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D N Stephens

Publications and source records attributed to D N Stephens.

At least 109 records · Page 6Linked to original sources
PubMed1984

Evaluation of the beta-carboline ZK 93 426 as a benzodiazepine receptor antagonist.

We describe here biochemical and pharmacological effects of the beta-carboline ZK 93426 was compared with Ro 15-1788 and CGS 8216, two compounds previously described as BZ receptor antagonists. Certain effects of ZK 93426, Ro 15-1788 and CGS 8216 were quite similar (e.g., 3H-FNM displacement, "GABA ratio", "photo-shift"). In most pharmacological tests ZK 93426 and Ro 15-1788 lacked overt effects; Ro 15-1788 was a weak agonist in some paradigms, while ZK 93426 exhibited a potent proconflict effect but also a weak anticonvulsant effect. This interesting finding with ZK 93426 suggests that BZ receptor ligands may possess differential efficacy at BZ receptor subtypes. In contrast, CGS 8216 exhibited potent proconvulsant effects in several paradigms in addition to proconflict and pentylenetetrazol generalizing effects. ZK 93426, Ro 15-1788 and CGS 8216 were almost equally potent as antagonists of the effects of BZ receptor agonists, such as diazepam and lorazepam. However, ZK 93426 was the most potent inhibitor of the convulsions produced by the BZ receptor inverse agonist DMCM.

Animals↗
PubMed1984

Growth and development of rats artificially reared on different milk-substitutes.

Rat pups were artificially reared (AR) from postnatal day 4 or 5 till day 20 or 21, by fitting them with gastric cannulas through which milk-substitutes could be infused automatically. Three milk-substitutes were compared: milk M, the usual diet for AR studies, which was somewhat low in protein and very high in carbohydrate; milk A, which resembled rats' milk much more closely in composition; and milk isoM, which was based on the high-energy milk M but was made isoenergetic with milk A. Pups given these diets were termed ARM, ARA and ARisoM respectively. Siblings of the AR rats were left with their mothers to form a mother-reared (MR) control group. Rats were autopsied at 20 or 21 d. Growth in body-weight of all groups of AR pups lagged behind that of their MR siblings for about the first week of AR, but the ARM group showed complete catch-up and the ARA group partial catch-up in body-weight during the second week. ARisoM rats were growth-retarded throughout. Inspection of organ weights expressed relative to body-weight revealed disturbances of organ growth in all AR groups compared with MR animals. ARM rats showed excessive epididymal fat pad and liver weights, but deficits in gastrocnemius muscle, heart and adrenal weights. In contrast, ARA rats usually displayed increased spleen and stomach weights, but lower weight of interscapsular brown adipose tissue. ARisoM rats had high brain, liver and stomach weights and low muscle and spleen weights relative to body-weight. All AR groups had elongated small intestines. Hence the patterns of abnormal organ growth differed between groups. Those shown by the ARM and ARisoM groups seemed the more seriously abnormal. The diet approximating the composition of rats' milk (milk A) appears, as intended, to be an improved milk-substitute.

Animal Nutritional Physiological Phenomena↗
PubMed1983

Growth and development of rats artificially reared on a high or a low plane of nutrition.

In order to exclude the possibility of differences in maternal care which are known to result from typical methods of undernutrition during the suckling period, rat pups were reared artificially on different planes of nutrition away from their mothers. Artificial rearing was accomplished by fitting infant rats with a gastric cannula through which a milk substitute was infused intermittently. Rats were fed thus from 4 to 21 d on a high (ARHI) or a low (ARLO; 44% of ARHI level) plane of nutrition. Underfeeding of the ARLO group was continued till 25 d, after which all rats were given a good-quality pelleted diet qd lib. Compared with mother-reared (MR) litter-mates, ARHI rats showed advanced eye-opening and, at 21 and 25 d, they resisted restraint more strongly. Growth in body-weight of ARHI and MR rats was similar but, when autopsied at 32 weeks, the ARHI rats were shorter (nose-rump length) and had lighter gastrocnemius muscles, adrenals and brains, but heavier epididymal-fat pads. ARLO rats had deficits at 32 weeks compared with ARHI rats in whole body, kidney and epididymal-fat-pad weights, and in tibia length. In a second experiment, ARHI and MR rats were killed at 21 d. All the differences found at 32 weeks were already present at 21 d. In addition, the ARHI pups had enlarged livers and intestines but shorter tibias. The milk substitute, which is one commonly used in such studies, has a low protein and high carbohydrate content compared with rats' milk. This difference probably caused the abnormal organ growth of ARHI rats.

