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Biomedical subjects

H J Little

Publications and source records attributed to H J Little.

At least 19 recordsLinked to original sources
PubMed1995

Nitrendipine prevents the decrease caused by chronic ethanol intake in the maintenance of tetanic long-term potentiation.

Prolonged ethanol consumption has previously been reported to decrease long-term potentiation (LTP) in isolated hippocampal slices. Dihydropyridine calcium channel antagonists, such as nitrendipine, have been previously found to prevent some of the adaptive responses to chronic ethanol intake. The present study investigated the effects of concurrent in vivo administration of nitrendipine and ethanol on LTP in isolated mouse hippocampal slices. LTP was produced by either one or two tetanic stimuli or by increased calcium. When one tetanus was used, although the potentiation of the population spike height was less after the ethanol treatment, the difference was not quite significant. However, the potentiation after in vivo administration of ethanol plus nitrendipine was significantly greater than after ethanol alone. When two tetanic stimuli were applied, the maintenance of the potentiation of the population spike height was significantly decreased by the chronic ethanol treatment. This decrease was not seen when nitrendipine was given with the ethanol. When LTP was produced by a transient increase in the calcium concentration in the bathing medium, the chronic ethanol treatment did not alter the potentiation of the population spike height, but in vivo treatment with ethanol plus nitrendipine decreased the potentiation.

Alcohol Drinking↗
PubMed1995

Do GABAB receptors have a role in causing behavioural hyperexcitability, both during ethanol withdrawal and in naive mice?

The effects of the GABAB agonist baclofen and the GABAB antagonist CGP35348 were examined on the behavioural hyperexcitability which is seen on cessation of chronic ethanol treatment. When baclofen was given to mice of the TO strain after withdrawal from ethanol inhalation, there was evidence of increased hyperexcitability with one dose, 2.5 mg/kg, but no significant change was seen with other doses, 1.25 and 10 mg/kg. When given after withdrawal from a liquid diet containing ethanol, baclofen, 10 mg/kg, produced a large, but short lasting, increase in the ratings of hyperexcitability during the withdrawal period. This effect was significantly decreased when the antagonist CGP35348, 300 mg/kg, was given with baclofen 10 mg/kg. When the antagonist was given alone at 300 mg/kg it significantly decreased the hyperexcitability during ethanol withdrawal. Increases in the ratings of hyperexcitability were seen when baclofen was given to control mice, which had not received ethanol, and these effects were significant, so the effects during ethanol withdrawal were not confined to that syndrome. CGP35348 decreased the behavioural ratings in control animals, and blocked the effects of baclofen 10 mg/kg. When the effects of the compounds on spontaneous locomotor activity in control mice were measured, this parameter was decreased both by baclofen and by CGP35348, at does which were effective in altering the handling-induced behaviour.

Animals↗
PubMed1995

Tolerance to competitive NMDA antagonists, but no crosstolerance with barbiturates.

Tolerance occurred to the sedative actions of the competitive NMDA antagonists, CGP39551 and CGP37849, as measured by a decrease in spontaneous locomotor activity after 1 week or 2 weeks of administration, respectively, in studies using the TO strain of mice. Crosstolerance was seen between these compounds. When CGP37849 was given after 2 weeks treatment with CGP39551, an increase in locomotor activity was seen. Chronic barbiturate treatment, producing tolerance to the actions of pentobarbitone, did not affect the sedative properties of CGP39551 or CGP37849. Chronic treatment with CGP39551 did not alter the ataxic actions of pentobarbitone. Seven days of treatment with HA966 caused complete tolerance to its sedative actions, but no crosstolerance was seen to pentobarbitone, CGP39551, or CGP37849. A small but significant decrease was seen in the convulsion thresholds to NMDA after 15 days of treatment with CGP39551, and a small significant increase in ratings of convulsive behavior after 16 days injections of CGP37849. No significant changes were found in either Bmax or Kd for [3H]-MK-801 binding in cerebrocortical tissue 24 h after the last chronic treatment with either of the NMDA antagonists.

2-Amino-5-phosphonovalerate↗
PubMed1995

Increases in non-N-methyl-D-aspartate glutamatergic transmission, but no change in gamma-aminobutyric acidB transmission, in CA1 neurons during withdrawal from in vivo chronic ethanol treatment.

