Biomedical subjects

T W Stone

Publications and source records attributed to T W Stone.

At least 91 records · Page 5Linked to original sources

PubMed1996

Maintenance of muscimol-induced long-term depression by neurosteroids.

1. The present study was undertaken to expand investigations of the interaction between neurosteroids and long-term depression (LTD) induced by muscimol 10 mu M. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz) 3. As previously reported, muscimol at 10 mu M induced a time, frequency of stimulation and concentration-dependent LTD of the amplitude of orthodromic potentials. Alphaxalone, at concentrations that had no significant effect themselves on the population spike (0.5 and 1 mu M) potentiated the inhibitory effect of muscimol on the population spike size. 4. It is now reported that low concentrations of alphaxalone are able to potentiate the ability of muscimol to induce LTD. In addition, concentrations of muscimol as low as 1 mu M which are not themselves able to induce LTD, as well as aiphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one 1 mu M were able to maintain the LTD induced by muscimol 10 mu M 5. It is suggested that the ability of such low concentrations of GABA receptor agonists to maintain LTD could be of physiological importance.

Anesthetics↗

PubMed1996

Muscimol-induced long-term depression in the hippocampus: lack of dependence on extracellular calcium.

We have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal site. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one. It was also shown that glutamate receptor activity is not involved in the induction of this type of long-term depression. The present study investigates the role of calcium in the induction of this novel form of long-term depression and attempts to determine the mechanism of reversal of muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that the muscimol-induced long-term depression can be obtained in the absence of calcium in the bathing medium. In addition to this, the long-term depression was reversed by N-methyl-D-aspartate, kainic acid, high potassium medium, veratrine and the calcium ionophore A23187 but not high calcium (10 mM) medium. High potassium medium in the absence of calcium reversed the long-term depression induced by muscimol 10 microM. The results suggest that this type of glutamate-independent long-term depression can be induced in the absence of extracellular calcium. Extracellular calcium is not necessary for reversal of the long-term depression, although when intracellular calcium levels are raised, as by A23187, this is capable of inducing reversal.

Animals↗

PubMed1996

Potential role of adenosine antagonist therapy in pathological tremor disorders.

The continuing lack of effective long-term therapies for Parkinson's disease and other disorders in which a primary symptom is involuntary tremor is leading to a search for alternative pharmacological strategies. Adenosine is a major modulator of neuronal activity and neurotransmitter release in the central nervous system, with A1 receptors inhibiting transmitter release and A2 receptors generally enhancing release of several transmitter systems relevant to the control of movement. The A2a subtype of receptor is especially concentrated in the neostriatum and is co-localised with D2 receptors for dopamine, the affinity of which are reduced by activation of the A2a population. Antagonists of adenosine, such as theophylline, have been reported to improve the tremor in cases of Parkinson's disease and essential tremor, and the development of better and more selective A2a receptor antagonists may prove of value in these disabling disorders.

Adenosine↗

PubMed1996

Changes in hippocampal gene expression associated with the induction of long-term potentiation.

The expression of four genes: zif/268, c-fos, tubulin and alpha Ca2+/calmodulin-dependent protein kinase II (alpha CAMKII) was studied following the induction of LTP in Schaffer collateral CA1 neurone synapses in rat hippocampal slices maintained in vitro. Levels of c-fos mRNA and tubulin (T26) mRNA in area CA1 were unchanged after induction of LTP, however, zif/268 and alpha CAMKII mRNA levels showed a significant increase compared to non-potentiated controls. It is possible, therefore, to measure changes in gene expression using in situ hybridisation following induction of LTP in vitro and these results strengthen the theory that zif/268 and alpha CAMKII are involved in some aspect of the induction or maintenance of hippocampal LTP.

Animals↗

PubMed1996

Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory.

