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Biomedical subjects

A McGregor

Publications and source records attributed to A McGregor.

At least 55 records · Page 3Linked to original sources
PubMed1997

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement.

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.

Amygdala↗
PubMed1996

Preparation of oligoribonucleotides containing 4-thiouridine using Fpmp chemistry. Photo-crosslinking to RNA binding proteins using 350 nm irradiation.

The preparation of a 4-thiouridine phosphoramidite suitable for RNA synthesis and its subsequent incorporation into oligoribonucleotides is described. The thiol group is protected with a 2-cyanoethyl group and the 2'-OH with a 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl function. Thiouridine-containing oligoribonucleotides were used as 350 nm UV crosslinking probes for the photoaffinity labelling of RNA binding proteins. Specific crosslinking was demonstrated between the Rev protein of HIV-1 (as a glutathione S-transferase fusion protein) and its RNA target, the Rev-responsive element. It was not possible to generate crosslinks between the RNA bacteriophage MS2 coat protein and the initiator stem-loop of the replicase gene, to which it binds. These results are consistent with the structural data available on both systems.

Affinity Labels↗
PubMed1996

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement.

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09-1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Multiple interactions control the intracellular localization of the herpes simplex virus type 1 capsid proteins.

Herpes simplex virus type 1 (HSV-1) capsid assembly takes place in the nucleus of infected cells. However, when each of the outer capsid shell proteins, VP5, VP23 and VP26, is expressed in the absence of any other HSV-1 proteins, it does not localize to the nucleus but is distributed throughout the cell. We have previously shown that the HSV-1 capsid scaffolding protein, preVP22a, can relocate VP5 into the nucleus but does not influence the distribution of VP23. We now demonstrate that the outer capsid shell protein, VP19C, is able to relocate both VP5 and VP23 separately into the nucleus. However, nuclear localization of VP26 is only observed when VP5 is present together with either VP19C or preVP22a. Thus, pair-wise interactions involving all of the abundant capsid proteins have now been identified. Electron microscope examination of insect cells coinfected with recombinant baculoviruses expressing VP19C and VP5 reveals the presence of 70 nm diameter 'capsid-like' structures, suggesting that these two proteins can form the basic capsid shell.

Amino Acid Sequence↗
PubMed1996

Thyroxine replacement increases central 5-hydroxytryptamine activity and reduces depressive symptoms in hypothyroidism.

Hypothyroidism is associated with both reduced central 5-HT function and an increased incidence of depression. This study tested the hypothesis that the reduced 5-HT function returns to normal with thyroxine replacement therapy. Seven hypothyroid patients were tested before and after adequate thyroxine replacement. Cortisol and prolactin responses to d-fenfluramine, a centrally acting 5-HT-releasing agent, were used as an index of central (hypothalamic) 5-HT responsiveness. 5-HT-mediated cortisol responses were significantly higher after thyroxine replacement. Basal prolactin levels were reduced, but 5-HT-mediated prolactin responses were not significantly higher after treatment, perhaps due to the pre-treatment responses being elevated by the direct stimulatory effects of hypothyroidism itself on pituitary prolactin secretion. Depressive symptomatology improved with thyroxine. TSH levels were positively related to depressive symptomatology, and inversely to cortisol responses. Depressive symptomatology was inversely related to cortisol responses. These findings thus provide further support that central 5-HT neurotransmission is affected by hypothyroidism. They also suggest that the reduction in 5-HT responsiveness is reversible with thyroxine replacement therapy.

Adult↗
PubMed1996

A disulfide bonding interaction role for cysteines in the extracellular domain of the thyrotropin-releasing hormone receptor.

