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T Sharp

Publications and source records attributed to T Sharp.

At least 37 records · Page 2Linked to original sources
PubMed1990

Repeated ECS enhances dopamine D-1 but not D-2 agonist-induced behavioural responses in rats.

The present study examined the effect of acute and repeated administration of electroconvulsive shock (ECS) on behaviours induced by various dopamine agonists in rats. Components of behavioural arousal induced by the dopamine D-1 agonist SKF 38393, the dopamine D-2 agonist RU 24213 and the mixed D-1/D-2 agonist apomorphine were assessed using a behavioural check-list method. Also, the overall behavioural syndrome produced by these drugs was measured using rating scales. Rats receiving repeated (5 times over 10 days) but not a single ECS showed enhanced grooming and sniffing in response to SKF 38393 (7.5 mg/kg) when compared to controls. Repetitive sniffing induced by apomorphine (0.5 mg/kg) was also enhanced by repeated ECS. Neither repeated nor a single ECS significantly changed behaviours induced by RU 24213 (0.75 mg/kg), although a downward trend was evident. The behaviour rating scale measurements also demonstrated that repeated administration to ECS increased behavioural responsiveness to SKF 38393 and apomorphine but not RU 24213. These results suggest that the increase of dopamine-mediated behaviour in rats seen after chronic ECS relates to an increase in central dopamine D-1 receptor function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Mixed agonist/antagonist properties of NAN-190 at 5-HT1A receptors: behavioural and in vivo brain microdialysis studies.

1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine, NAN-190, is a novel compound with putative 5-HT1A antagonist properties. In the present study, the effects of NAN-190 were examined with regard to functional pre- and post-synaptic 5-HT1A receptor-mediated events, using in vivo brain microdialysis and behavioural techniques. Our findings provide evidence that NAN-190 acts as a mixed agonist/antagonist at central 5-HT1A receptors. Thus, NAN-190 blocked (+)8-OH-DPAT-induced behaviour in reserpinized rats, indicating antagonist properties at postsynaptic 5-HT1A receptors. However, the compound was also able to decrease the release of 5-HT in vivo, tentatively due to an agonist action at somatodendritic 5-HT1A autoreceptors. These data extend previous information on the pharmacological profile of NAN-190 and further emphasizes the difference between pre- and postsynaptic 5-HT1A receptors in brain.

Analysis of Variance↗
PubMed1990

Application of brain microdialysis to study the pharmacology of the 5-HT1A autoreceptor.

5-Hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype are localized on serotoninergic cells and dendrites in the raphe nuclei of the brain stem and are believed to regulate synaptic 5-HT release through an inhibitory influence on serotoninergic impulse flow. The effects of 5-HT1A agonists on 5-HT release can, therefore, only be detected by measurement of 5-HT release from intact serotoninergic neurones. Here we review the evidence that the microdialysis technique, when applied to the anaesthetized rat, is able to detect extracellular 5-HT in the brain which derives from serotoninergic neurones and changes in accordance with serotoninergic neuronal activity. We have observed that a range of 5-HT1A agonists, including 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), inhibit 5-HT release in hippocampus, most probably by acting on somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus. The inhibitory action of 8-OH-DPAT and several other selective 5-HT1A receptor active drugs on 5-HT release is sensitive to pindolol, further supporting the idea that the 5-HT receptor being measured is of the 5-HT1 subtype. Two drugs, BMY 7378 and NAN-190, which show 5-HT1A antagonist properties in certain models, reduce 5-HT release indicating that they have mixed agonist/antagonist actions at the 5-HT1A receptor. Our data indicate that measurement of 5-HT release in rat brain using the microdialysis technique may be a useful method to probe the pharmacology of the 5-HT1A autoreceptor in vivo.

Animals↗
PubMed1990

Release of endogenous 5-hydroxytryptamine in rat ventral hippocampus evoked by electrical stimulation of the dorsal raphe nucleus as detected by microdialysis: sensitivity to tetrodotoxin, calcium and calcium antagonists.

