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M J Zigmond

Publications and source records attributed to M J Zigmond.

At least 19 recordsLinked to original sources
PubMed2002

Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time.

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. However, the effect of smaller lesions on a reaction time task has not been systematically assessed. We, therefore, used this test to examine behavioral deficits as a function of striatal dopamine loss. When injected at doses that produced striatal DA depletion <50%, 6-hydroxydopamine infused in the medial forebrain bundle produced no reliable impairment in the reaction time task. Higher doses producing > or = 60% DA depletion in the striatum produced a decrease in the percent correct responding throughout the 5 week testing period and akinetic deficits expressed by an increase in delayed responding. In addition, larger DA depletions (> or = 95%) profoundly altered motor control with decreases in percent correct responses, increases in delayed responses and increases in reaction time. These results suggest that reaction time may be a relatively sensitive measure of preclinical or subtle deficits, although it might be even more useful in quantitating the severity of depletion once overt deficits or symptoms appear and has the advantage of measuring such deficits over time to follow recovery of function. Furthermore since reaction time deficits required extensive loss of dopamine, these results are consistent with a predominant role of extrasynaptic dopamine in the mediation of relatively skilled motor tasks.

Adrenergic Agents↗
PubMed2001

Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine.

Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral sparing, these animals showed remarkable sparing of striatal DA, its metabolites, and the expression of the vesicular monoamine transporter, suggesting a decrease in the extent of DA neuron degeneration. Behavioral and neurochemical sparing appeared to be complete when the 7 d period of immobilization was initiated immediately after 6-OHDA infusion, only partial sparing was evident when immobilization was initiated 3 d postoperatively, and no sparing was detected when immobilization was initiated 7 d after 6-OHDA treatment. These results suggest that physical therapy may be beneficial in Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Stress-induced increase in extracellular dopamine in striatum: role of glutamatergic action via N-methyl-D-aspartate receptors in substantia nigra.

There is considerable support for an influence of excitatory amino acids released from corticofugal neurons on dopaminergic activity in the basal ganglia. However, the relative importance of cortico-striatal and cortico-mesencephalic projections remains unclear, particularly with respect to the nigro-neostriatal pathway. We have therefore examined the influence of endogenous excitatory amino acids in substantia nigra on stress-induced dopaminergic activity in neostriatum. Microdialysis probes were implanted unilaterally into substantia nigra and ipsilateral neostriatum, and dopamine release in neostriatum was monitored by measuring changes in extracellular dopamine. In separate animals, neostriatal dopamine synthesis was assessed by measuring extracellular DOPA in the presence of 3-hydroxylbenzylhydrazine (NSD-1015; 100 microM), an inhibitor of aromatic amino acid decarboxylase. Thirty minutes of intermittent foot shock increased both dopamine release (+41%) and synthesis (+37%) in neostriatum. Infusion of 2-amino-5-phosphonovalerate (APV; 100 microM), an inhibitor of N-methyl-D-aspartate (NMDA) receptors, into substantia nigra greatly attenuated the stress-induced increase in neostriatal dopamine release, while having no effect on the apparent increase in stress-induced dopamine synthesis. These data suggest that excitatory amino acids such as glutamate act on NMDA receptors in substantia nigra to increase striatal dopamine release produced by exposure to stress, but that the increase in dopamine synthesis is mediated through a separate mechanism.

Animals↗
PubMed2001

Promoting responsible conduct in research through "survival skills" workshops: some mentoring is best done in a crowd.

For graduate students to succeed as professionals, they must develop a set of general "survival skills". These include writing research articles, making oral presentations, obtaining employment and funding, supervising, and teaching. Traditionally, graduate programs have offered little training in many of these skills. Our educational model provides individuals with formal instruction in each area, including their ethical dimensions. Infusion of research ethics throughout a professional skills curriculum helps to emphasize that responsible conduct is integral to succeeding as a researcher. It also leads to the consideration of ethical dimensions of professional life not covered in traditional ethics courses.

Education↗
PubMed2001

Glutamate regulates the spontaneous and evoked release of dopamine in the rat striatum.

