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J Mellanby

Publications and source records attributed to J Mellanby.

At least 19 recordsLinked to original sources
PubMed1992

The playground maze: a new method for measuring directed exploration in the rat.

A new test, called the 'playground maze', is described. Rat exploratory responses to a single novel object are measured in the context of responses to 7 familiar objects in a familiar environment. Responses are measured as time spent in areas around the objects on a circular open field. These times are expressed as percentages of the total time spent exploring all the objects and a value which is significantly greater than the expected chance level (12.5%) indicates a novelty response. The paths traversed by the animals on the maze are also recorded and the lengths of these give a measure of locomotion. Preliminary experiments on the effects of chlordiazepoxide (CDP) (1-5 mg/kg) and amphetamine (1.5-4 mg/kg) are reported. CDP significantly increased the novelty response but had no effect on locomotion. Amphetamine treatment at 4 mg/kg abolished the response to novel objects while lower doses (1.5 and 2 mg/kg) did not affect it. All 3 doses of amphetamine significantly increased locomotion. This test provides a new way of measuring the exploratory response to novelty under low stress conditions and allows the separation of drug effects on directed exploration and locomotion.

Amphetamine↗
PubMed1990

Tetanus toxin-induced seizures cause microglial activation in rat hippocampus.

Tetanus toxin (about 20 mouse LD50) injected into the ventral hippocampus of rats leads to brief seizures occurring intermittently over a period of weeks. Toxin injection leads to the appearance of activated microglia (detected with OX42 immunohistochemistry) in the hippocampus. After 7-14 days, many activated microglia are visible in CA1 area of dorsal hippocampus aligned with the pyramidal cell dendrites and having the morphology characteristic of 'rod cells'. Extensive cell loss is found in dorsal CA1, but not at the injection site, in about one third of injected rats.

Animals↗
PubMed1990

Fragment A-B of tetanus toxin does not block neuromuscular transmission in the goldfish.

While 4 micrograms of Fragment A-B of tetanus toxin (which lacks the binding site for nervous tissue) causes flaccid paralysis and death in mice, 26 micrograms has no toxic effect in goldfish. Antibodies to either A-B or to fragment C (which contains the binding site) block the paralytic effect of whole toxin in goldfish. It is concluded that binding is necessary for the neuromuscular blocking action of the toxin in goldfish.

Animals↗
PubMed1988

The effect of lanthanum on nerve terminals in goldfish muscle after paralysis with tetanus toxin.

Lanthanum (1.9 mM) has previously been shown to produce a massive increase in the frequency of spontaneous miniature junction potentials at the neuromuscular junctions of goldfish fin muscles. In fins where transmission has been blocked by previous injection of tetanus toxin and where there are few (if any) spontaneous miniature potentials, lanthanum treatment is able to restore a modest frequency. The results of parallel experiments in which the ultrastructure of the nerve endings has been investigated by electron microscopy are reported. In normal goldfish muscles, the lanthanum-induced increase in frequency is accompanied by depletion of synaptic vesicles. In contrast, there is no depletion in tetanus toxin-paralysed nerve endings subjected to lanthanum treatment, which parallels the relative insensitivity of the endings to activation by lanthanum. Of particular interest is the finding that the lanthanum treatment of the toxin muscles apparently causes accumulation of vesicles in a row just inside the terminal membrane, both at synaptic and non-synaptic positions. The results are discussed with respect to the mechanisms of transmitter release and to the actions of tetanus toxin and lanthanum.

Animals↗
PubMed1986

The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: extinction and successive discrimination.

