Biomedical subjects

H J Little

Publications and source records attributed to H J Little.

At least 37 records · Page 2Linked to original sources

PubMed1999

Effects of repeated ethanol administration in the plus maze; a simple model for conditioned abstinence behaviour.

Classical conditioning is considered to be an important factor in drug dependence. Exposure to an environment in which alcohol has been repeatedly consumed may produce feelings of anxiety and dysphoria in a currently abstinent patient, and may precipitate relapse drinking. The present study modeled this process, by repeatedly exposing mice to an elevated plus maze after ethanol administration. When ethanol injections and maze exposure were repeated for 9 days, and the ethanol injections replaced by saline on the tenth day, mice consistently exhibited a characteristic behaviour pattern, with increased stretched attend postures and proportion of time spent in the central square. This behaviour was different from that previously seen during withdrawal from ethanol, and was not observed when repeated injections of ethanol were given either without, or after, maze exposure. Thus the characteristic behaviour pattern appeared to be contingent on the animals being repeatedly exposed to the maze environment while under the influence of ethanol. In particular, the reduction in stretched attend postures produced by acute ethanol, the tolerance to this behaviour seen after repeated ethanol and the increase in it after replacement of ethanol by saline, are consistent with the pattern predicted for a behavioural response to the absence of ethanol, conditioned to the environment of the maze.

Alcoholism↗

PubMed1999

Low alcohol preference among the "high alcohol preference" C57 strain of mice; preference increased by saline injections.

RATIONALE AND OBJECTIVE: This study investigated individual alcohol preference among the "high alcohol preferring" strain of C57BL10 (line ScSn) mice. METHODS: Alcohol preference was assessed in free choice two-bottle preference tests, using 8% ethanol and tap water, under various conditions. RESULTS: Between 15 and 40% of the mice, bred in house, showed a low preference for alcohol with ethanol/water ratios of 0.4 or less. There was a biphasic distribution of preference, and no relationship between alcohol preference and gender. Mice of the C57BL/6 strain from an outside breeder also contained animals with low preference for alcohol. Selective breeding from "in house" stock did not demonstrate evidence of a simple genetic link. Ethanol preference showed no correlation with locomotor activity or the effects of alcohol on such activity. Daily intraperitoneal injections of saline increased the preference of low preference mice, an effect prevented by the CCK(B) antagonist, CAM1028. The preference of "low preference" mice was significantly increased when the effects of saline injections were compared with those of handling alone. Diazepam, at 1 mg/kg, did not affect the low preference, compared with Tween vehicle. This demonstration of C57 strain mice with low preference for alcohol may provide a valuable model for the effects of stress on alcohol consumption.

Alcohol Drinking↗

PubMed1999

Prolonged effects of chronic ethanol treatment on responses to repeated nicotine administration: interactions with environmental cues.

The most common combination of dependence on two drugs occurs with alcohol and nicotine, but little is known of the way in which these drugs interact in the brain. This study investigated the effects in mice of prolonged consumption of alcohol, by liquid diet, on the actions of nicotine on locomotor activity, and the influence of environmental cues on these effects. Administration of nicotine after chronic alcohol intake did not show any significant changes on first administration, but after 28 days of daily nicotine injections, nicotine produced significant locomotor stimulation and increased rearing activity in the mice which had previously received the alcohol diet, compared with the activity of animals that received the control diet. However, significantly increased locomotor activity was also seen, after the repeated nicotine administration, immediately prior to the nicotine injection, only in the mice that had previously consumed alcohol. Examination of the influence of the environment in which the activity was tested demonstrated that the effect on activity prior to injections was seen only if measurement was made in a test environment that was familiar to the animals. The results demonstrate an interaction between chronic alcohol consumption and the effects of environment on the actions of nicotine, that may have relevance to the consumption of these drugs in humans.

Animals↗

PubMed1999

The contribution of electrophysiology to knowledge of the acute and chronic effects of ethanol.