The roles of disulfide and sulfhydryl groups in the specific binding of TRH to its receptor have been examined. In all TRH receptors (TRH-Rs) isolated from different species so far, there are only two extracellular cysteine residues (Cys98 in the extracellular loop between transmembrane helices 2 and 3 and Cys179 in the extracellular loop between transmembrane helices 4 and 5) that are in positions homologous to cysteine residues in other G protein-coupled receptors. Another Cys (Cys100) is located in close proximity to Cys98 at the interface between the first extracellular loop and third transmembrane domain. To assess the role of these TRH-R Cys residues in disulfide bonding interactions, they were mutated to either Ser or Ala. Six mutant receptors (Cys98Ser, Cys98Ala, Cys179Ser, Cys179Ala, Cys100Ser, and Cys100Ala) were expressed in COS-1 cells and tested for their ability to bind TRH and to activate total inositol phosphate (IP) formation. TRH-R mutants Cys100Ser and Cys100Ala showed TRH binding affinities and IP activation similar to the wild-type (WT). In contrast, mutants Cys98Ser, Cys98Ala, Cys179Ser, and Cys179Ala showed no high affinity TRH binding. The potencies of Cys98Ala and Cysl79Ala as measured by IP stimulation were decreased by four orders of magnitude when compared with WT. Cys98Ser potency decreased by five orders of magnitude, whereas Cys179Ser showed no IP production. Northern blotting confirmed expression of all the mutant TRH-Rs at the messenger RNA (mRNA) level. An epitope tag derived from the Haemophilus influenza hemagglutinin protein was incorporated at the NH2 termini of the TRH-R WT and TRH-R Cys mutants to allow the independent assessment of cell surface expression of receptor protein. TRH-R mutants that failed to show receptor binding (Cys98Ser, Cys98Ala, Cys179Ala) showed WT levels of cell surface receptor expression, indicating that loss of receptor binding in these mutants is not attributable to loss of receptor expression. In contrast, cell surface expression of Cysl79Ser, which showed no ligand induced IP stimulation, could not be detected. Dithiothreitol, a disulfide bond reducing agent, and p-chloromercuribenzoic acid (p-CMB), a sulfhydryl blocking compound, reduced specific TRH binding in a dose-dependent manner. The inhibition of binding by dithiothreitol implies that the integrity of a disulfide bond is important for TRH binding to its receptor. The dramatic inhibition of TRH binding by p-CMB indicates that free sulfhydryl groups are also associated with the binding of the ligand to its receptor. This study presents evidence that a disulfide bond exists between Cys98 and Cys179 which is essential for maintaining the receptor in the correct conformation for ligand binding. Cys100 is not thought to have a disulfide bonding interaction role. Results obtained after chemical modification have shown that free sulfhydryl groups within the TRH-R may also have a role in ligand interactions.

Amino Acid Sequence↗
PubMed1995

Contrasting neuroendocrine responses in depression and chronic fatigue syndrome.

Hypothalamic-pituitary-adrenal (HPA) axis and central 5-HT function were compared in chronic fatigue syndrome (CFS), depression and healthy states. 10 patients with CFS and 15 patients with major depression were matched for age, weight, sex and menstrual cycle with 25 healthy controls. Baseline-circulating cortisol levels were highest in the depressed, lowest in the CFS and intermediate between the two in the control group (P = 0.01). Prolactin responses to the selective 5-HT-releasing agent d-fenfluramine were lowest in the depressed, highest in the CFS and intermediate between both in the healthy group (P = 0.01). Matched pair analysis confirmed higher prolactin responses in CFS patients than controls (P = 0.05) and lower responses in depressed patients than controls (P = 0.003). There were strong inverse correlations between prolactin and cortisol responses and baseline cortisol values. These data confirm that depression is associated with hypercotisolaemia and reduced central 5-HT neurotransmission and suggest that CFS may be associated with hypocortisolaemia and increased 5-HT function. The opposing responses in CFS and depression may be related to reversed patterns of behavioural dysfunction seen in these conditions. These findings attest to biological distinctions between these disorders.

