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Biomedical subjects

J F Deakin

Publications and source records attributed to J F Deakin.

At least 91 records · Page 5Linked to original sources
PubMed1981

Beta-endorphin-related peptides in the pituitary gland: isolation, identification and distribution.

A new procedure is described for isolation of four forms of beta-endorphin from bovine pituitary. The four peptides are: the C-fragment of lipotropin (bovine lipotropin residues 63-93, or beta-endorphin, the alpha, N-acetyl derivative of the C-fragment, the C'-fragment (bovine lipotropin residues 63-89) and the alpha, N-acetyl derivative of the C'-fragment. Of these peptides, beta-endorphin alone possesses potent analgesic activity. The procedure has been applied in studying the distribution of beta-endorphin-related peptides in two regions of the pituitary. The results show that in the anterior pituitary of the pig and the rat, beta-endorphin is produced with a high degree of specificity in its opiate active form. In contrast, in the pars intermedia of both species at least six peptides related to beta-endorphin are elaborated and beta-endorphin represents only a minor component. The principal peptides in the pars intermedia have been identified as acetylated derivatives of lipotropin C'-fragment: in the pig the predominant peptide is alpha,N-acetyl C'-fragment and in the rat the major peptide appears to be an epsilon-acetylated derivative of alpha,N-acetyl C'-fragment. Thus, beta-endorphin is activated in the anterior pituitary and inactivated in the pars intermediate. The results demonstrate selective and specific processing of the 31K ACTH-endorphin prohormone in the different regions of the pituitary. In the anterior pituitary two biologically active peptides, ACTH and beta-endorphin, are generated together; in the pars intermedia alpha-melanotropin (alpha-MSH) is accompanied by forms of beta-endorphin that have been inactivated by acetylation and proteolysis.

Analgesia↗
PubMed1981

Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters.

There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and alpha-noradrenergic (alpha-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro 3H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA, alpha-NA or opiate receptor binding. Binding of the beta-receptor ligand dihydroalprenolol (3H-DHA) was significantly reduced in ECS-treated rat brain membranes. This may be secondary to effects on NA neurones since ECS-induced reduction of 3H-DHA binding did not occur in animals with 6-hydroxydopamine-induced depletion of cortical noradrenaline. In conjunction with other studies, the results suggest that electroconvulsive therapy may have a noradrenergic mechanism of action.

Animals↗
PubMed1980

Influence of N-terminal acetylation and C-terminal proteolysis on the analgesic activity of beta-endorphin.

Removal of one, two and four amino-acid residues from the C-terminus of beta-endorphin ('lipotropin C-Fragment', lipotropin residues 61--91) led to the formation of peptides with progressively decreased analgesic potency; there was no change in the persistence of the analgesic effects. The four C-terminal residues are thus important for the activity of beta-endorphin, but not for the duration of action. Removal of eight amino-acid residues from the N-terminus provided a peptide that had no specific affinity for brain opiate receptors in vitro and was devoid of analgesic properties. The N-terminal sequence of beta-endorphin is therefore necessary for the production of analgesia, whereas the C-terminal residues confer potency. The N alpha-acetyl form of beta-endorphin had no specific affinity for brain opiate receptors in vitro and possessed no significant analgesic properties. Since lipotropin C'-Fragment (lipotropin residues 61--87) and the N alpha-acetyl derivative of beta-endorphin occur naturally in brain and pituitary and are only weakly active or inactive as opiates, it is suggested that proteolysis at the C-terminus and acetylation of the N-terminus of beta-endorphin may constitute physiological mechanisms for inactivation of this potent analgesic peptide.

Acetylation↗
PubMed1980

Brain noradrenaline depletion prevents ECS-induced enhancement of serotonin- and dopamine-mediated behaviour.