Animal Nutritional Physiological Phenomena↗
PubMed1982

Differences between rats and undernourished preweaning, and controls in learning about a redundant stimulus during acquisition of a conditioned emotional response.

Male rats were undernourished during the first three weeks of life by restricting maternal food consumption. Following nutritional rehabilitation, previously undernourished (PU) and control (C) rats were trained to operate a lever to obtain food reward on a variable interval schedule. When rates of responding had stabilised, the rats were tested for suppression of lever-pressing during the illumination of a light which preceded footshock. There were not differences between PU and C groups in the acquisition of this conditioned emotional response, nor were there differences in suppression when a redundant, tone stimulus was presented contemporaneously with the light to predict shock. When the tone was subsequently tested alone for its ability to suppress lever-pressing it was found to have acquired this property in C, but not in PU animals. In a second experiment, PU and C rats were found not to differ in their response to the tone when it was presented as a novel stimulus, nor in suppression to the tone when it was made the sole predictor of footshock. It was concluded that PU and C rats differed in learning about a stimulus predicting footshock, only when that stimulus was redundant. Among the possible explanations for this behavioural difference between PU and control rats are differences in motivation, curiosity, or strength of conditioning. These possibilities are evaluated within the context of current formal theories of conditioning.

Animals↗
PubMed1982

Comparison of cerebellar Purkinje cell simple spike discharges in adult rats after undernutrition during the suckling period and nutritionally normal rats.

The spontaneous activity of cerebellar Purkinje cells was compared in 100- to 130-day-old rats undernourished during the suckling period (i.e. 0-21 days) and subsequently nutritionally rehabilitated (PU rats), with that in rats of the same strain and of similar age fed normally (age controls), and in normally fed rats of the same strain but approximately one month younger (weight controls). Simple spike activity of single cells was recorded with extracellular microelectrodes in pentothal-anaesthetized animals. The discharge patterns were assessed by on-line computer analysis of the interspike interval distributions with subsequent transformation of the data to enable the results to be evaluated by an analysis of variance. In addition, the distribution of the mean interval, the percentage of intervals less than 30 ms, the percentage of intervals greater than or equal to 150 ms, and the time spent in intervals greater than 150 ms, were compared for the PU rats and pooled controls by a nonparametric statistical test on the untransformed data. None of the results indicated that there were any significant differences between the simple spike activity of Purkinje cells from age- and weight- control rats nor between that in PU rats and the control groups. These results are discussed in relation to the previously reported deficits of granule cells in the cerebella of PU rats.

Action Potentials↗
PubMed1982

Changes in metabolic rate and brown adipose tissue composition during nutritional rehabilitation of postnatally undernourished rats.

Rats previously undernourished (PU) during the first 3 postnatal weeks gained less weight than controls during the subsequent rehabilitation period, in spite of similar levels of food intake per body weight 0.75. Resting oxygen consumption (ml/min/kg0.75) was significantly elevated (15-22%) in the PU group after 36 days of age but this difference was almost completely abolished by beta-adrenergic blockade with propranolol. PU rats also showed a greater thermogenic activity after noradrenaline (25 micrograms/100 g b.wt.) than controls. The mass of brown adipose tissue (BAT, mg/100 g b.wt.) was reduced by undernutrition but during rehabilitation BAT increased in PU rats to a value greater than that of controls. These results indicate that the low weight gain of PU rats may result partly from a high metabolic rate due to sympathetic activation of BAT.

Adipose Tissue, Brown↗
PubMed1981

Dietary obesity in adult and weanling rats following removal of interscapular brown adipose tissue.

In order to investigate the role of brown adipose tissue (BAT) in diet-induced thermogenesis (DIT), a selection of palatable, energy-dense foods (Cafeteria diet) was used to increase the energy intakes of adult and weanling male rats, from some of which interscapular BAT (IBAT) had been surgically excised. Removal of IBAT had no effect upon energy intakes of the cafeteria-fed rats, nor of controls fed a pelleted stock diet. The rate of weight gain of intact controls was similar for the two diets, but adults with IBAT removed and fed with the cafeteria diet gained weight more rapidly than those fed the stock diet. Similarly, although intact weanlings did not exhibit excess weight gain when fed the cafeteria diet, removal of IBAT did result in more rapid weight gain of the cafeteria-fed weanlings relative to their stock-fed siblings. Nevertheless, total carcass energy was increased by some 20% in cafeteria-fed animals, irrespective of whether they had had IBAT removed. Thus there was no evidence of removal of IBAT having improved the efficiency of energy utilisation for growth. The failure to find evidence for altered levels of energy expenditure following removal of IBAT does not necessarily contradict the hypothesis that BAT mediates DIT, however, since, following removal of IBAT, there was hypertrophy of remaining BAT sites which may have compensated for the BAT removed.

