens (ACB), prefrontal cortex (PFC), and olfactory tubercle (OT), dopaminergic terminal fields. These effects were dependent on chronic drug treatment, as imipramine administration for 1 or 7 days did not significantly influence levels of TH activity in either SN or VTA. In contrast to drug regulation of enzyme activity, chronic imipramine treatment did not decrease levels of TH immunoreactivity in any of the dopaminergic cell body or terminal field regions studied, although levels of TH immunoreactivity were decreased in locus coeruleus (LC) as previously reported. However, imipramine treatment increased levels of TH back phosphorylation in VTA, suggesting that the antidepressant-induced decrease in levels of TH activity is a result of decreased phosphorylation of the enzyme. These results demonstrate that imipramine treatment regulates levels of TH enzyme activity in dopaminergic brain regions, and may account for some of the previously observed effects of these drugs on dopaminergic function. Finally, imipramine regulation of TH enzyme activity in VTA and immunoreactivity in LC was observed in Sprague Dawley, but not Wistar rats, demonstrating that different rat strains exhibit different biochemical responses to antidepressant treatment.
Animals↗
Selective increase in dopamine utilization in the shell subdivision of the nucleus accumbens by the benzodiazepine inverse agonist FG 7142.
We examined the effects of the benzodiazepine inverse agonist FG 7142 on dopamine metabolism in the core and shell subdivisions of the nucleus accumbens. FG 7142 (15 mg/kg i.p.) or vehicle was administered to adult male rats 30 min before they were killed. Selected brain regions, including samples from the whole nucleus accumbens as well as core and shell subdivisions, were collected and assayed for tissue concentrations of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Consistent with previous reports, FG 7142 administration increased dopamine utilization in the medial prefrontal cortex but not the whole nucleus accumbens. Examination of subdivisions revealed that FG 7142 produced increased dopamine utilization in the shell subdivision of the nucleus accumbens. No effect of FG 7142 on dopamine utilization in the core region of the nucleus accumbens was observed. These data are discussed in terms of in vivo microdialysis studies reporting increased dopamine release in the nucleus accumbens after FG 7142 administration.
3,4-Dihydroxyphenylacetic Acid↗
Occlusion and condylar position.
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Centric Relation↗
Stress-induced activation of prefrontal cortex dopamine turnover: blockade by lesions of the amygdala.
Stress consistently has been found to activate peripheral and central catecholamine systems. Dopamine (DA) turnover in the prefrontal cortex is especially sensitive to stress produced by relatively mild footshock, conditioned fear, or exposure to a novel cage. Because lesions of the central nucleus of the amygdala block the effects of both stress and fear in many experimental paradigms, the present study evaluated whether such lesions would block stress-induced increases in prefrontal dopamine turnover using either mild footshock or novelty as stressors. In Experiment 1 electrolytic lesions of the central nucleus of the amygdala attenuated the increase in the dopamine metabolite homovanillic acid (HVA) in the prefrontal cortex evaluated in post-mortem tissue normally produced by footshock. In Experiment 2 similar lesions attenuated the increase in dopamine turnover in the prefrontal cortex using a different stressor, novelty, and a different measure of dopamine turnover, DOPAC/DA ratios. These data provide further evidence for the critical role of the amygdala in stress.
3,4-Dihydroxyphenylacetic Acid↗
Tryptophan pretreatment augmentation of p-chloroamphetamine-induced serotonin and dopamine release and reduction of long-term neurotoxicity.
The impact of tryptophan (TRP) pretreatment on the neurochemical effects of p-chloroamphetamine (PCA) was investigated. The neurotoxic effects of PCA on serotonin (5-HT) neurons, the acute effects of PCA on extracellular 5-HT and dopamine (DA), and the displacement by PCA of whole blood 5-HT were examined. TRP pretreatment (400 mg/kg of the methyl ester) significantly reduced the long-term (1 week) decrease in tissue 5-HT resulting from PCA (2 mg/kg, i.p., of the hydrochloride salt) in the prefrontal cortex and striatum, but not in the dorsal hippocampus. Microdialysis studies in awake animals showed that this pretreatment regimen resulted in augmented PCA-induced increases in extracellular 5-HT (4-fold) and DA (2-fold). TRP pretreatment also resulted in increased displacement of 5-HT from whole blood. The implications of these results toward possible mechanisms of action of PCA-induced neurotoxicity are discussed.
Animals↗
Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment.