When rats are given a series of electroconvulsive shocks (ECSs) over several days, they display enhanced behavioural responses to both serotonin- and dopamine-receptor agonists. Because these changes are seen when the ECS is given in ways closely mimicking the clinical administration of electroconvulsive therapy (ECT), it has been suggested that the changes in postsynaptic monoamine function may be involved in the antidepressant mechanisms of ECT. Ligand-binding studies have excluded the possibility that ECS alters the characteristics of either the serotonin or dopamine receptor; ECS may therefore be acting on neuronal systems which modulate monoamine neurotransmission. As repeated ECS has recently been reported to decrease both noradrenaline (NA)-sensitive adenylate cyclase and beta-adrenoreceptor binding, we have examined here whether changes in NA function are related to the effects of ECS on the serotonin- and dopamine-mediated behaviours. We demonstrate that although selective depletion of NA does not alter the drug-induced serotonin- and dopamine-mediated responses, it abolishes the ECS-induced enhancement of these behaviours.

Animals↗
PubMed1980

On the neurochemical basis of self-stimulation with midbrain raphe electrode placements.

Bar-pressing for electrical stimulation of the median raphe nucleus in rats was not attenuated by 5HT receptor blockade with metergoline or cyproheptadine, by 5HT depletion induced with parachloroamphetamine or by prior destruction of ascending 5HT pathways with intracerebral microinjections of 5,7-dihydroxytryptamine. Furthermore, in a shuttle box paradigm in which rats could both initiate and terminate stimulation, parachlorophenylalanine did not antagonize initiation of stimulation. It is concluded that the rewarding effects of raphe stimulation are not mediated by serotonergic mechanisms. In contrast to these results, alpha-methyl-paratyrosine induced catecholamine depletion exerted an inhibitory effect on initiation behaviour without impairing termination of stimulation. It is concluded that the rewarding component of raphe stimulation is mediated by catecholamines. Termination of (escape from) stimulation was not materially affected by catecholamine or 5HT depletion suggesting the aversive component of raphe stimulation may not be mediated by these monoamines.

5,7-Dihydroxytryptamine↗
PubMed1980

Chemical lesions of both dorsal and median raphe nuclei and changes in social and aggressive behaviour in rats.

Microinjections of 5,7-dihydroxytryptamine into both the dorsal and median raphe nuclei resulted in 90% depletions of striatal and hippocampal 5-HT concentrations. Compared with vehicle-injected controls the lesioned rats showed reduced active social interaction scores in all four of the test conditions and also reduced levels of locomotor activity. The lesioned rats did not differ from the controls in their latency to start drinking in a novel environment; or in their response to intruder rats placed in their home cages, or in their behaviour as intruders when they were placed in the home-cages of unoperated rats. The difficulties of interpreting the behavioural effects of a lesion when the lesion produces hypoactivity, and the differences between the effects of these joint lesions of both dorsal and median raphe nuclei amd the effects of separate lesions of each nucleus are discussed.

5,7-Dihydroxytryptamine↗
PubMed1979

Ascending 5-HT pathways and behavioural habituation.

Microinjections of 5,7 -dihydroxytryptamine into both the dorsal and median raphe nuclei resulted in 70-85% depletions in striatal and hippocampal 5-HT concentrations but did not affect habituation of orienting in the lick-distraction test, habituation of activity in an open-field or habituation of exploration in the holeboard test. Lesioned animals were hypoactive in the latter two tests and defaecated more than control rats in the open-field suggesting an increase in emotionality or fear. Rats with selective 5,7 -dihydroxtryptamine lesions of either the dorsal or the median raphe nucleus also showed no impairment of habituation of orienting or exploration. However, median raphe lesioned animals were hyperactive at some stages of the holeboard test. In contrast to previous studies, the results suggest intact ascending 5-HT pathways are not necessary for behavioural habituation of orienting, activity or exploration. Rather, 5-HT neurones may be involved in modulation of activity or responsiveness to aversive environments.

Acoustic Stimulation↗
PubMed1979

Personality and male-female influences on the EEG alpha rhythm.