Resting and evoked extracellular dopamine levels in the striatum of the anesthetized rat were measured by fast-scan cyclic voltammetry in conjunction with carbon fiber microelectrodes. Identification of the substance detected in vivo was achieved by inspection of background-subtracted voltammograms. Intrastriatal microinfusion of kynurenate, a broad-spectrum antagonist of ionotropic glutamate receptors, caused a decrease in the resting extracellular level of dopamine. The kynurenate-induced decrease was unaffected by systemic pretreatment with pargyline, an inhibitor of monoamine oxidase, but was significantly attenuated by systemic pretreatment with alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase. Although glutamate by itself did not affect resting extracellular dopamine levels, glutamate did attenuate the kynurenate-induced decrease. Kynurenate decreased dopamine release in response to electrical stimulation of the medial forebrain bundle, an effect that was also attenuated by glutamate. These results suggest that both spontaneous and evoked dopamine release in the rat striatum are under the local tonic excitatory influence of glutamate. Interactions between central dopamine and glutamate systems that have been implicated in the etiologies of Parkinson's disease, schizophrenia, stress, and substance abuse. The precise nature of those interactions, however, remains a matter of some controversy.

Animals↗
PubMed2000

Analysis of tyrosine hydroxylase gene transcription using an intron specific probe.

The nuclear run-on assay is the most commonly used technique to determine transcription rates of specific genes such as tyrosine hydroxylase. Its application to studies in the nervous system is problematic, however, as a result of limitations in sensitivity and the loss of anatomical integrity. We observed that the relative levels of tyrosine hydroxylase intron 2-containing RNA using a ribonuclease protection assay in the adrenal medulla changed in response to pharmacological treatments consistently with changes shown by the nuclear run-on assay. Our results indicate that measures of tyrosine hydroxylase primary transcript levels offer an alternative to the nuclear run-on assay and validate the application of intron-specific in situ hybridization as a means of assessing the relative transcriptional activity of the tyrosine hydroxylase gene. Similar quantitative results were obtained using intron-specific in situ hybridization with oligonucleotide probes specific for rat tyrosine hydroxylase intron 2. Furthermore, we observed that intron-specific in situ hybridization could be used to measure tyrosine hydroxylase transcription rates in the locus coeruleus, providing resolution at the level of single neurons. Thus, measuring the levels of tyrosine hydroxylase intron 2 provides a sensitive measure of tyrosine hydroxylase transcription rate that can be applied to the study of brain catecholaminergic neurons.

Adrenal Medulla↗
PubMed2000

Effects of NADH on dopamine release in rat striatum.

Nicotinamide adenine dinucleotide (NADH) may be utilized for the synthesis and regeneration of tetrahydrobiopterin (BH(4)), which in turn is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (DA). NADH has been reported to relieve some of the symptoms of Parkinson's disease, presumably by altering dopaminergic function. The present study examines the efficacy of NADH in influencing DA activity in the rat striatum. In striatal slices, NADH (350 microM) significantly increased basal DA and DOPAC efflux and caused a 2-fold increase in the DA overflow evoked by high KCl (25 mM). Tissue levels of BH(4), basal BH(4) efflux, and KCl-evoked BH(4) overflow were unaffected by NADH, as was [(3)H]DA uptake into striatal synaptosomes. In contrast to the effects of NADH on DA function in vitro, no effects were observed when NADH was administered systemically. NADH (10 or 100 mg/kg, s.c.) did not influence the tissue content of DA, 5-HT, or their metabolites in the midbrain or striatum, nor did it alter DA extracellular concentrations. These results indicate that NADH can increase DA release from striatal slices, although we are as yet unable to detect this effect in vivo.

Animals↗
PubMed2000

Differential effects of dopamine receptor subtype blockade on performance of rats in a reaction-time paradigm.

RATIONALE: Pharmacological manipulation of the dopaminergic system with antipsychotic agents disrupts motor behavior. Although most antipsychotic drugs have high affinity for D2 receptors, they also interact with other dopamine receptor subtypes. Therefore, the role of each of these receptor subtypes on motor performance is unclear. OBJECTIVE: The present study sought to investigate the relative importance of D1, D2, and D3 receptors on performance in a conditioned reaction-time task known to be extremely sensitive to dysfunction of the dopaminergic nigrostriatal pathway. METHODS: Rats were trained to release a lever in response to a visual cue within a reaction-time limit to receive a reinforcer (45mg food pellet). After the behavior of the rats had stabilized, the effects of a D1 (A69024), D2 (eticlopride), and D3 (nafadotride) receptor antagonists were assessed. RESULTS: A-69024 had no effect on performance at any dose tested (0.3, 0.6, and 1.3 mg/kg s.c.). Nafadotride (0.1, 0.3, and 1 mg/kg s.c.) produced only a mild deficit in performance at the highest dose. This deficit was characterized by an increase in the number of delayed responses with a non-significant decrease in the number of premature responses indicative of non-specific sedative effects. In contrast, the D2 receptor antagonist eticlopride (0.005, 0.01, and 0.02 mg/kg s.c.) produced profound deficits in performance as evidenced by a dose-dependent decrease in the number of correct responses. This decrease was accompanied by an increase in the number of delayed responses and a lengthening of the reaction time at the highest doses. CONCLUSIONS: These results provide further evidence that the execution of the reaction-time task is dependent preferentially upon the activation of D2 receptors, but not D1 or D3 receptors.