The N-methyl-D-aspartate (NMDA) receptor polyamine site antagonist, ifenprodil, had no effect on spontaneous alteration or locomotor activity in the Y-maze when given alone. The NMDA receptor/ion channel blocker, dizocilpine, induced a deficit in spontaneous alteration, but when ifenprodil was co-administered with dizocilpine, it showed a strong tendency to attenuate the dizocilpine-induced deficit. In the plus-maze, ifenprodil had an anxiolytic profile which was accompanied by an increase in locomotion. Dizocilpine had an anxiolytic profile in this model and increased locomotor activity. When co-administered with dizocilpine, ifenprodil reduced both the anxiolytic and locomotor effects of dizocilpine. When co-administered with ifenprodil, cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (CPX) reduced the anxiolytic effect of ifenprodil. CPA and CPX in combination did not reverse the anxiolytic effect of ifenpropil. It is concluded that NMDA antagonists with different sites of action can show distinct behavioural profiles, with dizocilpine but not ifenprodil inducing a deficit in working memory, while both are anxiolytic. Blockade of NMDA receptors by ifenprodil, however, can preclude any response to dizocilpine. The anxiolytic activity of ifenprodil may involve the release of purines acting at adenosine receptors.

Animals↗

PubMed1995

Modulation by adenosine of a neuronal inhibitory interaction in the rat hippocampus.

Adenosine is acknowledged to have a primarily inhibitory function in the central nervous system, but is believed to have little effect on inhibitory neurones themselves. It is, however, difficult to determine the effect of adenosine on inhibitory synaptic potentials since adenosine directly depresses evoked potentials and, in the presence of bicuculline to block GABAA-mediated inhibition, the bicuculline-resistant fraction of paired-pulse inhibition (ppi) is greater between pairs of small potentials than between pairs of larger potentials. Here, adenosine increased bicuculline-resistant ppi when stimulus strength was constant between adenosine and control but ppi of responses in adenosine was markedly less than ppi of control responses of the same size. Adenosine had less effect on the size of 'conditioned' potentials than on control potentials. It is concluded that adenosine can reduce the bicuculline-resistant fraction of paired-pulse inhibition in the hippocampus. Further quantitative comparison of the effects of adenosine on ppi and on single evoked potentials excluded a difference in the potency of adenosine at excitatory and inhibitory terminals as an explanation for this activity. The results suggest that adenosine may diminish bicuculline-resistant paired-pulse inhibition by enhancing a simultaneous facilitatory component of the neuronal responses.

Adenosine↗

PubMed1995

Potentiation by neurosteroids of muscimol/adenosine interactions in rat hippocampus.

Extracellular recordings were made from the CA1 pyramidal cell layer of hippocampal slices in response to stimulation of Schaffer collateral fibres in stratum radiatum. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one potentiated the inhibitory effect of muscimol on the population spike size at low concentrations (0.5 and 1 microM) that had no significant effect on the spike size by themselves. This profile is in agreement with other reports which have described the effect of these neurosteroids as barbiturate-like. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one also at low concentrations potentiated the inhibitory effect of adenosine alone and in the presence of 1 mM barium which blocked adenosine activated potassium channels. Alphaxalone failed to potentiate the inhibitory effect of adenosine in the presence of 1 microM bicuculline. It is concluded that these neurosteroids enhanced the potentiative interaction between adenosine and muscimol in the presence of barium. The results indicate that adenosine's effects are normally enhanced by virtue of the potentiative interaction occurring with endogenous GABA.

Adenosine↗

PubMed1995

Effect of adenosine on bicuculline-resistant paired-pulse inhibition in the rat hippocampal slice.