Adult↗
PubMed1995

Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a disorder characterized by severe physical and mental fatigue and fatiguability of central rather than peripheral origin. We hypothesized that CFS is mediated by changes in hypothalamopituitary function and so measured the adrenocorticotrophic hormone (ACTH), cortisol, growth hormone, and prolactin responses to insulin-induced hypoglycemia, and the ACTH, cortisol, and prolactin responses to serotoninergic stimulation with dexfenfluramine in nondepressed CFS patients and normal controls. We have shown attenuated prolactin responses to hypoglycemia in CFS. There was also a greater ACTH response and higher peak ACTH concentrations (36.44 +/- 4.45 versus 25.60 +/- 2.78 pg ml), whereas cortisol responses did not differ, findings that are compatible with impaired adrenal cortical function. This study provided evidence for both pituitary and adrenal cortical impairment in CFS and further studies are merited to both confirm and determine more precisely their neurobiological basis so that rational treatments can be evolved.

Adrenocorticotropic Hormone↗
PubMed1995

Effect of medial prefrontal cortex injections of SCH 23390 on intravenous cocaine self-administration under both a fixed and progressive ratio schedule of reinforcement.

Rats were trained to self-administer cocaine (1.5 mg/kg i.v.) under either a fixed ratio (FR) or progressive ratio (PR) schedule of reinforcement. Following acquisition, bilateral intracerebral cannulae were directed at the medial prefrontal cortex (mPFC) or striatum (STRM). Intracranial injections of the D1 receptor antagonist, SCH 23390 (0-2.0 micrograms/0.5 microliter/side), were made immediately prior to a self-administration session. Under the FR 1 schedule, SCH 23390 caused a dose-dependent increase in the rate of cocaine intake following injection into either the mPFC or the STRM. In contrast, under the PR schedule similar injections into the STRM had no effect on the breaking point, but large decreases were produced following injection into the mPFC. These results indicate that dopaminergic systems within the mPFC have a significant role to play in the reinforcing properties of cocaine. Moreover, the STRM does not appear to have a role in those reinforcing properties of cocaine measured under the PR schedule. The significant rate-increasing effects obtained from the STRM under the FR schedule, indicate that the two schedules must measure different aspects of cocaine's CNS action.

Animals↗
PubMed1995

The MicroScan WalkAway diagnostic microbiology system--an evaluation.

The MicroScan WalkAway is an automated bacterial identification and susceptibility testing system that has only recently been marketed in Australasia. We evaluated the performance of the instrument using MicroScan Rapid fluorescent panels to determine the identity and antibiotic susceptibilities of 100 Gram negative and 100 Gram positive organisms representing both common clinical isolates and selected organisms of interest. MicroScan results were compared with those obtained by conventional biochemical identification, and antibiotic susceptibility testing using agar dilution following the National Committee on Clinical Laboratory Standards guidelines. MicroScan and reference identifications were in agreement for 93% of Gram negative organisms. MicroScan results were available within 2 hrs. Additional tests were required to confirm the identity of 9 isolates but on only 2 occasions would a definitive identification been delayed beyond 24 hrs. Very major or major discrepancies were seen in 2% and minor discrepancies in 8% of Gram negative susceptibility tests. Susceptibility results were available within 7 hrs but could not be obtained for 13 slow growing organisms. With Gram positive organisms MicroScan agreed with the reference identification of 87% of isolates cultured on horse and 90% of those cultured on sheep blood agar. Discrepancies that occurred in the identification of some streptococci made us question the suitability of MicroScan as the sole means of identifying these organisms. All identifications were available within 24 hrs and the requirement for additional tests was minimal. Susceptibility results closely matched those obtained by agar dilution with < 1% major and 7% and 9% minor discrepancies occurring with sheep and horse blood respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriological Techniques↗
PubMed1995

The C. elegans sex-determining gene fem-2 encodes a putative protein phosphatase.

The genetic and molecular analysis of genes involved in the regulation of sex determination in Caenorhabditis elegans suggests that the gene fem-2 plays an important role in regulating a pathway transducing a non-cell-autonomous signal to a nuclear transcription factor. The wild-type fem-2 gene was cloned by identifying sequences from the C. elegans physical map that could restore normal Fem-2 function to homozygous mutant fem-2 transgenic animals. cDNA sequences mapping to the minimal rescuing region correspond to an open reading frame with a sequence similar to protein phosphatase 2C enzymes from systems as diverse as yeast, humans, and plants, but the alignments suggest that FEM-2 falls into a separate class of proteins than the canonical homologues. Several fem-2 mutant alleles were sequenced, and the mutations are predicted to cause protein changes consistent with their observed phenotypes, such as missense mutations in conditional alleles, and a nonsense mutation in a predicted null allele. This is the first evidence implicating phosphorylation and/or dephosphorylation as a control mechanism in C. elegans sex determination.