Evoked fast excitatory postsynaptic potentials and slow inhibitory postsynaptic potentials were measured in mouse CA1 neurons in hippocampal slices after chronic ethanol treatment in vivo. Intracellular recordings were made 2, 4 and 6 hr after ethanol withdrawal, i.e., after the beginning of slice preparation. The resting membrane potentials were standardized to -60 mV by using constant current injection. The fast excitatory postsynaptic potentials were isolated by adding DL-2-amino-5-phosphonopentanoic acid, bicuculline and nitrendipine to the bathing solution and injecting QX-314 into the recording cell; stimulation then evoked a monophasic depolarization with a maximum of 16.3 mV at about 30 msec after stimulation, which was inhibited by 6-cyano-7-nitroquinozaline-2,3-dione. At 4 and 6 hr after withdrawal, but not at 2 hr, the estimated fast excitatory postsynaptic potential conductance in slices from ethanol-treated mice was significantly larger than in those from control animals. There were no changes in stimulus/response relation or voltage-dependency of the depolarization. In the presence of these blocking agents, the thresholds for elicitation of field potentials was decreased at 6 hr from withdrawal. The slow inhibitory postsynaptic potentials were isolated by adding DL-2-amino-5-phosphonopentanoic acid, 6-cyano-7-nitroquinozaline- 2,3-dione and bicuculline to the bathing solution; stimulation of the Schaffer collateral fibers then evoked a monophasic hyperpolarization with a maximum of 5.7 mV at about 180 msec after stimulation, which was inhibited by the gamma-aminobutyric acidB antagonist saclofen. At the three time points, the stimulus/response relation, voltage dependency of the hyperpolarization and estimated slow inhibitory postsynaptic conductance in ethanol-treated mice did not differ from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Increased NMDA receptor and calcium channel activity underlying ethanol withdrawal hyperexcitability.

Withdrawal from chronic ethanol administration results in hyperexcitability. In the hippocampus, evoked bursting activity and spontaneous epileptiform events are seen. The present study investigated the effect of ethanol withdrawal on N-methyl-D-aspartate (NMDA) receptor-mediated postsynaptic potentials and on voltage-gated calcium currents, in mouse hippocampal pyramidal cells. The NMDA receptor-mediated component of synaptic excitation was increased during withdrawal, accompanied by an increase in synaptic activation of calcium spikes. Evidence for a direct effect of ethanol withdrawal on calcium channel function was seen in voltage clamp recordings of isolated, slowly inactivating calcium currents. A synergistic effect of increased NMDA receptor and calcium channel function is therefore suggested to contribute to hyperexcitability during ethanol withdrawal.

Animals↗
PubMed1995

Effects on ethanol withdrawal hyperexcitability of chronic treatment with a competitive N-methyl-D-aspartate receptor antagonist.

The effects of the competitive N-methyl-D-aspartate receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CGP39551) on the hyperexcitability produced by withdrawal from chronic ethanol treatment were studied in mice, to which CGP39551 was given chronically with the ethanol. When an interval of 72 or 96 hr was left between the last of the repeated CGP39551 injections and withdrawal from ethanol, the severity of the ethanol withdrawal syndrome was increased. When shorter time intervals were left between the end of the CGP39551 treatment and the ethanol withdrawal, the chronic CGP39551 treatment protected against the withdrawal hyperexcitability. When a single low dose of CGP39551 was given immediately after ethanol withdrawal, the compound protected against the withdrawal hyperexcitability. It is therefore suggested that the protective effects of concurrent chronic treatment with CGP39551, seen when the shorter intervals were allowed, were caused by residual compound. The increased severity of withdrawal, when sufficient time was left for washout of CGP39551, suggests that chronic administration of CGP39551 increased the adaptive changes that cause or contribute to ethanol withdrawal hyperexcitability. The results differ from the previously reported effects of N-methyl-D-aspartate antagonists on ethanol tolerance, because this was reduced by concurrent chronic treatment. They are also in contrast with the effects of chronic dihydropyridine calcium channel antagonists, which decreased both the development of tolerance and the ethanol withdrawal syndrome, when given chronically, concurrently with the ethanol. Cessation of prolonged ethanol intake results in a period of neuronal hyperexcitability, described as the withdrawal or abstinence syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1995

Identification of distinct components, with different time courses, of the changes in response to convulsive stimuli during ethanol withdrawal.