This review describes the effects of ethanol on the components of neuronal transmission and the relationship of such effects to the behavioural actions of ethanol. The concentrations of ethanol with acute actions on voltage-sensitive ion channels are first described, then the actions of ethanol on ligand-gated ion channels, including those controlled by cholinergic receptors, 5-hydroxytryptamine receptors, the various excitatory amino acid receptors, and gamma-aminobutyric acid receptors. Acute effects of ethanol are then described on brain areas thought to be involved in arousal and attention, the reinforcing effects of ethanol, the production of euphoria, the actions of ethanol on motor control, and the amnesic effects of ethanol; the acute effects of ethanol demonstrated by EEG studies are also discussed. Chronic effects of alcohol on neuronal transmission are described in the context of the various components of the ethanol withdrawal syndrome, withdrawal hyperexcitability, dysphoria and anhedonia, withdrawal anxiety, craving, and relapse drinking. Electrophysiological studies on the genetic influences on the effects of ethanol are discussed, particularly the acute actions of ethanol and electrophysiological differences reported in individuals predisposed to alcoholism. The conclusion notes the concentration of studies on the classical transmitters, with relative neglect of the effects of ethanol on peptides and on neuronal interactions between brain areas and integrated patterns of neuronal activity.

Alcoholism↗

PubMed1999

Effects of corticosterone on excitatory amino acid responses in dopamine-sensitive neurons in the ventral tegmental area.

The ventral tegmental area is involved in reward processes and in drug dependence and sends dopaminergic projections to the nucleus accumbens and prefrontal cortex. Stress, and glucocorticoid hormones, are thought to play an important role in the development of drug dependence, but there has been little investigation of the effects of these hormones on ventral tegmental function. The present study examined the effects of corticosterone on single-unit recordings from dopamine-sensitive neurons in the ventral tegmental area in midbrain slices. At concentrations of 100 nM and above, corticosterone potentiated the responses to N-methyl-D-aspartate. This effect was not seen when the calcium concentration of the bathing medium was reduced to 0.1 mM. Responses to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainic acid were also considerably potentiated, at concentrations of corticosterone over 100 nM, while there was some evidence of decreases in these responses at the 100 nM concentration of this hormone. Aldosterone, at concentrations of 100 nM and above reduced the responses to N-methyl-D-aspartate, but had no effects at lower concentrations. RU38486, which acts as an antagonist at glucocorticoid (Type II) receptors, prevented the effects of corticosterone on responses to N-methyl-D-aspartate, with no effect on the spontaneous firing rate or on the effects of N-methyl-D-aspartate in the absence of corticosterone. The latter result, and the effects of aldosterone, suggest that the potentiation of responses to N-methyl-D-aspartate was mediated through Type II glucocorticoid receptors. This study suggests that potentiation of responses to excitatory amino acids by corticosterone may alter the function of ventral tegmental neurons during stress, and it is possible that this effect is involved in the development of drug dependence.

Action Potentials↗

PubMed1999

The calcium channel antagonist, nimodipine, decreases operant self-administration of low concentrations of ethanol.

This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol.

Alcohol Deterrents↗

PubMed1998

Differing acute interactions of ethanol with two structurally related dihydropyridines, nitrendipine and felodipine.

Previous work showed that while several dihydropyridine calcium channel antagonists have protective effects against the ethanol withdrawal syndrome, felodipine differed in lacking this action. Dihydropyridine calcium channel antagonists have also been shown to potentiate the acute behavioral actions of ethanol. The present study compares the effects of felodipine on the acute effects of ethanol, with those of nitrendipine, a dihydropyridine previously shown to be effective against the ethanol withdrawal syndrome. Comparison was made at doses of the compounds that have previously been shown to produce similar displacement of dihydropyridine binding in central nervous system (CNS) tissue. Felodipine had a small potentiating effect on the general anesthetic effects of ethanol, but was considerably less effective in this respect than nitrendipine. Some potentiation of the ataxic effect of ethanol was seen after concurrent administration of felodipine, but this was less than that seen after nitrendipine. In the locomotor studies, both felodipine and nitrendipine significantly decreased the locomotor stimulation produced by ethanol; the effects of the two compounds were similar, but dose-dependency was not seen at the doses tested. Chronic administration of felodipine for 2 weeks did not produce tolerance to the sedative effect of felodipine or cross-tolerance to nitrendipine. After chronic administration of the felodipine, administration of an acute dose of ethanol resulted in an increase in locomotor activity, but this was not seen after chronic administration of nitrendipine or vehicle. The results, therefore, suggest that felodipine was considerably less effective in potentiating the acute effects of ethanol than nitrendipine at doses that were equi-effective in displacing central dihydropyridine binding. The interactions of these two calcium channel antagonists with ethanol, therefore, did not parallel their effects on central dihydropyridine binding.