Animals↗
PubMed2000

Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress.

Footshock-evoked change in transcriptional activity of tyrosine hydroxylase in neurons of the locus coeruleus was examined using an intron-specific in situ hybridization histochemical technique. A significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts was found in locus coeruleus neurons 3h following 30 min of intermittent footshock. However, the footshock-induced increase in tyrosine hydroxylase transcription was not homogeneously expressed in locus coeruleus neurons. Similarly, administration of the alpha(2)-adrenergic receptor antagonist idazoxan produced a significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts that was heterogeneously distributed among locus coeruleus neurons. Both footshock and idazoxan significantly increased the regional levels of tyrosine hydroxylase messenger RNA in the locus coeruleus. The time-course of changes in tyrosine hydroxylase transcription rate and messenger RNA levels in the locus coeruleus was examined after a 15 min exposure to footshock. A robust increase in tyrosine hydroxylase transcription rate was found at the end of 15 min of footshock, which remained elevated for 6h and was back to the control levels by 24h. In contrast, in response to a 15 min period of footshock tyrosine hydroxylase messenger RNA concentrations in the locus coeruleus did not increase until 6h and remained elevated at 24h. These findings demonstrate that transcription of the tyrosine hydroxylase gene in locus coeruleus neurons in response to footshock stress occurs rapidly, is sustained for many hours and is heterogeneously distributed. These data also suggest that the increase in tyrosine hydroxylase messenger RNA following footshock is mediated, at least in part, by an increase in tyrosine hydroxylase gene transcription.

Animals↗
PubMed2000

Inhibitory glutamatergic regulation of evoked dopamine release in striatum.

Certain aspects of schizophrenia and Parkinson's disease suggest that glutamate might have an inhibitory effect on dopamine release. Several studies have reported that the excitatory actions of ionotropic glutamate agonists on extracellular dopamine levels in striatum are resistant to tetrodotoxin, which suggests that glutamate excites an impulse-independent mechanism of dopamine release. We tested the hypothesis that an inhibitory action of glutamate on dopamine terminals in the striatum specifically involves an impulse-dependent mechanism of dopamine release. We used voltammetry to monitor electrically-evoked dopamine release in striatal slices, which is completely tetrodotoxin- and Ca(2+)-sensitive and so provides a model of impulse-dependent dopamine release. Agonists of the ionotropic glutamate receptors significantly decreased the amplitude of the response, while antagonists significantly increased the amplitude of the response, by as much as approximately 60% in the case of kynurenic acid. These results support the hypothesis that ionotropic glutamate receptors can inhibit impulse-dependent dopamine release by a mechanism that acts locally within the striatum. This finding contrasts with previous reports that glutamate can excite impulse-independent dopamine release. This extends earlier findings that glutamate may both excite and inhibit subcortical dopamine systems by suggesting that the excitatory and inhibitory actions of striatal ionotropic glutamate receptors are specifically associated with impulse-independent and impulse-dependent dopamine release, respectively.

Animals↗
PubMed1999

Sensitization of norepinephrine release in medial prefrontal cortex: effect of different chronic stress protocols.

Previously, we demonstrated that continuous exposure of rats to cold (5 degrees C) for 2-3 weeks potentiates the increase in extracellular norepinephrine in the medial prefrontal cortex produced by acute tail shock. In the present study, we used in vivo microdialysis to examine whether this sensitization of evoked norepinephrine release also occurs in the medial prefrontal cortex following exposure to other chronic stress protocols. Rats exposed to 30 min of intermittent foot shock (0.6 mA) each day for 14 days, did not exhibit a greater increase in extracellular norepinephrine in response to acute tail shock. To determine whether this discrepancy between cold exposure and foot shock might be related to differences in the nature or the pattern of exposure to the chronic stressor, we also examined the effect of intermittent exposure to cold or continuous exposure to a foot shock protocol on tail shock-evoked norepinephrine release. Sensitized norepinephrine release did not develop following either intermittent exposure to cold (5 degrees C; 4 h/day for 14 days) or continuous exposure to a foot shock protocol (0.6 mA trains at random intervals 24 h/day for 14 days), suggesting that both the nature of the stressor as well as the pattern of exposure to the chronic stressor play a role in the development of sensitized norepinephrine release.

