Biomedical subjects
D Jefferys
Publications and source records attributed to D Jefferys.
Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks.
BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.
Social phobia. The most common anxiety disorder.
Social phobia, the avoidance of social situations for fear of humiliation and embarrassment, has historically been under-recognised. Today, social phobia is the third most common psychiatric disorder that, left untreated, has been shown to have a marked impact upon the quality of life and success of sufferers. Specific pharmacotherapy and psychological therapies used simultaneously or alone, have been shown to be efficacious in the treatment of this disorder.
Nitric oxide modulates retention of immobility in the forced swimming test in rats.
Although originally developed as a possible screen for antidepressants, the Porsolt forced swimming test has more recently been extensively used as a model for studying the involvement of the endocrine system in the acquisition and retention of behavioural responses. In previous studies we have shown that while adrenalectomised rats acquire the immobile response normally, they are unable to retain it on retest next day. In the present study we show that retention of the immobile response in the Porsolt swim test is impaired in intact rats given the nitric oxide (NO) inhibitor L-N-arginine methyl ester (L-NAME), in a dose- and time-dependent manner. At a dose of 50 mg/kg levels of immobility are similar to those in adrenalectomised animals, an effect reversed by the simultaneous administration of L-arginine (50 mg/kg). L-Arginine also reverses the behavioural effect of adrenalectomy, and L-NAME blocks the ability of dexamethasone or the kappa-selective opioid ketocyclazocine to reverse the effect of adrenalectomy on retention of the immobile response. We conclude that the kappa-opioid and glucocorticoid mediated pathways previously shown to independently facilitate retention are mediated by nitric oxide.
Trichotillomania. A common hidden disorder.
Trichotillomania is a chronic impulse control disorder that has recently seen increased public awareness resulting in more sufferers seeking treatment. Use of SSRIs, or cognitive behavioural interventions either alone or in combination, brings about a reduction in symptoms for most who, until recently, have been a silent group of sufferers who believed they alone plucked their hair.
The effect of water temperature on immobility in the forced swimming test in rats.
In the Porsolt swimming test intact rats acquire and retain the immobile response indistinguishably at 25 and 30 degrees C; at both temperatures retention is abolished by administration of the glucocorticoid antagonist RU38486 and the kappa-selective opiate receptor antagonist MR2266 when given together, but not when either is given alone. At 20 degrees C, however, the animals do not acquire the response, and have levels of retention significantly lower than at the higher temperature. This deficit is not restored by administration of glucocorticoids, kappa-opioid receptor-selective agonists, thyroid hormone or glucose.
EMEA (European Medicines Evaluation Agency) and the new pharmaceutical procedures for Europe.
Regulation of medicines in the United Kingdom has changed considerably since the establishment of the Medicines Control Agency in 1989, and other changes will take place throughout the European Community (EC) over the next few years. 1995 will see the introduction of a centralised procedure, applicable to a small number of innovative drugs, and a decentralised procedure, based on mutual recognition of licences granted by existing control authorities in other EC countries.
Obsessive compulsive disorder. An update.
Developments in the neurosciences, neuropharmacology and in cognitive/behavioural therapy have helped in providing effective treatment for OCD. That OCD can be treated successfully is likely to lead to greater public demands on clinicians for diagnosis and treatment. It is thus hoped that the quality of life for sufferers will improve and the secretiveness and shame they now feel about their illness will no longer occur.
The forced swimming test: effects of glucose administration on the response to food deprivation and adrenalectomy.
Rats food deprived for 24 h prior to a 15 min swimming test have no difficulty in acquiring the immobile response but showed significantly reduced levels of immobility (40%) on retest compared with controls (70%). This effect of food deprivation was reversed, by glucose (100 mg/kg), dexamethasone (6 micrograms/rat) and ketocyclazocine (25 micrograms/rat). Adrenalectomised animals also acquire but cannot retain the immobile response, however, adrenalectomised rats given 1000 mg/kg glucose within 2 h of the initial swimming test are immobile for 75-85% of the retest period. We interpret these findings as suggesting a complex interplay of endocrine and metabolic factors are necessary for retention of the behavioural response.
Thyroid hormones and the acquisition and retention of behavioural responses.
Naive rats placed in a plexiglass cylinder from a 15 minute test period show progressive immobility, and retain the immobile response when given a 5-minute retest 24 hours later. In the present study we show that hypothyroidism markedly attenuates the acquisition of the immobile response; that this effect on acquisition is reversed 5-10 minutes after the administration of thyroxine; and that hypothyroid rats treated with a single dose of thyroxine up to 2 hours after the initial test show levels of immobility on re-test indistinguishable from intact rats.
Glucocorticoids, adrenal medullary opioids, and the retention of a behavioral response after stress.