This study extends previous investigations into the effect of adenosine on bicuculline-resistant paired-pulse inhibition between field potentials evoked 300 ms apart in the CA1 area of the rat hippocampal slice. A direct assessment of the effect of adenosine on paired-pulse inhibition is complicated by the facts that adenosine directly depresses evoked potentials and bicuculline-resistant paired-pulse inhibition is greater between pairs of small potentials than between pairs of larger potentials. Adenosine increased bicuculline-resistant paired-pulse inhibition when stimulus strength was constant between adenosine and control but paired-pulse inhibition of responses in adenosine was markedly less than paired-pulse inhibition of control responses of the same size. Furthermore, adenosine decreased the size of conditioned potentials to a significantly lesser extent than unpaired potentials of the same initial size. Taken together the results indicate that adenosine can decrease bicuculline-resistant paired-pulse inhibition in the hippocampus. A possible mechanism for this effect is that adenosine is suppressing transmission at excitatory terminals onto interneurones which would suggest that these receptors are more sensitive to adenosine than those on the Schaffer collateral/CA1 pyramidal cell synapses. In this case adenosine should reduce paired-pulse inhibition at lower concentrations than are required for depression of single evoked potentials. A comparison of the concentration-response relationships for the effects of adenosine on paired-pulse inhibition and on single evoked potentials ruled out greater sensitivity of adenosine receptors at excitatory terminals onto interneurones as an explanation for adenosine's action on bicuculline-resistant paired-pulse inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1995

Efficacy of an adenosine antagonist, theophylline, in essential tremor: comparison with placebo and propranolol.

Propranolol, which has long been used as the standard treatment for essential tremor, has been compared with placebo and theophylline in ten newly diagnosed patients without other, prior drug treatments. Patients were treated for four weeks with one drug, followed by placebo for four weeks, and then the second drug for the same period, in a blind cross-over trial. Tremor was quantified using the volumetric method, and was decreased significantly after one week on propranolol, 80 mg/day. Theophylline 150 mg/day reduced tremor to the same extent, although the improvement was not significant until the second week. Three patients reported side effects on propranolol. It is suggested that theophylline may be a useful alternative agent in the treatment of essential tremor, probably due to a chronic up-regulation of adenosine receptors.

Adenosine↗

PubMed1995

Delayed development of symptomatic improvement by (--)-deprenyl in Parkinson's disease.

Twenty de novo patients with Parkinson's disease (Hoehn-Yahr stages I, II, III) were studied in a double blind trial after introducing (--)-deprenyl monotherapy. The parkinsonian symptoms were assessed by a novel graded clinical rating scale, by UPDRS and by the North Western self-rating scale. A significant change was observed in motor behaviour and daily activity (UPDRS) after 3 weeks of treatment with (--)-deprenyl at 10 mg/day. The total scores using UPDRS and the North Western ratings were changed significantly after 4 weeks. The greatest changes observed were in walking and in hypokinesia. Rigidity was not modified by (--)-deprenyl.

Aged↗

PubMed1995

Adenosine selectively depresses muscarinic compared with non-muscarinic receptor mediated depolarisation of the rat superior cervical ganglion.

1. A grease gap d.c. recording technique was used to measure electrophysiological responses of the isolated rat superior cervical ganglion. 2. Adenosine at 100 microM depressed depolarisations to the muscarinic agonists carbachol, muscarine and methylfurmethide. In contrast adenosine (100 microM) did not alter depolarisations to 1,1-dimethyl-4-phenylpiperazinium, 2-methyl-5-hydroxytryptamine and potassium and enhanced depolarisations to 5-hydroxytryptamine and gamma-aminobutyric acid. 3. Adenosine-induced depressions of the depolarisations to carbachol, muscarine, and methylfurmethide tended to be increased in the presence of 0.3 microM methoctramine (a muscarinic receptor antagonist with slight selectivity for M2 receptors). The increase was statistically significant (P < 0.01) for carbachol. 4. Medium containing 0.1 mM Ca2+ and 0.3 microM pirenzepine augmented the hyperpolarising phase of the response to carbachol. Adenosine (10-300 microM) hyperpolarised ganglia and did not significantly alter the hyperpolarisation to 0.3 or 1 microM carbachol but selectively reduced the depolarisation response to 3 microM carbachol. 5. Adenosine-induced hyperpolarisations (100 microM) were enhanced when applied during depolarisations to muscarinic agonists (muscarine, pilocarpine, N-methyl-N-(l-methyl-4-pyrrolidine-2-butynyl)acetamide (BM-5)), and other M-current inhibitors, barium and eledoisin-related-peptide. Adenosine induced hyperpolarisations were not affected by D-Ala6-luteinizing-hormone-releasing-hormone or uridine 5'-triphosphate which produced small depolarisations. 6. It is concluded that adenosine acts selectively in opposing mechanisms of depolarisation of the rat SCG that are due to the action of muscarinic agonists (acting via M1-receptors) and by other M-current inhibitors.