Adipose Tissue, Brown↗
PubMed1980

Growth and the development of dietary obesity in adulthood of rats which have been undernourished during development.

1. The effect of feeding a highly-palatable and varied diet on growth and body composition was assessed in male rats, some of which had undergone a period of undernutrition early in their development. 2. Undernutrition during gestation had no effects on weight, length or fat content of offspring in adulthood. Rats underfed during the first 3 weeks of postnatal life were shorter, lighter and more lean as adults than controls which had been well nourished through life. 3. Feeding the palatable diet from weaning led to increases in length and fat-free mass, and to comparable extents of obesity in all groups, irrespective of whether they had suffered either period of undernutrition. Access of palatable food for 30 d in adulthood also led to obesity, but to increases in length and fat-free mass in only the groups undernourished during suckling. 4. Withdrawal of the palatable diet led to some initial weight loss in all groups, irrespective of whether they had been undernourished during development; and 100 d following the replacement of the palatable with stock diet, there were no longer differences in weight between groups which had received palatable food, and those given stock diet throughout. 5. Nevertheless, those rats which had been undernourished during the suckling period and subsequently fed on the palatable diet still showed increased length and fat-free mass relative to their controls fed on the stock diet throughout. 6. All groups which had received the palatable diet, whether from weaning or as adults, and irrespective of early nutrition, were significantly less fat 100 d after its withdrawal than were those rats fed on the stock diet throughout life.

Aging↗
PubMed1979

Dopamine--acetylcholine "balance" in nucleus accumbens and corpus striatum and its effect on hypothalamic self-stimulation.

Three experiments investigated the suppression of hypothalamic self-stimulation in rats by neuroleptics and its restoration by centrally acting anticholinergic agents. Scopolamine (0.1--1.0 mg/kg i.p.) and benztropine (1.0--10.0 mg/kg i.p.) each enhanced self-stimulation when administered alone, and partially restored performance suppressed by spiroperidol (0.05--0.15 mg/kg i.p.). Benztropine strongly inhibits transmitter reuptake at DA synapses but scopolamine does not, thus inhibition of DA reuptake cannot fully account for the stimulant or antineuroleptic action of anticholinergic drugs. Neuroleptic and anticholinergic effects on self-stimulation rate were mutually subtractive, and statistical evidence of interaction was not obtained. Scopolamine was shown also to restore performance extinguished by discontinuation of the stimulating current. Smaller doses of scopolamine (50 nmol; 19 microgram) injected directly into the nucleus accumbens septi partially restored responding suppressed by spiroperidol, though similar doses of scopolamine injected bilaterally into the caudate-putamen were ineffective. These findings suggest that hypothalamic self-stimulation may be influenced by ACh-and DA-containing systems which exert independent effects on a third system controlling performance. These effects appear to reflect the level of arousal or motivation rather than the reinforcement process itself.

Acetylcholine↗
PubMed1977

Effects on hypothalamic self-stimulation of drugs influencing dopaminergic neurotransmission injected into nucleus accumbens and corpus striatum of rats.

The role of the nucleus accumbens septi (ACB) and corpus striatum (CPU) in self-stimulation were investigated by injecting directly or indirectly acting stimulant drugs or a dopamine-(DA)-receptor blocking agent into each site bilaterally. d-Amphetamine (68 nmol) facilitated hypothalamic self-stimulation when injected into either side. Apomorphine (40 nmol) depressed or facilitated responding, the direction and magnitude of this effect being contingent (C = 0.52) on the effect of systemic injection (0.3 mg/kg.i.p.), and correlated with the difference between the effects of d- and l-amphetamine (0.5 mg/kg i.p.) but not with injection site. Haloperidol (6.6 nmol) in either site depressed self-stimulation. Tyramine (730 nmol), an agent believed to cause noncontingent displacement of transmitter from catecholamine terminals, depressed self-stimulation when injection into CPU, but facilitated it when injected into ACB. The site-specific effects found with tyramine but not with apomorphine may have been due to release by tyramine of transmitters other than DA.