In the Porsolt model swimming test, naive rats become progressively more immobile over a 15-min initial test (0-5 min, approximately 30% immobile; 5-10 min, approximately 50%, 10-15 min, approximately 70%). Twenty-four hours later, rats have retained the response, being immobile for about 70% of a 5-min retest period. We previously reported that in this test adrenalectomized rats are indistinguishable from intact rats over the 15-min test period, but are immobile for only approximately 30% of a 5-min retest period 24 h later. The finding that this behavioral effect of adrenalectomy can be reversed by glucocorticoids or kappa-selective opioids led us to hypothesize that retention of the immobile behavior can be effected by glucocorticoids from the adrenal cortex or kappa-selective opioids from the adrenal medulla. To test this hypothesis, we have given intact rats the antiglucocorticoid RU38486 and the anticholinergics atropine and mecamylamine to block adrenal medullary discharge, either alone or simultaneously. Administered alone, neither class of antagonist affected the response; administered together, they profoundly reduced immobility to levels seen in adrenalectomized rats. Additional evidence for medullary kappa-selective opioids mediating the behavioral effect was that the administration to hypophysectomized rats of atropine plus mecamylamine or the kappa-selective antagonist MR2266 reduced immobility to the levels seen in adrenalectomized animals. We conclude that secretion from either the adrenal cortex or medulla is sufficient for the incorporation of this learned response after stress, and that in intact animals input from both zones may contribute to the terms of this behavioral response.
Both adrenal opioids and glucocorticoids involved in the incorporation of information into memory post-stress.
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A kappa-selective opioidergic pathway is involved in the reversal of a behavioural effect of adrenalectomy.
We have shown previously that adrenalectomized rats are immobile for only approximately 30% of a 5 min retest period, 24 h after an initial 15 min swimming exposure, compared with approximately 70% immobility for intact animals. The administration of ketocyclazocine, dynorphin-(1-17) or [Met5]enkephalin[Arg6,Phe7] immediately after initial exposure reversed the effect of adrenalectomy, whereas equimolar doses of morphine sulphate, [D-Ala2,D-Leu5]enkephalin and dynorphin-(1-8) were inactive. MR2266, a kappa-selective partial agonist/predominant antagonist, did not reverse immobility but antagonized the reversing effect of ketocyclazocine. In conjunction with our previous studies, we interpret these data to show that one of the opioidergic pathways for the incorporation of information post-stress is kappa-selective. This kappa selectivity in turn suggests a possible physiological role for prodynorphin-derived peptides in memory.
Naloxone inhibits both glucocorticoid and [D-Ala2,Met5]enkephalinamide reversal of behavioural effect of adrenalectomy.
Intact rats treated immediately after a 15-min swimming exposure with i.m. 1 or 10 mg/kg naloxone (but not with 10 mg/kg of MRZ2593, a quaternary analogue) showed significant reduction in immobility (55, 30%) compared with controls (70%) during a 5-min retest 24 h later. This effect of naloxone was seen when administered 1 h prior to retest. Adrenalectomized rats, as previously shown, are only approximately 30% immobile on retest; administration of [D-Ala2,Met5]enkephalinamide (50 micrograms i.m.) or dexamethasome (6 micrograms i.m.) elevated immobility to 66 and 69% respectively. Administration of naloxone (0.1-10 mg/kg) progressively antagonized the effect of both [D-Ala2,Met5]enkephalinamide and dexamethasone, to 36 and 41% immobility on retest at 10 mg/kg. We conclude that the incorporation of information post-stress normally involves at least two opioidergic pathways, and that the integrity of one of these pathways is an absolute requirement for such incorporation to occur, based on the naloxone studies. In contrast, either glucocorticoids or enkephalin analogues are sufficient to restore behaviour post-adrenalectomy, suggesting that corticosteroid-dependent neural mechanisms may substitute for this second opioidergic pathway.
Behavioural effect of adrenalectomy: reversal by glucocorticoids or [D-Ala2,Met5]enkephalinamide.
Rats adrenalectomized 4-6 d before a 15-min swimming test showed levels of immobility indistinguishable from controls. Retested 24 h later, adrenalectomized rats showed significantly reduced (28%) immobility compared with controls (70%) or hypophysectomized rats (60%), but not hypophysectomized-adrenalectomized rats (41%). The effect of adrenalectomy was reversed by the administration (within 1 h of initial test, but not subsequently) of dexamethasone (6-20 micrograms; 65% immobility) and corticosterone (6 mg; 74%), but not by the mineralocorticoid deoxycorticosterone (6 mg; 33%). [D-Ala2,Met5]enkephalinamide (5-50 micrograms) also restored immobility (66%). We postulate that hormones from both adrenal medulla and cortex are involved in the retention of information post-stress, and that these hormones act directly on the CNS rather than via the pituitary, since the response to adrenalectomy is not dependent on the presence of the pituitary gland.
The interaction of a fixed time food delivery schedule and body weight on self-administration of narcotic analgesics.
Experiment 1 reported the effects of the interaction of a fixed 1 min delivery schedule and body weight, using schedule-induced self-injection paradigm, in the rate of acquisition of methadone and heroin. Eighty-one rats were assigned to 100% and 80% reduced body weight conditions with and without a schedule. The findings show that: (a) voluntary heroin and methadone intake was enhanced when a schedule was introduced to animals at 80% but not at 100% body weight; (b) high intake of heroin and methadone was accompanied by increased levels of plasma 11-OHCS. Experiment 2 showed that the high rate of self-injection was due to the interaction of pharmacological properties of opiates and environmental variables rather than to a general increase in activity arising from the deprivation state or the effects of the schedule. The results are discussed in terms of a stress factor arising from an interaction between environmental and pharmacological factors.
The future with the UK Medical Devices Agency.
The medical device industry is facing a period of profound change and opportunity. This is partly arising from rapid developments in various fields of science and technology and partly from sociological and perceptual changes in society. One regulatory agency describes how it is responding to the challenge.