The amplitude and frequency of the alpha rhythm was measured in electroencephalic recordings from 45 male and 46 female university students. The mean alpha frequency of the female group was significantly greater than the male group. There was no significant difference in alpha frequency between females in the first half of the menstrual cycle and those in the second half. The relationship between questionnaire measures of psychoticism, extraversion and neuroticism, and the alpha rhythm was investigated using analysis of variance, correlation analysis and factor analysis. Alpha amplitude was significantly greater in extraverted subjects, alpha amplitude and extraversion scores were significantly correlated and both had high loadings on a single factor. No relationship between psychoticism or neuroticism and alpha frequency or amplitude was observed.

Adult↗
PubMed1978

The locus coeruleus noradrenergic system--evidence against a role in attention, habituation, anxiety and motor activity.

Lesions of the locus coeruleus system were induced by combined stereotaxic injections of 6-OH-dopamine to the ascending fibres and just lateral to the locus coeruleus itself, to deplete the noradrenaline content of both the cerebral and cerebellar cortices. A group of rats with cortical noradrenaline concentrations of less than 30 ng/g were compared with a group with lesser destruction of the system (mean noradrenaline concentration 71 +/- 44 ng/g) and with controls (mean noradrenaline 347 +/- 58 ng/g). Lesioned rats showed normal motor activity and exploration (assessed with a holeboard) and showed normal habituation of these behaviours. The lesioned rats gave no evidence of increased susceptibility to distracting auditory stimuli whilst licking for water, and the groups did not differ in their rate of habituation to these stimuli, or in dishabituation. In a social interaction test, lesioned animals showed a decrease in social contacts in an unfamiliar situation (interpreted as a response to anxiety) of similar magnitude to that seen in the control group. In this test, lesioned animals engaged in more 'aggressive' behaviour (boxing and wrestling) than did the controls. These findings are incompatible with hypotheses that the locus coeruleus system is an integral part of the physiological mechanisms which control gross motor behaviour, attention, habituation or anxiety. Together with previous findings with the benzodiazepines, the results with the social interaction test make it unlikely that the benzodiazepines exert their anxiolytic effects by inhibiting the locus coeruleus system.

Acoustic Stimulation↗
PubMed1978

Involvement of the periaqueductal grey matter and spinal 5-hydroxytryptaminergic pathways in morphine analgesia: effcts of lesions and 5-hydroxytryptamine depletion.

1 Electrolytic lesions of the periaqueductal grey matter (PAG) were made in rats. The analgesia produced by intraperitoneal injection of morphine (10 and 20 mg/kg), tested by the tail flick and hot plate methods, was substantially reduced in the lesioned rats. Baseline pain thresholds were unaffected by the lesions.2 The lesion effects were not due to damage to the dorsal raphé nucleus. The extent of histologically determined damage to the dorsal raphé and the resulting decrease in striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations did not correlate with the reduction in morphine analgesia produced by the lesion. Furthermore, microinjections of 5, 6-dihydroxytryptamine (5,6-DHT) into the dorsal raphé nucleus produced a similar fall in 5-HIAA levels but had no effect on morphine analgesia.3 Selective destruction of the periventricular catecholamine system produced by microinjection of 6-hydroxydopamine (6-OHDA) caused a slight decrease in morphine analgesia, thus raising the possibility that catecholamines may be involved in the action of morphine in the PAG.4 5,7-Dihydroxytryptamine-induced lesions of the spinal cord 5-hydroxytryptaminergic pathways reduced cord 5-HT concentration by 70% and markedly attenuated morphine analgesia as determined by the tail flick test.5 These experiments provide additional evidence that the PAG is a major site of action of opiates in producing analgesia. Furthermore, they have demonstrated the probable involvement of spinal 5-hydroxytryptaminergic pathways in the mediation of opiate analgesic effects.

Analgesia↗
PubMed1978

The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats.

1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour.

Animals↗