We have utilized the brain microdialysis technique in an attempt to measure excitation-secretion coupled release of endogenous 5-hydroxytryptamine in rat brain in vivo and investigated the pharmacology of the voltage-sensitive calcium channel involved in this process. All experiments were carried out using chloral hydrate anaesthetized rats. Ascending serotoninergic neurons were electrically stimulated using an electrode implanted into the dorsal raphe nucleus. A dialysis probe was implanted into the ventral hippocampus and continuously perfused with artificial cerebrospinal fluid containing the selective 5-hydroxytryptamine uptake inhibitor citalopram (1 microM). Twenty-minute perfusates were analysed for endogenous 5-hydroxytryptamine using high performance liquid chromatography with electrochemical detection. Electrical stimulation (cathodal monophasic 1 ms pulses, 300 microA, 2-10 Hz) of the dorsal raphe nucleus for 20 min induced an immediate release of 5-hydroxytryptamine which lasted for the duration of the stimulus and was frequency-dependent. The calculated amount of 5-hydroxytryptamine release per electrical impulse was constant over the frequency range used. Addition of tetrodotoxin (10 microM) to, or omission of calcium from, the perfusion medium reduced the spontaneous output of 5-hydroxytryptamine by 60-70% and caused a near complete inhibition of the effect of low frequency (3 Hz) electrical stimulation of the dorsal raphe nucleus. Local perfusion with cadmium (30 and 300 microM), which is reported to antagonize both N- and L-type voltage-sensitive calcium channels, also caused a pronounced decrease of basal output of 5-hydroxytryptamine and a marked, but not complete inhibition of the effect of nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Relatives' involvement in caring for the elderly mentally ill following long-term hospitalization.

The involvement of relatives in patient care is frequently associated with 'good nursing practice'. However, according to recent literature it is a practice that is not widely adopted. The intention of this study was to ascertain the extent of relatives' involvement in caring for the elderly mentally ill, from both relatives' and nurses' perspectives. Following analysis of more than 130 questionnaires it was found that nursing staff responded very positively towards greater involvement of relatives wishing to encourage their participation. In comparison relatives felt that their role in patient care was negligible, but despite this did not wish to seek greater involvement. The discussion that follows examines possible reasons for these findings and the implications for future practice.

Activities of Daily Living↗
PubMed1990

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Changes in blood lipids during six days of overfeeding with medium or long chain triglycerides.

Although medium chain triglyceride (MCT) is less calorically dense than long chain triglyceride (LCT), it produces a greater thermic effect following ingestion. We hypothesized that the previously observed high rate of thermogenesis produced by MCT overfeeding was due to hepatic de novo synthesis of long chain fatty acids (LCFA) from the excess medium chain fatty acids (MCFA). To study this, we compared the effects of overfeeding MCT- and LCT-containing diets on blood lipid profiles. Ten in-patient, nonobese males were overfed (150% of estimated energy requirements) two formula diets for 6 days each, in a randomized crossover design. Diets differed only in the composition of the fat and contained either 40% of energy as MCT or LCT (soybean oil). The major differences between diets in the resulting pattern of blood lipids were: 1) a reduction in fasting serum total cholesterol concentrations with the LCT, but not the MCT diet; and 2) a threefold increase in fasting serum triglyceride concentrations with MCT, but not LCT, diet. Moreover, 10% of the fasting triglyceride fatty acids were medium chain and 40% were 16:0 with the MCT diet. This compared to 1% and 20% for medium chain and 16:0, respectively, with the LCT diet. In addition, there were increases in 16:1, 18:0, and 18:1 in the triglycerides during MCT feeding. The changes in fatty acids in triglycerides with MCT feeding are consistent with the hypothesis that excess dietary MCT cause a significant increase in the hepatic synthesis of these fatty acids from MCFA through de novo synthesis and/or chain elongation and desaturation. These processes could account for the higher rate of postprandial thermogenesis with MCT as compared to LCT.

Adult↗
PubMed1989

Partial postsynaptic 5-HT1A agonist properties of the novel stereoselective 8-OH-DPAT analogue (+)cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, (+)ALK-3.

The present study assessed the pharmacological activity of the stereoisomers of the novel 8-OH-DPAT analogue cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, ALK-3, at postsynaptic 5-HT1A receptors involved in 5-HT-mediated behaviour. Reserpine-pretreated rats were injected with (+)8-OH-DPAT (0.03-1.0 mg/kg s.c.), (+)ALK-3 (0.3-10.0 mg/kg s.c.) or (-)ALK-3 (3.0-10.0 mg/kg s.c.), and components of the '5-HT behavioural syndrome' were scored. (+8-OH-DPAT dose dependently elicited forepaw treading, flattened body posture and hindlimb abduction. In this respect, (+)ALK-3 was significantly less efficacious although its behavioural action was prevented by pindolol (8 mg/kg s.c.), indicating that it was 5-HT1A receptor mediated. Following pretreatment, (+)ALK-3 dose dependently, but partially, attenuated the effect of (+)8-OH-DPAT. (-)ALK-3 did not elicit 5-HT behaviours per se, and only very weakly antagonized the behavioural actions of (+)8-OH-DPAT at the highest dose tried. Our data indicate that the (+) enantiomer of ALK-3 is a partial but stereoselective agonist at postsynaptic 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Thermogenesis in humans during overfeeding with medium-chain triglycerides.