Adenosine↗

PubMed1995

Purine suppression of proliferation of Sertoli-like TM4 cells in culture.

The effect of adenosine and related compounds on the proliferation of cultured TM4 cells, a Sertoli-like cell line, has been examined. Adenosine, as well as A1 and A2 adenosine receptor agonists (cyclohexyladenosine and N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine) inhibited cell proliferation. These effects were prevented by 8-cyclopentyl theophylline, 1,3-dimethyl-propargylxanthine and caffeine, antagonists at the A1, A2 and both receptors, respectively. The xanthines had no effect by themselves and, consistent with this, the bathing medium was found not to contain detectable levels of adenosine. It is concluded that TM4 cell proliferation can be regulated by receptors for adenosine.

Adenosine↗

PubMed1995

Induction of a novel form of hippocampal long-term depression by muscimol: involvement of GABAA but not glutamate receptors.

1. Unlike long-term potentiation, long-term depression (LTD) in the central nervous system remains poorly understood. The present study was undertaken to investigate the role of GABAA receptors in LTD and synaptic plasticity. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). 3. Muscimol induced a time- and concentration-dependent LTD of the amplitude of orthodromic potentials. Increasing the stimulation frequency from 0.01 Hz to 1 Hz for 10 s reversed the LTD induced by muscimol. Muscimol also induced LTD in the absence of electrical stimulation. 4. Adenosine decreased the spike size in a concentration-dependent manner, but failed to induce LTD. 5. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one at concentrations that did not have any effect themselves on the population spike (0.5 and 1 microM), potentiated the inhibitory effect of muscimol on the population spike size, including concentrations which were not effective by themselves. Both steroids were able to potentiate the ability of muscimol to induce LTD. 6. Bicuculline, 5 microM, reversed the LTD induced by muscimol, 10 microM. 7. The NMDA receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (2-AP5), the NMDA/metabotropic antagonist 2-AP3 and selective metabotropic antagonist L-(+)-2-amino-3-phosphonopropionic acid (L(+)-AP3) failed to modify the LTD. Similarly, quisqualic acid and (1S, 3R)-aminocyclopentane dicarboxylic acid (ACPD) a selective agonist at metabotropic receptors did not induce LTD or short-term depression, whereas kynurenic acid prevented the reversal of the LTD obtained at 1 Hz. 8. It is concluded that LTD can be induced by the selective activation of GABAA receptors. The lack of involvement of glutamate receptors in our protocol confirms the unique nature of the LTD described here. The phenomenon of GABA-induced LTD and its reversal by 1 Hz stimulation may represent a novel type of long-lasting depression by which inhibitory interneurones can modulate pyramidal cell excitability in a frequency-dependent manner.

Action Potentials↗

PubMed1995

Anxiolytic activity of adenosine receptor activation in mice.

1. Purine analogues have been examined for anxiolytic- and anxiogenic-like activity in mice, by use of the elevated plus-maze. 2. The selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 10 and 50 microg kg(-1), with no effect on locomotor performance at these doses. 3. The A1 selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4. Caffeine had anxiogenic-like activity at 30 mg kg(-1) which was prevented by CPA at 50 micro kg(-1). 5. The A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg(-1). The A2 receptor antagonist, 1,3-dimethyl-l-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6. Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter. 7. The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic-like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine.