The time courses of changes in sensitivity to handling-induced hyperexcitability, audiogenic seizures and a variety of chemical convulsants were compared in mice during a 24-hr period after withdrawal from chronic ethanol treatment. The peak increase in handling-induced hyperexcitability was seen between 3 and 5 hr after the withdrawal, disappearing by 12 hr, whereas the peak sensitivity to an audiogenic stimulus was found 8 hr into the withdrawal period. No changes were seen in thresholds to bicuculline during the 24-hr study. The thresholds to N-methyl-D-aspartate were decreased during the withdrawal period, with a maximum change at the 16-hr interval. In contrast, the thresholds to aminophylline were increased at 4 hr into withdrawal. The thresholds to 4-aminopyridine were also increased, with maximum changes at the 8-hr and 12-hr intervals. The only alterations in sensitivity to methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and kainate were increases in the thresholds immediately on withdrawal, which were likely to have been due to residual ethanol. The results indicate that a complex pattern of neuronal changes occurs during ethanol withdrawal with a series of alterations in responses to convulsive stimuli which differ both in direction and in time course, suggesting different underlying mechanisms.

4-Aminopyridine↗
PubMed1994

Effects of diltiazem in convulsive states differ from those previously reported for dihydropyridine calcium channel antagonists.

Unlike the dihydropyridine calcium channel antagonists studied previously, the benzothiazepine calcium channel antagonist, diltiazem, increased the incidence of convulsions caused by bicuculline, N-methyl-DL-aspartate or 4-aminopyridine. However, the latencies to convulsions were also increased. Diltiazem increased the ratings of convulsive behaviour on handling after intraperitoneal administration of bicuculline, or pentylenetetrazol and after the calcium channel activator, Bay K 8644, administered ICV. When the binding of the dihydropyridine, [3H]-nitrendipine in the CNS was measured in vivo, this was increased by diltiazem. This compound therefore showed a different pattern of interaction with convulsant drugs then that previously demonstrated for other calcium channel antagonists, appearing to possess both pro- and anticonvulsant actions, and a different pattern of interaction with the dihydropyridine receptor complex.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Interactions between diltiazem and ethanol: differences from those seen with dihydropyridine calcium channel antagonists.

It has previously been shown that dihydropyridine calcium channel antagonists prevent the ethanol withdrawal syndrome and potentiate the acute effects of ethanol and other central depressant drugs. We now report that, in contrast, the benzothiazepine calcium channel antagonist, diltiazem, gave no protection against the behavioural hyperexcitability seen during ethanol withdrawal, when given either acutely, on withdrawal, or chronically, during the ethanol treatment. A significant increase in convulsive behaviour on handling was seen during the withdrawal period when diltiazem was given on cessation of a mild chronic ethanol treatment schedule. Diltiazem decreased the acute general anaesthetic effects of ethanol, and did not appear to potentiate the ataxic action of ethanol. Centrally administered diltiazem did not enhance the hypothermic action of ethanol, but this effect was significantly increased by diltiazem when the calcium channel antagonist was given peripherally. When given alone by the intraperitoneal route, diltiazem decreased spontaneous locomotor activity and lowered body temperature. When the intracerebral route was used for administration of diltiazem, a significantly decrease in body temperature was seen when this compound was given alone, accompanied by a brief hyperexcitability. The interactions between ethanol and diltiazem therefore appear to differ from those seen with other calcium channel antagonists.

Anesthesia, General↗
PubMed1994

The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice.