In a first set of experiments rats were trained to run in a straight alley for food reward on a continuous reinforcement schedule and the running response was then extinguished. On the last 2 days of training and daily throughout extinction different groups of animals were injected IP with saline, 5 mg/kg chlordiazepoxide, 0.75 mg/kg picrotoxin, chlordiazepoxide + picrotoxin, chlordiazepoxide + 1.5 mg/kg bicuculline, 0.00125 or 0.25 mg/kg muscimol, 1 mg/kg baclofen, chlordiazepoxide + baclofen, or 0.00125 mg/kg muscimol + baclofen. Chlordiazepoxide increased resistance to extinction, a well-known anxiolytic effect. This effect was blocked by both picrotoxin and bicuculline. Picrotoxin on its own reduced resistance to extinction (an anxiogenic-like effect). Whether given alone or in combination with other drugs, muscimol and baclofen had no effect. In a second set of experiments rats were trained in a successive operant discrimination (signalled by a flashing or steady light) between components in which sucrose reward was available on a variable-interval schedule for barpressing and components in which no reward was given. Chlordiazepoxide at 10 mg/kg increased responding in both rewarded and nonrewarded components, but more in the latter than could be accounted for by change in the former. This effect is as expected with an anxiolytic drug. It was not altered by administration of bicuculline at 1.5 or 1.75 mg/kg; at 2 mg/kg bicuculline acted synergistically with chlordiazepoxide. Picrotoxin (1 and 1.5 mg/kg) also acted synergistically with chlordiazepoxide, enhancing the latter's rate-increasing effects, but only during rewarded components. Neither muscimol (0.00125 and 0.25 mg/kg) nor baclofen (0.01 mg/kg) affected response rates, whether given alone or in combination. However, baclofen in a dose of 1 mg/kg, provided it was given to rats also injected with muscimol (0.00125 or 0.25 mg/kg) at other times, significantly reduced responding during nonrewarded components (an apparently anxiogenic effect). The results of the two sets of experiments are discussed in relation to the hypothesis that anxiolytic drugs affect behaviour by increasing GABAergic inhibition.

Animals↗
PubMed1985

The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: punished barpressing.

Rats were trained to press a bar for sucrose reward on a random-interval (RI) schedule and footshock punishment was then introduced for 3-min intrusion periods (signalled by a tone) on an independent RI schedule. Shock intensity was individually adjusted to produce stable intermediate levels of response suppression during the tone for each animal. Groups of animals were then allocated to a number of separate experiments in which they were systemically injected with anxiolytics (chlordiazepoxide HCl or sodium amylobarbitone), GABA antagonists (picrotoxin or bicuculline), the GABA (A) agonist muscimol, the GABA(B) agonist baclofen, an antagonist (RO 15-1788) at the benzodiazepine receptor and, an inverse agonist (FG 7142) at this receptor. The results showed that the alleviation of punishment-induced suppression of barpressing produced by chlordiazepoxide was blocked or partially blocked by RO 15-1788, picrotoxin and bicuculline but not by FG 7142; that picrotoxin (but not FG 7142) increased the suppression of responding by punishment; that neither muscimol nor baclofen affected responding on their own, but their combination weakly but reliably released punished responding from suppression; and that the anti-punishment effect of amylobarbitone was unaffected by either picrotoxin or bicuculline, though the barbiturate reversed the punishment-enhancing effect of picrotoxin. These results are discussed in the light of the hypothesis that anxiolytic behavioural effects are due to increased GABAergic inhibition.

Amobarbital↗
PubMed1985

The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: choice behaviour in the T-maze.

Two methods were used to test rats' responses to novelty in the T-maze: (1) a test of spontaneous alternation allowing separate measurement of place and body turn alternation; and (2) a test of entry into an arm of changed brightness ("response to stimulus change"). Chlordiazepoxide reduced spontaneous alternation by specifically weakening body turn alternation and eliminated the response to stimulus change. These findings are similar to those previously reported for the barbiturate sodium amylobarbitone. The same pattern of change in the two tests was seen after a low dose of the GABAA agonist muscimol (0.00125 mg/kg); when the dose of muscimol was raised (0.01 and 0.25 mg/kg), place alternation was also reduced. Picrotoxin but not bicuculline (both GABAA blockers) reversed the effects of muscimol and partially those of chlordiazepoxide on the response to stimulus change; in the spontaneous alternation test picrotoxin only marginally affected the response to 0.25 mg/kg muscimol and actually enhanced the effect of 0.000125 mg/kg. The GABAB agonist baclofen (1 mg/kg) acted in the test of response to stimulus change like chlordiazepoxide and muscimol; however, when baclofen was combined with muscimol, the two drugs tended to show mutual blocking. These results are generally consistent with the hypothesis that GABAergic mechanisms play a role in anxiolytic behavioural activity, but many details are difficult to explain.

Animals↗
PubMed1985

Septal driving of hippocampal theta rhythm: role of gamma-aminobutyrate-benzodiazepine receptor complex in mediating effects of anxiolytics.