Anesthesia, General↗

PubMed1998

Chronic ethanol administration alters activity in ventral tegmental area neurons after cessation of withdrawal hyperexcitability.

The present study investigated the activity of neurons in the mesolimbic dopamine system after the end of the acute phase of the behavioural signs of ethanol withdrawal in mice. This was designed to provide a comparison with earlier behavioural studies, in which greater development of sensitisation to amphetamine and cocaine, but no change in the initial effects of these compounds, or in the behaviour in the absence of drug treatment, was seen when repeated injection of these psychostimulants were given after chronic ethanol consumption. In the present study, single unit recordings were made from dopamine-sensitive neurons in the ventral tegmental area in perfused midbrain slices prepared 24 h after cessation of chronic ethanol consumption. Profound decreases in firing of the ventral tegmental area (VTA) neurons were seen in slices prepared after the ethanol treatment. Firing rates increased after application of N-methyl-dl-aspartate, but still remained lower and more variable after the ethanol treatment. Application of dopamine or amphetamine, following stimulation of firing with a low concentration of N-methyl-dl-aspartate, also resulted in lower firing rates in slices from ethanol-treated mice. No changes were seen in release of tritiated dopamine, in response to applied KCl or amphetamine, from slices of striatum or cerebral cortex, prepared 24 h after cessation of the chronic ethanol consumption, compared with control values. The results demonstrate that very substantial decreases in firing rate, and in the number of active cells, occur in VTA neurons at a time when withdrawal hyperexcitability was no longer apparent and overt changes in behaviour were not seen.

Action Potentials↗

PubMed1998

CCK(B) antagonists protect against anxiety-related behaviour produced by ethanol withdrawal, measured using the elevated plus maze.

The effects of the CCK(B) antagonists, CAM1028 and CI988 and a CCK(A) antagonist, CAM1481, were studied on the anxiety-related behaviour produced by withdrawal from chronic ethanol treatment, using the elevated plus maze. Cessation of chronic ethanol administration produced a profile, in both mice and rats, consistent with increase in anxiety-related behaviour. In mice, SC administration of CAM1028 or CI988 reduced the decrease in the time spent on the open arms, the number of entries into these arms and the increases in the latencies to first open arm entry, after withdrawal from the ethanol treatment. The increases in stretched attend postures and head dips from the closed arms and the central square seen during the withdrawal phase, were also decreased by the CCK(B) antagonists, but the decreases in the number of rears and in general activity were unaffected. The doses of CAM1028 and CI988 tested were 0.1 and 1 mg/kg; for some of the withdrawal-induced changes in behaviour only the 1 mg/kg dose was effective. In contrast, the CCK(A) antagonist, CAM1481, at the same doses, had little effect on the anxiety-related behaviour produced by withdrawal from chronic ethanol treatment, although it did decrease the changes in the number of rears and the head dipping behaviour. In rats, the majority of the changes produced by withdrawal from chronic ethanol treatment were decreased by CAM1028 at 1 mg/kg, although the decreases in open arm entries, rearing behaviour and in overall activity were unaffected. CAM1028, CI988 and CAM1481 had no effects on the behaviour of control mice or rats in the plus-maze. The results show that CCK(B) antagonists were effective in decreasing the majority of the anxiogenic effects of withdrawal from chronic ethanol treatment.

Animals↗

PubMed1998

CCK(B) antagonists protect against some aspects of the ethanol withdrawal syndrome.