1. The ability of two dihydropyridine calcium channel antagonists, felodipine and nitrendipine both to displace [3H]-isradipine binding in CNS tissue measured ex vivo and to protect against the ethanol withdrawal syndrome has been investigated. 2. Mice were injected with various doses of felodipine or nitrendipine and [3H]-isradipine binding measured in brain homogenates prepared 0.5, 3 or 5 h later. Inhibition versus dose curves were sigmoid and the dose required to produce 50% inhibition increased linearly with time after administration. Felodipine was approximately 10 times more potent than nitrendipine. 3. Nitrendipine (50 mg kg-1, i.p.) and felodipine (10 mg kg-1, i.p.) produced around a 75% inhibition of [3H]-isradipine binding 3 h later. Binding of [3H]-nitrendipine to cerebral tissues measured after in vivo injection of the ligand was decreased by nitrendipine (50 mg kg-1) and felodipine (10 mg kg-1) to a similar extent. 4. Nitrendipine (50 mg kg-1) prevented the behavioural signs of ethanol withdrawal as measured by handling induced convulsions, but felodipine (10 mg kg-1 or 2 mg kg-1) did not provide any protection against this effect of ethanol withdrawal. Felodipine (10 mg kg-1, twice daily) during the course of ethanol treatment also failed to attenuate the withdrawal syndrome. 5. The convulsive response to a mild audiogenic stimulus during ethanol withdrawal was increased following one dose of felodipine (5 mg kg-1, i.p.) but unaffected by nitrendipine. 6. Injection of Bay K 8644 (60 microgram, i.c.v.) produced a significant increase in handling-induced convulsive behaviour. Felodipine (10 mg kg-1, i.p.) reduced this behaviour both 60 and 120 min later, while nitrendipine (50 mg kg-1) showed a modest reduction only at 120 min.7. In contrast, nitrendipine (50mg kg-1) and felodipine (10 mg kg-1) produced similar effects on the hyperexcitability produced by handling following administration of bicuculline. Hexamethonium(8 mg kg-1) had no effect on this response.8. No change was found in [3H]-isradipine or [125I]-w-conotoxin binding to cerebral tissue prepared from ethanol-dependent mice.9. These results demonstrate that while felodipine and nitrendipine have similar actions on some CNS-mediated effects (raising seizure thresholds to several convulsant drugs), felodipine, in contrast to nitrendipine, has no effect on the ethanol withdrawal syndrome. Suggested explanations for the results include the possibility that nitrendipine may protect against the ethanol withdrawal syndrome via sites other than dihydropyridine receptors: that felodipine has partial agonist actions at dihydropyridine receptors in the CNS or that felodipine has actions which mask its protective effect in ethanol withdrawal.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Possible involvement of NMDA receptor-mediated transmission in barbiturate physical dependence.

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.

2-Amino-5-phosphonovalerate↗
PubMed1993

Changes in voltage-operated calcium channels modify ethanol withdrawal hyperexcitability in mouse hippocampal slices.

Measurements of hippocampal excitability were made from area CA1 of isolated mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, and the effects of the stereoisomers of the dihydropyridine Bay K 8644, that act at calcium channels, were investigated. The decrease in the threshold stimulation required to produce a single population spike, the leftward shift in the population spike input-output curves, and the increase in population spike amplitude, that were seen during ethanol withdrawal, were all increased by the (-) isomer of Bay K 8644. This isomer has been shown to increase opening of calcium channels. These effects of ethanol withdrawal were decreased by the (+) isomer of Bay K 8644, that is a calcium channel blocker. In contrast, the increase in paired-pulse potentiation of the population spike, seen during the initial phase of ethanol withdrawal, was significantly decreased by both isomers of Bay K 8644. After the chronic ethanol treatment, single orthodromic stimuli produced epileptiform field potentials, consisting of two independent phases, a short latency series of multiple population spikes, superimposed upon the initial observed EPSP, and a longer latency train of spikes, occurring on a second EPSP, temporally distinct from the first. The (-) isomer of Bay K 8644 increased both these phases of epileptiform activity during ethanol withdrawal in a dose-dependent manner, while (+)-Bay K 8644 reduced the initial phase of multiple spiking and abolished the later phase. In slices from control animals, the higher concentration of (-)-Bay K 8644 (2 microM), but not the lower concentration (500 nM) decreased the stimulation required to produce multiple population spikes. Neither produced the long latency epileptiform activity. The (+) isomer of Bay K 8644 had no effect on control recordings. Lesioning the Schaffer collateral-commissural fibre pathway, or removing area CA3, in slices from ethanol-treated animals, abolished the later phase of epileptiform activity without affecting the initial multiple spiking. Intracellular recordings from area CA1 showed both the short latency and the longer latency epileptiform activities in slices from ethanol-treated mice and in control hippocampal slices after application of the (-) isomer of Bay K 8644, but these patterns of activity were not seen in control slices in the absence of Bay K 8644. Spontaneous activity during ethanol withdrawal was seen in intracellular recordings, but such activity was not seen in the field potential recordings.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Calcium channel antagonists prevent adaptive responses to ethanol.