To test whether excess dietary energy as medium-chain triglycerides (MCT) affects thermogenesis differently from excess dietary energy as long chain triglycerides (LCT), ten male volunteers (ages 22 to 44) were overfed (150% of estimated energy requirement) liquid formula diets containing 40% of fat as either MCT or LCT. Each patient was studied for one week on each diet in a double-blind, crossover design. Resting metabolic rate (RMR) did not change during either week of overfeeding. The thermic response to food (TEF) was greater on day 1 following a meal (1,000 kcal) containing MCT than following an isocaloric meal containing LCT (8 +/- .8% v 5.8 +/- .8% of ingested energy; P less than .05). Moreover, the TEF observed after a 1,000 kcal meal containing MCT increased significantly to 12% (+/- 1.3%) overfeeding. The TEF of the 1,000 kcal meal containing LCT was unchanged by five days of LCT overfeeding (6.6 +/- 1.0% of ingested energy). Energy expenditure during a 20-hour continuous enteral infusion of the diet on day 7 was also significantly higher with the MCT diet than with the LCT diet (15.7 +/- 1.7% v 7.3 +/- .9% of ingested energy; P less than .05). Our results demonstrate that excess dietary energy as MCT stimulates thermogenesis to a greater degree than does excess energy as LCT. This increased energy expenditure, most likely due to lipogenesis in the liver, provides evidence that excess energy derived from MCT is stored with a lesser efficiency than is excess energy derived from dietary LCT.

3-Hydroxybutyric Acid↗
PubMed1989

Structural and functional analysis of raphe neurone implants into denervated rat spinal cord.

The ability of grafts of embryonic raphe cells to the adult rat spinal cord to reverse the morphological, neurochemical and functional deficits caused by ablation of the serotoninergic afferents has been studied. After grafting, extensive reinnervation was observed by 5HT-immunoreactive fibres, many of which appeared to make contacts with host motoneurones. The neurotransmitter complement was apparently normal. There was also a reinstatement of 5HT levels in the denervated cord after transplantation, amounting to some 40% of normal at the level of the graft. Similarly, Na+-dependent uptake of [3H]-5HT into P3 fractions was over 40% of that recorded in unlesioned animals. Antidromic stimulation of the ventral roots of the spinal cord was used to assess the degree of motoneurone excitability. The field potential in the ventral horn of grafted animals was increased by electrical stimulation of discrete regions along the cord, probably corresponding to the graft loci. It is concluded that serotoninergic neurones transplanted to the denervated spinal cord survive and develop normally, reinnervating the host tissue extensively. Furthermore, the graft/host connections appear to be functionally viable.

Action Potentials↗
PubMed1989

Evaluation of an alternating-calorie diet with and without exercise in the treatment of obesity.

This study examined the effects of calorie alternation and exercise on weight loss. Moderately obese women (130-160% of ideal body weight) were randomly assigned to an alternating- or constant-calorie diet with or without aerobic exercise. Both diets provided an average of 1200 kcal/d over a 12-wk period; daily intake of subjects in the alternating-diet condition varied in a prescribed pattern from 600 to 1800 kcal/d. Exercising subjects walked 5 d/wk. All subjects participated in an intensive outpatient behavior-modification program. At the end of the study, exercised subjects had greater reductions in body weight and body fat percentage than did nonexercised subjects. The type of caloric restriction did not affect weight or fat loss. Changes in resting metabolic rate did not differ among groups. Alternating calories was neither beneficial nor detrimental as a weight-loss strategy whereas exercise was clearly beneficial in weight-loss therapy.

Adult↗
PubMed1989

In vivo measurement of extracellular 5-hydroxytryptamine in hippocampus of the anaesthetized rat using microdialysis: changes in relation to 5-hydroxytryptaminergic neuronal activity.