Animals↗
PubMed1999

Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.

Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.

14-3-3 Proteins↗
PubMed1999

Do the right thing.

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Ethics, Professional↗
PubMed1998

Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum.

We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.

Animals↗
PubMed1998

Postsynaptic integration of cholinergic and dopaminergic signals on medium-sized GABAergic projection neurons in the neostriatum.

The effects of cholinergic drugs and the interaction between cholinergic and dopaminergic compounds were studied on electrically evoked [3H]gamma-aminobutyric acid (GABA) overflow in slices of the rat neostriatum. Slices were prepared and loaded with [3H]GABA in the presence of beta-alanine and then superfused with Krebs-bicarbonate buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA uptake and metabolism, respectively. The nonselective muscarinic agonist oxotremorine (0.1-10 microM) increased the release of [3H]GABA and the selective M1 receptor agonist McN-A-343 (0.1-10 microM) exerted similar effect. The stimulatory effect of oxotremorine (10 microM) on [3H][GABA overflow was antagonized by the nonselective muscarinic antagonist atropine (1 microM) and the selective M1 receptor antagonist pirenzepine (0.1-1.0 microM). The M2 receptor antagonist methoctramine (1.0 microM) did not alter the stimulatory effect of oxotremorine. Of the muscarinic receptor antagonists atropine, pirenzepine, and methoctramine (1.0 microM) failed to affect [3H]GABA overflow. The M3 receptor antagonist p-F-HHSiD (1 microM) increased [3H]GABA overflow and p-F-HHSiD and oxotremorine were found to be additive in increasing this effect. The D2 dopamine receptor antagonist sulpiride (10 microM) increased the electrical stimulation-induced [3H]GABA overflow, and this stimulation was counteracted by concomitant administration of atropine (1 microM). McN-A-343 and sulpiride also increased the KCl-induced [3H]GABA overflow from superfused neostriatal slices and tetrodotoxin (1 microM) did not affect these stimulations. These data indicate that the release of GABA in the neostriatum is under the control of M1 stimulatory and M3 inhibitory muscarinic receptors. Dopamine, which exerts inhibition on GABA release via D2 receptors, may counteract the M1 facilitation, and M1 and D2 receptors involved in the cholinergic-dopaminergic interaction may be located postsynaptically on medium-sized spiny GABAergic projection neurons.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1997

Do compensatory processes underlie the preclinical phase of neurodegenerative disease? Insights from an animal model of parkinsonism.

Lesions of the DA neurons innervating the striatum is accompanied by permanent gross neurological deficits only when the loss of striatal DA is almost complete, a finding reminiscent of Parkinson's disease. This appears to result at least in part from an enhanced capacity of the remaining DA neurons to continue to modulate DA-sensitive targets in the striatum. Among the neurochemical changes that may be responsible for this enhanced capacity are a loss of high-affinity DA uptake sites and time-dependent increases in the synthesis and release of DA. Following very large lesions, an increase in the sensitivity of striatal cells to DA also gradually occurs (Fig. 1). A lesion-induced increase in the functional activity of residual neurons may be a rather general phenomenon. We have made analogous observations in the sympathoadrenal system (Fluharty et al., 1985) and in the noradrenergic (Acheson & Zigmond, 1981; Chiodo et al., 1983; Abercrombie et al., 1989) and serotonergic (Stachowiak et al., 1986) systems of CNS. Thus, during many neurodegenerative diseases, compensatory changes in the affected neural system and its targets may be involved in the extended preclinical stage that often is observed. This hypothesis has several implications. First, many clinical disorders that appear late in life may in fact have their origins in events that had occurred many years earlier, and the emergence of neurological or psychiatric symptoms may represent the end stage of the neurodegenerative-process, rather than its onset. Second, to reverse clinical symptoms one may not need to reverse the entire neurobiological deficit; instead, clinical recovery might be achieved with a relatively modest restoration of the injured projections. Third, it may be possible to achieve recovery even without restoring the connections that have been lost if the capacity of the remaining elements of the injured system can be enhanced further. Finally, in some cases arresting the degenerative process may be sufficient; the natural compensatory processes of the nervous system might then be permitted the time needed to restore function.

Adaptation, Physiological↗