Adenosine↗

PubMed1994

Interaction between adenosine and GABAA receptors on hippocampal neurones.

Extracellular recordings were made from the CA1 pyramidal cell layer of hippocampal slices in response to stimulation of Schaffer collateral fibres in stratum radiatum. Adenosine and muscimol induced concentration-dependent reductions in the amplitude of orthodromically induced population potentials. In order to eliminate effects of these agents on potassium channels, experiments were performed in the presence of barium, 1 mM. This concentration increased potential size, and reduced the inhibitory effect of adenosine on population spike size, but not synaptic potential size. This profile is consistent with the blockade of potassium channels associated only with the postsynaptic effects of adenosine. Muscimol responses were unaffected. Adenosine potentiated the ability of muscimol to inhibit evoked potentials in the absence or presence of barium. The potentiation was prevented by the A1 selective antagonist 8-cyclopentyltheophylline. The effects of adenosine as well as muscimol were reduced by the chloride channel blockers DIDS, which also prevented the adenosine potentiation of muscimol. The results indicate the ability of adenosine to operate chloride channels in hippocampal neurones, and suggest a potentiative interaction between adenosine and muscimol which may also involve chloride channels.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1994

Mechanism of the hippocampal loss of adenosine sensitivity in calcium-free media.

Adenosine depresses the excitability of pyramidal neurones in the hippocampus. This effect is lost in calcium-free media and we have now investigated the mechanism of this. Extracellular recordings were made of antidromically and orthodromically evoked population potentials from CA1 region of rat hippocampal slices. It was observed that the activity of adenosine can be restored in the presence of procaine or carbamazepine, known inhibitors of sodium channels. The GABAB agonist baclofen was able to depress potential size but did not restore sensitivity to adenosine. It is concluded that the loss of postsynaptic sensitivity to adenosine in calcium-free solution results from the increased sodium conductances.

Adenosine↗

PubMed1994

A paradoxical inhibitory effect of xanthines on hippocampal excitability in calcium-free media.

In calcium-free media, neurones in the rat hippocampal slice develop bursts of population potentials and lose their sensitivity to adenosine. The present paper reports the unexpected and paradoxical finding that the xanthines theophylline and cyclopentyltheophylline, the latter of which is selective for A1 purine receptors, depressed the excitability of hippocampal pyramidal neurones in calcium-free media. Chelating residual calcium with EGTA reduced excitability which was additive with the xanthine effect, while 100 microM calcium depressed the response to theophylline. The inhibition by xanthines was prevented by adenosine, which had no effect by itself, but was not reproduced or modified by adenosine deaminase. The xanthine effects were also prevented by baclofen and carbamazepine. A common feature of adenosine, baclofen and carbamazepine which may account for their antagonism of the xanthines is the blockade of calcium fluxes. It is proposed that in the presence of low external concentrations of calcium xanthines can reduce excitability by promoting the mobilisation and trans-membrane movement of residual calcium in the medium or neuronal membranes.

Adenosine↗

PubMed1994

Blockade by 1,3-dipropyl-8-cyclopentylxanthine (CPX) of purine protection against kainate neurotoxicity.

The adenosine A1 receptor selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (CPX) has been administered systemically to rats together with the neurotoxin kainic acid. At the lower doses of CPX tested, 10 and 50 micrograms/kg, which were sufficient to prevent the neuroprotective activity of exogenous agonists, there was no exacerbation of the neuronal damage. At 250 micrograms/kg, some enhancement of damage was found, which was also produced by 8-(p-sulphophenyl)theophylline, a non-selective xanthine which does not cross the blood-brain barrier. The results are consistent with the involvement of a central A1 receptor in the neuroprotective activity of purines, and suggest that blockade of a peripheral adenosine receptor, possibly of the A2 type, may increase neuronal damage.

Animals↗