Effects of the CCK(B) antagonists, CAM1028 and C1988, and the CCK(A) antagonist, CAM1481, were studied on the ethanol withdrawal syndrome. When handling-induced behavior was measured hourly for 12 h from withdrawal of ethanol, a small, but significant, protective effect was seen with 3 mg/kg CAM1028, but not with 0.3, 1, or 10 mg/kg. C1988 (0.3 1,3, or 10 mg/kg), or CAM1481 (0.1 or 1 mg/kg), had no effects. At 16 h from ethanol withdrawal, these ratings were significantly decreased by 3 mg/kg CAM1028 or C1988, but not by lower doses. At 16 h, CAM1481 had very small, but significant, protective effects. At 3 mg/kg, CAM1028, increased the latencies to audiogenic seizures, but had only small effects on convulsion incidence. CAM1481 did not alter the audiogenic convulsions. The decrease in convulsion thresholds to NMDLA, at 16 h from ethanol withdrawal, was completely prevented by CAM1028 or C1988, at 1 and at 3 mg/kg, but not by lower doses; CAM1481 had no significant effects. The results suggest change in CCK(B) receptors may be involved in the later stages of the ethanol withdrawal syndrome.

Acoustic Stimulation↗

PubMed1998

Comparison of the effects of drugs on hyperexcitability induced in hippocampal slices by withdrawal from chronic ethanol consumption.

1 The effects of drugs, previously demonstrated to have a range of effects on the behavioural signs of ethanol withdrawal hyperexcitability, were examined in area CA1 in isolated hippocampal slices prepared after withdrawal from chronic ethanol in vivo. 2 The decreases seen after the ethanol treatment in the thresholds for production of single and multiple population spikes were prevented when the dihydropyridine calcium channel antagonist, isradipine, was included in the perfusion medium at 4 microM. 3 Another dihydropyridine, felodipine, which had no activity against withdrawal signs in vivo, did not affect the changes in field potentials, at concentrations up to 10 microM. 4 Diltiazem, which increased withdrawal hyperexcitability in vivo, had no effect on the withdrawal changes in field potentials at 30 microM; higher concentrations affected the control slices. 5 The novel anticonvulsant, gabapentin, at 1 microM but not at 100 nM, significantly decreased the signs of withdrawal hyperexcitability in the hippocampal slices. When the CCKB antagonist, CI988, was added to the bathing medium, at 1 microM, there were small, but significant decreases in the withdrawal hyperexcitability. 6 The results showed that the actions of these drugs on the changes in the field potentials in isolated hippocampal slices were very similar to their previously demonstrated effects on the convulsive signs of ethanol withdrawal in vivo, but differences were seen in the corresponding comparison with anxiolytic actions in vivo.

Acetates↗

PubMed1997

The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome.

The effects of the anticonvulsant, gabapentin, were investigated, in mice, on the withdrawal convulsive behaviour and anxiety-related behaviour that are produced by cessation of prolonged intake of ethanol. When given at 50 or 100 mg/kg, this compound decreased the rise in handling-induced hyperexcitability which occurs during the withdrawal period; the effects were most pronounced for the first 4 hr after administration. Gabapentin also decreased the convulsive response to an audiogenic stimulus during the withdrawal period. The elevated plus-maze, with both traditional and ethological indices of activity was used as a test of anxiety-related behaviour after cessation of chronic ethanol treatment. Gabapentin, at 50 and 100 mg/kg, was found to decrease some, although not all, of the signs of withdrawal-induced anxiety. At doses up to and including 200 mg/kg, gabapentin had no effect on motor co-ordination or spontaneous locomotor activity in control animals. The results demonstrated that gabapentin has a selective action in decreasing both convulsive and anxiety-related aspects of withdrawal behaviour after chronic ethanol treatment. It is possible that further studies with this compound may shed further light on the mechanisms involved in the withdrawal syndrome.

Acetates↗

PubMed1997

Enhancement of amphetamine- and cocaine-induced locomotor activity after chronic ethanol administration.