In free-moving male rats, when the hippocampal theta rhythm is artificially driven by stimulation in the septum at frequencies between 5 and 10 Hz, the function relating frequency to the threshold current required to drive the theta rhythm has a minimum at 7.7 Hz. This minimum is eliminated by anxiolytic drugs. Dose-response curves for this effect are reported for chlordiazepoxide, diazepam and meprobamate. The effect of meprobamate was reversed by two gamma-aminobutyrateA antagonists, picrotoxin and bicuculline, which have previously been shown to be without effects of their own. The gamma-aminobutyrateB agonist, baclofen, also without effect on its own, blocked the elimination of the 7.7-Hz minimum caused by the gamma-aminobutyrateA agonist, muscimol. The beta-carboline, ethyl-beta-carboline-3-carboxylate, had mixed agonist/antagonist properties, blocking the effects of chlordiazepoxide, diazepam and muscimol (though not sodium amylobarbitone) but itself acting like a benzodiazepine. Coupled with earlier data, these findings support a role for gamma-aminobutyrate receptors in mediating the effects of anxiolytic drugs.

Animals↗
PubMed1985

Long-term changes in hippocampal physiology and learning ability of rats after intrahippocampal tetanus toxin.

A chronic epileptic syndrome can be induced by injecting minute doses of tetanus toxin into rat hippocampi. This causes intermittent epileptic fits over a period of 2-4 weeks, after which the fits cease, and the electroencephalogram (e.e.g.) appears to return to normal over the following 2-3 weeks. However, once they have recovered from the seizures, the rats exhibit a remarkably persistent impairment of learning and memory, which is the subject of the present study. Learning ability was assessed using a radial arm maze task, in which the rats had to visit each of eight arms for a food reward. The toxin-injected rats learnt this task more slowly than control-injected. Evoked potentials from the CA3 pyramidal cells were recorded in terminal experiments under halothane anaesthesia. Long term potentiation of the post-synaptic response to the commissural pathway from the contralateral hippocampus appeared to be unaffected by the previous toxin treatment, at least over periods of up to 5 h. The toxin-injected group differed from the control in having consistently smaller post-synaptic population spikes in their evoked responses, so that stimuli were less effective in exciting the post-synaptic neurones. This applied both to the contralateral commissural input, and to the ipsilateral mossy fibre input. No differences were found between the toxin and control groups in the size of the antidromic population spike in the commissural response, or in the population excitatory post-synaptic potential (e.p.s.p.) for either input. Thus the depressed output from CA3 pyramidal cells cannot be explained either by a loss of these neurones (confirming earlier neuropathological observations), or by a loss of excitatory afferents. While its precise cause remains unknown, the depressed output from the CA3 region was statistically correlated with the learning impairment, and we believe provides a reasonable explanation of this behavioural deficit.

Action Potentials↗
PubMed1985

Antiepileptic and antiamnesic effect of carbamazepine in experimental limbic epilepsy.

Carbamazepine (20 mg/kg, 40 mg/kg or 60 mg/kg) given three times a day, has been demonstrated to have a significant anti-epileptic effect in rats with chronic limbic epilepsy induced by injecting tetanus toxin bilaterally into their hippocampi. This effect involved a reduction in the maximum number of fits occurring on one day, and with the highest dose, a significant reduction in the total number of fits. In a pilot experiment in which continuous EEG records were obtained throughout the syndrome, it appeared that the effect of carbamazepine was to reduce the proportion of EEG seizure discharges which lead to overt motor fits. With the higher drug dose plasma levels of carbamazepine were maintained around 2 micrograms/ml. This experimental epilepsy produces enduring deficits in the rats' memories for a light-discrimination task in a Y-maze learned before induction of epilepsy (8 weeks after initial learning). If the rats are dosed with carbamazepine during their epilepsy this memory deficit is abolished.

Amnesia↗
PubMed1977

Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus.

An epileptiform syndrome in rats produced by injecting small doses (a few (mouse)LD50) of tetanus toxin into the hippocampus is described. The animals had intermittent seizures, with at least a superficial resemblance to human epilepsy, for some weeks but they eventually recovered. They were hyperkinetic for several weeks after the injection of toxin, and showed intermittent aggressive behaviour. Control animals which received similar injections of tetanus toxin first neutralised with antitoxin did not have seizures, and their behaviour appeared normal. EEG recordings showed characteristic seizure activity. Histological examination of the site of injection showed very little morphological damage.

Animals↗