The effect of chronic treatment with clozapine on extracellular dopamine levels in the rat striatum, nucleus accumbens and medial prefrontal cortex (mPFC) was examined using intracerebral microdialysis. Clozapine (20 mg/kg/day x 21 days in drinking water) increased basal dopamine release in the mPFC but had no effect in the striatum or nucleus accumbens. After chronic treatment, an acute dose of clozapine (20 mg/kg i.p.) produced large and long-lasting increases in extracellular dopamine in all three brain regions. The data suggest that chronic clozapine produces a sustained enhancement in dopaminergic tone in the mPFC.
Animals↗
5-HT1a agonist +/-8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine.
Serotonergic 5-HT1a agonists have recently been suggested to be effective in the treatment of human anxiety disorders. The neural mechanisms responsible for their clinical efficacy are unknown. In this study, we investigated the effects of +/-8-hydroxy-2(di-n-propylamino)tetralin [+/-8-OH-DPAT], a serotonergic 5-HT1a agonist, on basal and stress-induced changes in dopamine utilization and release in selected forebrain dopamine terminal fields in the rat. Dopamine utilization and release were respectively assessed by neurochemical analysis of ex vivo brain tissue and by microdialysis in the freely moving animal. Systemic +/-8-OH-DPAT at doses below 225 micrograms/kg had not effect in any region except to slightly decrease dopamine utilization in the nucleus accumbens. However, at a dose of 225 micrograms/kg, +/-8-OH-DPAT significantly increased basal dopamine utilization and release in the medial prefrontal cortex, while simultaneously decreasing serotonin release in this area. By contrast, the same dose of +/-8-OH-DPAT decreased extracellular dopamine in the striatum. The effect of +/-8-OH-DPAT on the response of the dopamine system to mild footshock stress was also assessed. This 5-HT1a agonist diminished the magnitude of footshock-induced increases in prefrontal cortical dopamine utilization. These data suggest that 5-HT1a agonists may dose-dependently modulate both basal and stress-induced changes in dopamine utilization in the medial prefrontal cortex. The possible relevance of these findings to the observed clinical efficacy of 5-HT1a agonists in anxiety disorders is discussed.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Novel radioligands for the dopamine transporter demonstrate the presence of intrastriatal nigral grafts in the MPTP-treated monkey: correlation with improved behavioral function.
This preliminary study demonstrates by in vitro autoradiography the value of novel radiolabeled cocaine analogs to characterize the neurochemical identity and measure the density and growth of fetal ventral mesencephalic cells transplanted to the caudate nucleus of the adult MPTP-treated monkey. Two cocaine derivatives were used, one with extremely high affinity for both dopamine and serotonin transporters and one which was selective for the dopamine transporter. The results suggest that the transplantation procedure was able to increase the density of transporter sites in most of the caudate nucleus, although the proportion of dopaminergic and serotonergic fibers may have been altered from normal.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Peripheral nerve-dopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems.
Previous studies of rats in our laboratory indicate that a molecule or molecules released by Schwann cells exert survival and growth-promoting effects on mesencephalic dopamine neurons. In the present study, we have begun to investigate the potential for Schwann cell augmentation of host dopamine fiber systems and embryonic dopamine neuron grafts in non-human primates. Ten adult male St Kitts African Green monkeys treated with the dopaminergic neurotoxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine one year previously, but behaviorally asymptomatic, served as hosts for implant studies. A segment of young adult monkey saphenous nerve was collected to serve as an implanted tissue source of Schwann cell-derived growth factors. Nerve was enclosed in a hollow semi-permeable polymer fiber for implantation into the lateral ventricle, with embryonic ventral mesencephalic tissue co-grafts containing developing dopamine neurons aimed at nearby locations in the caudate nucleus. Control implants consisted of an empty polymer fiber co-grafted with embryonic ventral mesencephalon. Our morphological observations indicate that while no clear augmentation of the morphology of grafted dopamine neurons attributable to co-grafted nerve was observed, this lack of influence may be related to the spatial separation of the co-grafted tissues. In contrast, some monkeys with nerve segments in the lateral ventricle exhibited increased tyrosine hydroxylase-positive fiber staining in the immediately adjacent lateral septal area and the ventricular wall of the caudate nucleus. This enhancement was not associated with empty polymer implants. Levels of dopamine and its metabolite homovanillic acid derived from tissue punches in the caudate nucleus and septal area support the view that monkeys exhibiting morphological enhancement of host dopamine systems also show biochemical increases in dopamine levels and changes in the direction of normalization of the homovanillic acid/dopamine ratio. Biochemical values from a single septal area tissue punch in one animal were an exception to this rule. This study suggests that while the utility of peripheral nerve as a source of dopamine graft augmentation in non-human primates remains to be demonstrated, grafted nerve has a stimulatory effect on host brain dopamine systems in adult, dopamine-depleted monkeys, and that this morphological effect can be dissociated from previously hypothesized injury-induced regeneration.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