The effects of amphetamine and cocaine on locomotor activity in mice were studied after 3 weeks of chronic administration of ethanol by liquid diet. When testing was started 24 h after cessation of the ethanol treatment, no differences were seen on the first administration between the effects of the psychostimulants in controls and ethanol-treated animals, but after subsequent daily injections of amphetamine and cocaine, at doses that were insufficient to cause sensitization in controls, sensitization to both of these drugs was seen in ethanol-treated mice. When testing was started on the sixth day after cessation of the ethanol treatment, the effects of amphetamine on the first administration were significantly greater in ethanol-treated animals than in controls. After subsequent repeated daily injections, the locomotor stimulant effects of cocaine were greater in ethanol-treated mice than in controls. Administration of amphetamine for the first time 2 months after cessation of ethanol treatment also had a greater stimulant effect, compared with that in control animals. Two months after cessation of ethanol treatment, the first dose of cocaine caused a locomotor stimulation that was not seen in control animals, but sensitization was not seen after repeated cocaine administration in either group of animals. No differences in the effects of amphetamine or cocaine were seen after only 7 days of ethanol treatment. The results indicate that changes are still present in the CNS long after ethanol withdrawal hyperexcitability has subsided and that these changes result in increases in the effects of amphetamine and cocaine. Analysis of brain concentrations of the two psychostimulants suggested that metabolic changes were not responsible for the differing effects in control and ethanol-treated animals. It is possible that alterations in mesolimbic dopamine transmission are responsible for the effects of the ethanol treatment.

Amphetamine↗

PubMed1996

How has molecular pharmacology contributed to our understanding of the mechanism(s) of general anesthesia?

This review discusses the mechanism(s) of general anesthesia from a pharmacological viewpoint; in particular, the ability of drugs to produce many different effects is emphasised. The problems of experimental measurement of general anesthesia are discussed, and the possibilities for antagonism and potentiation of anesthesia considered. Physicochemical studies on anesthesia are described, as are the advancement of ideas beyond consideration of lipids and proteins as separate sites of action. The importance of studies on different areas of the brain is highlighted, and the review finishes with a survey of the effects of general anesthetics on synaptic transmission which emphasises the problems of extrapolation from in vitro to in vivo.

Anesthesia, General↗

PubMed1996

Ethanol withdrawal hyperexcitability in vivo and in isolated mouse hippocampal slices.

Withdrawal hyperexcitability was seen in isolated mouse hippocampal slices, prepared after chronic treatment with ethanol, by inhalation for 2 weeks. The pattern of hyperexcitability differed from those seen previously when a different method of ethanol administration and a different strain of mice were used. Thresholds for field potentials were decreased, but the transient increase in paired pulse potentiation, reported earlier, was not evident. Chronic administration of the calcium channel antagonist, isradipine (PN-200-110) during ethanol treatment significantly decreased the withdrawal syndrome, both in vivo and in vitro. Brain concentrations of isradipine during the test period were found to be sufficient to produce acute effects on the withdrawal hyperexcitability. No changes were seen in the field potentials when slices were prepared after treatment with isradipine alone. A small, but significant, increase in excitability was seen in vivo after the treatment with isradipine alone. Previous studies showed that isradipine did not protect against the hyperexcitability due to gamma-aminobutyric acid (GABA)A antagonism, so the results suggest that neuronal calcium channels may be involved in ethanol withdrawal hyperexcitability, but decreases in GABAA inhibition may not be important.

Alcohol Withdrawal Delirium↗

PubMed1995

Ethanol withdrawal hyperexcitability in vitro is selectively decreased by a competitive NMDA receptor antagonist.

Hippocampal slices were prepared immediately after withdrawal from chronic ethanol in vivo. The decreases in thresholds for production of single and multiple population spikes seen after the ethanol treatment were not evident when CGP39551 was included in the perfusion medium at 20 microM. The decrease in paired pulse potentiation seen during ethanol withdrawal, however, was not prevented by CGP39551. For comparison, the effects of CGP39551, at the same concentration, were examined on the changes in field potentials seen in control slices when the magnesium concentration in the bathing medium was lowered to 250 microM. The decreases in thresholds for multiple population spikes produced by the lowered magnesium were prevented, but not other changes including decreases in single spike thresholds. In addition, this 20 microM concentration of CGP39551 did not prevent epileptiform activity, measured by decreases in thresholds for production of single and multiple population spikes caused by addition of the GABAA antagonist, bicuculline, to control hippocampal slices.

2-Amino-5-phosphonovalerate↗

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↗