Prolonged ethanol administration causes upregulation of dihydropyridine-sensitive binding sites, thought to represent neuronal calcium channels, and these channels appear to play an important role in ethanol physical dependence. Dihydropyridine calcium channel antagonists, when given chronically with ethanol, prevent the development of tolerance to ethanol and the ethanol withdrawal syndrome. The upregulation of binding sites for these compounds was also prevented. Epileptiform activity has been described in isolated hippocampal slices after chronic ethanol treatment in vivo. This was prevented, stereoselectively, by the dihydropyridine calcium channel antagonist, isradipine, that did not affect the hyperexcitability produced in control slices by the GABAA antagonist, bicuculline.

Adaptation, Physiological↗
PubMed1992

Chronic treatment with a benzodiazepine agonist in vivo increases the actions of the benzodiazepine partial inverse agonist, FG7142, on the hippocampal slice in vitro.

We have shown previously that chronic treatment of mice with a benzodiazepine agonist, flurazepam, increased the pharmacological actions of the partial inverse agonist, FG7142. We have investigated the neurophysiological basis for this using extracellular recordings of evoked field potentials in area CA1 of isolated hippocampal slices. The slices were prepared 48 h after the end of the chronic in vivo treatment, a time when no evidence of residual benzodiazepine agonist activity was found in the CNS. During perfusion with standard Ringer solution, no significant differences were seen between the field potentials in slices from flurazepam-treated mice and those from control animals. When FG7142 was added to the perfusion medium there was an increase in the secondary discharges that followed the initial population spikes, and an increase in paired pulse potentiation. These increases were significantly greater in slices from flurazepam-treated mice, compared with controls. The results show that the effects of the partial inverse agonist, FG7142, on an isolated neuronal preparation, were increased by chronic administration of a benzodiazepine agonist in vivo. This effect is suggested to be due to a decrease in GABAergic inhibition.

Animals↗
PubMed1992

Changes in intrinsic inhibition in isolated hippocampal slices during ethanol withdrawal; lack of correlation with withdrawal hyperexcitability.

1. Intracellular recordings were made from pyramidal cells in area CA1 in mouse isolated hippocampal slices, after chronic ethanol treatment in vivo. 2. Fast i.p.s.ps were isolated by injection of the impaled neurones with QX314 (to block fast sodium currents and the slow i.p.s.p.) and stimulating the interneurones in the presence of the glutamatergic blockers, CNQX and APV. 3. The isolated fast-inhibitory postsynaptic potential (f.-i.p.s.p.) was measured at intervals during the 7 h withdrawal period. The reversal potential and sensitivity to bicuculline suggested that the isolated f.-i.p.s.p. was mediated by activation of the GABAA receptor-chloride ionophore complex. 4. Measurement of stimulus-response relationships for the f.-i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of -50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, Ei.p.s.p., with no observed change in conductance, Gi.p.s.p. 5. No differences in f.-i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings. 6. Paired pulse depression of the f.-i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period. 7. The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABAA receptor-chloride ionophore complex.4. Measurement of stimulus-response relationships for the f.-i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of - 50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, Ejp.sp with no observed change in conductance, Gj ps p.5. No differences in f.-i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings.6. Paired pulse depression of the f.-i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period.7. The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABAA receptor-chloride ionophore complex.The increase in the f.-i.p.s.p. during the initial stages of the withdrawal might prevent the overt expression of epileptiform activity at this time.

Animals↗
PubMed1992

The effects of chronic treatment with the dihydropyridine, Bay K 8644, on hyperexcitability due to ethanol withdrawal, in vivo and in vitro.

1. The effects of chronic treatment with the dihydropyridine, Bay K 8644, were studied on the ethanol withdrawal syndrome, in vivo and in vitro. 2. Addition of racemic Bay K 8644 to the drinking mixture, throughout the chronic ethanol treatment, decreased the behavioural excitability seen during ethanol withdrawal in vivo. 3. All the signs of hyperexcitability in field potentials in the isolated hippocampal slice, caused by ethanol withdrawal, were decreased by the chronic administration of Bay K 8644. 4. These effects resembled those previously reported for chronic administration of calcium channel antagonists; racemic Bay K 8644 has both calcium channel activating and antagonist properties. 5. Measurement of brain levels of Bay K 8644 at the end of the chronic treatment showed that the compound reached micromolar concentrations during the treatment, but none could be detected in the tissues at the time of the above measurements. 6. It is possible that the results might be explained by predominance of the calcium channel antagonist properties of this compound, owing to the high central concentrations achieved during the treatment. Tolerance to the calcium channel activating properties of Bay K 8644 may also have occurred during the chronic treatment.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