The effect of manipulating the activity of central 5-hydroxytryptamine (5-HT) neurones on extracellular 5-HT in ventral hippocampus of the chloral hydrate-anaesthetized rat was studied using the brain perfusion method, microdialysis. Basal levels of 5-HT in the dialysates were close to the detection limits of our assay using HPLC with electrochemical detection. However, addition of the selective 5-HT reuptake inhibitor citalopram (10(-6) M) to the perfusion medium produced readily measurable amounts of dialysate 5-HT. Citalopram, therefore, was used throughout our experiments. Hippocampal dialysate levels of 5-HT sharply declined over the first hour after dialysis probe implantation, but then became constant. This stable output of 5-HT was reduced by 57% in rats treated 14 days previously with intracerebroventricular injections of the 5-HT neurotoxin 5,7-dihydroxytryptamine. Electrical stimulation (1-ms pulse width, 300 microA, 2-20 Hz) of the dorsal raphe nucleus for 20 min caused a rapid rise in hippocampal 5-HT output, which immediately declined on cessation of the stimulus and was frequency-dependent. Addition of tetrodotoxin (10(-6) M) to the perfusion medium reduced 5-HT levels to 75% of predrug values. Injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.5 and 2.5 micrograms) into the dorsal raphe nucleus caused a dose-related fall in hippocampal output of 5-HT compared to saline-injected controls. We conclude from these data that the spontaneous output of endogenous 5-HT into hippocampal dialysates, measured under our experimental conditions, predominantly originates from central 5-HT neurones and changes in accordance with their electrical activity.

5,7-Dihydroxytryptamine↗
PubMed1989

In vivo measurement using microdialysis of the release and metabolism of 5-hydroxytryptamine in raphe neurones grafted to the rat hippocampus.

The overflow and metabolism of serotonin (5-hydroxytryptamine; 5-HT) from transplants of embryonic medullary and mesencephalic raphe neurones in the previously 5-HT-denervated hippocampus have been analyzed in vivo using intracerebral dialysis. The average density of 5-HT-immunoreactive fibres in the grafted hippocampus was less than in nonlesioned hippocampus. Nonetheless, both basal and potassium-stimulated levels of 5-HT in the dialysates were restored to approximately normal after transplantation of medullary raphe cells, whereas mesencephalic implants resulted in over twice the 5-HT output observed in control hippocampus. However, 5-hydroxyindoleacetic acid (5-HIAA) overflow was increased only after grafting of mesencephalic raphe and then only to normal levels; medullary implants, by contrast, failed to enhance 5-HIAA output above that from lesion-only hippocampus. The evidence of a relative hyperactivity of the grafted neurones may explain the disproportionate improvements in various lesion-induced behavioural deficits after grafting of nervous tissue. In addition, differences in the presynaptic regulation of 5-HT release and metabolism are also apparent in the transplants; these variations are dependent on the precise origin of the serotoninergic cells.

5,7-Dihydroxytryptamine↗
PubMed1989

5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis.

1. An intracerebral perfusion method, brain microdialysis, was used to assess changes of 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of the chloral hydrate-anaesthetized rat in response to systemic administration of a variety of 5-HT1 receptor agonists. 2. A stable output of reliably detectable endogenous 5-HT was measured in dialysates collected from ventral hippocampus with the 5-HT reuptake inhibitor, citalopram, present in the perfusion medium. 3. Under these conditions the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a dose-dependent (5-250 micrograms kg-1, s.c.) reduction of 5-HT in hippocampal dialysates. 4. Similarly, the putative 5-HT1A agonists gepirone (5 mg kg-1, s.c.), ipsapirone (5 mg kg-1, s.c.) and buspirone (5 mg kg-1, s.c.) markedly reduced levels of 5-HT in hippocampal perfusates whereas their common metabolite 1-(2-pyrimidinyl) piperazine (5 mg kg-1, s.c.), which does not bind to central 5-HT1A recognition sites, had no effect. 5. 5-Methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a drug with reported high affinity for brain 5-HT1B binding sites, also produced a dose-dependent (0.25-5 mg kg-1, s.c.) decrease of hippocampal 5-HT output. 6. These data are direct biochemical evidence that systemically administered putative 5-HT1A and 5-HT1B agonists markedly inhibit 5-HT release in rat ventral hippocampus in vivo.

8-Hydroxy-2-(di-n-propylamino)tetralin↗