Amphetamine↗
PubMed1977

Interaction of hunger and thirst in the motivational arousal underlying hoarding behavior in the rat.

Rats were studied in which hoarding of food could be elicited by a 16-hr food deprivation schedule. It was found that (a) prolonged water restriction, with food ad lib, failed to induced hoarding in spite of a spontaneous reduction in food intake and a fall in body weight to below levels normally critical for the onset of hoarding. Thus, different physiological deficits are not necessarily equivalent or additive in the elicitation of food hoarding, and water lack may suppress it. (b) Hoarding behavior was released in water-deprived animals by a brief drink of water. A 30-min delay to allow absorption of the ingested water significantly enhanced the release of hoarding. Air drinking by water-deprived rats did not release hoarding. Thus, the absence of hoarding during water lack may be caused by an active inhibitory process that can itself be inhibited or canceled by postingestional effects of drinking but not by oropharyngeal stimulation mimicking water signals. (c) Although water lack prevented hoarding in response to concomitant self-imposed fasting, hoarding ensued at maximal rates when a further mild degree of food deprivation was superimposed. Thus, the inhibition of hoarding by dehydration operates subtractively, not multiplicatively, and, with free access to food, the inhibition of hoarding by thirst tends to be balanced, exactly, by the facilitatory effect of concomitant fasting; thus superadded food deprivation can take full effect. It is concluded that in states of motivational arousal, specific inhibitory mechanisms may inhibit, subtractively, certain activities biologically irrelevant to prevailing physiological needs.

Animals↗
PubMed1976

Cyclic AMP and central noradrenaline receptors: failure to activate diencephalic adrenergic feeding pathways.

Intracranial injection of graded doses of dibutyryl 3',5'-cyclic adenosine monophosphoric acid (cAMP) at sites in the accumbens/stria terminalis nuclei of satiated rats elicited behavioural arousal and occasional convulsive episodes at higher doses, but failed to affect food consumption even in sites where injection of noradrenaline (65 nmol) consistently elicited increased feeding. Intracranial aminophylline (550 nmol) or dopamine (65 nmol) were also without effect on food consumption. This result does not support recent suggestions that cAMP serves as the second messenger in central noradrenergic motivational pathways.

Aminophylline↗
PubMed1976

Catecholamines and self-stimulation: evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine.

Investigation of the role of noradrenaline (NA) and dopamine (DA) in self-stimulation showed that d-amphetamine (which releases more DA than does l-amphetamine, but not more NA) was much more effective than l-amphetamine in enhancing self-stimulation of NA sites in the locus coeruleus and near-lateral hypothalamus. In DA sites in the substantia nigra and far-lateral hypothalamus the effects of the 2 isomers were confirmed to be more nearly equal. Thymoxamine HCl (10 mg/kg IP), a specific alpha-adrenergic receptor blocker, depressed self-stimulation at all sites, but significantly more severely at DA sites. Thus the drugs most effective in influencing self-stimulation at a particular site were those acting predominantly on the unstimulated system. These findings were interpreted in terms of a hypothesis that DA and NA play complementary roles in self-stimulation and that both are essential; or, more specifically, that DA pathways, implicated in other motivational activites, contribute to a state of drive or arousal necessary for self-stimulation; while response-contingent noradrenergic activity (elicited by the electrodes directly via a transsynaptic route) mediates reinforcement. Further predictions from this hypothesis were tested as follows: (1) Direct pharmacological stimulants of adrenergic alpha-receptors should disrupt self-stimulation by acting randomly on the reinforcement system and disrupting response-reward contingencies; this was confirmed by the finding that the alpha-receptor stimulant clonidine HCl (0.05 mg/kg) depressed self-stimulation at all sites tested. (2) Drect stimulants of DA receptors should enhance self-stimulation of NA sites by augmenting dopaminergic motivational activity; but in rats with DA electrodes, noncontingent stimulation of DA receptors would also impose similar noncontingent activity on the transsynaptic noradrenergic reinforcement pathways and thus depress self-stimulation; this was confirmed by the finding that apomorphine (0.3-1.0 mg/kg) was strongly stimulant for NA electrodes but strongly depressant for DA electrodes, and that the degree and direction of these effects was highly correlated with the differential effects of d- l-amphetamine (rho = .65, p less than 0.01). Neither effect of apomorphine depended on the occurrence of motor stereotypy. These results can be interpreted in terms of 2-component models for self-stimulation, with the predominant transmitter of the drive component being identified as DA and that g the reinforcing component as NA.

Amphetamine↗