Alleles↗
PubMed1995

Antibiotic use in upper respiratory tract infections in New Zealand.

Upper respiratory tract infections (URTIs) are a common reason for presentation to general practitioners. The current study used computerised consultation records of 100,222 patients from 17 general practices in New Zealand for the 12-month period 1 July 1991-30 June 1992. URTIs were noted in 8.9% of all consultations: 44.1% of cases were children aged less than 10 years. Females presented more frequently than males for all ages above five years. Fifteen different antibiotics were prescribed for URTIs, but in 22.5% of cases no antibiotic was prescribed. There was no statistically significant difference in the likelihood of a successful outcome with or without antibiotic therapy (chi 2 = 0.76, P > 0.05). The treatment failure profile of some antibiotics highlights the need for more prescriber education, especially as the range of medications available for general practitioner prescribing increases.

Adolescent↗
PubMed1995

Luteinized unruptured follicle: morphology, endocrine function and blood flow changes during the menstrual cycle.

A case of spontaneous luteinized unruptured follicle syndrome is presented with full documentation of hormonal, morphological and haemodynamic changes. Changes in uterine blood flow were also noted. Growth of the leading follicle was slow during the follicular phase of the cycle. After the luteinizing hormone (LH) surge, growth of the follicle was more rapid. Concurrently, the follicle developed internal echogenicity with ultrasonic evidence of separation of the granulosa cell layer. The follicle was no longer visible 144 and 132 h after the LH rise and peak respectively. There was no primary progesterone rise associated with either the LH rise or peak, but a secondary progesterone rise occurred 42 h after the onset of the LH surge. Peri-follicular blood flow velocity was detected for the first time on cycle day 5 and appeared to rise after the onset of the LH surge. Peri-follicular blood flow velocity appeared to reduce after the LH surge to values associated with the follicular phase. These observations are consistent with an association of a primary granulosa cell defect with luteinized unruptured follicle syndrome which would account for the initial slow follicular growth, absent primary progesterone rise and reduction in blood flow in the wall of the follicle after the LH surge.

Adult↗
PubMed1995

Description of circadian rhythm in uterine artery blood flow during the peri-ovulatory period.

Uterine artery blood flow was assessed by transvaginal colour and pulsed Doppler ultrasound prospectively in six women during the peri-ovulatory period. All patients had regular ovulatory menstrual cycles and a mid-luteal serum progesterone consistent with spontaneous ovulation in the preceding cycle. Each patient underwent serial transvaginal ultrasound examination and Doppler assessment of blood flow in the uterine arteries. When the mean follicular diameter was > 16 mm or day -2 from the estimated day of ovulation was reached, patients were scanned at 6 hourly intervals at 0600, 1200, 1800 and 2400 h until follicular rupture. The pulsatility index (PI) and time averaged maximum velocity (TAMX) were calculated as Doppler indices of impedance to blood flow and velocity respectively. A venous blood sample was taken at each visit for subsequent hormonal analysis. The mean uterine artery PI showed a marked daily fluctuation with a nadir occurring most commonly at 0600 h. A comparison between the mean PI values at 0600 and 1800 h showed significantly lower results at 0600 h in both dominant (P < 0.05) and nondominant (P < 0.02) uterine arteries. Furthermore, mean uterine artery TAMX showed daily fluctuations with peak values most commonly occurring at 0600 h with the nadir occurring during the afternoon and late evening. There was no temporal relationship between the fluctuations in PI and changes in luteinizing hormone, follicle stimulating hormone, oestradiol or progesterone concentrations. These observations suggest that there is a circadian rhythm in uterine artery blood flow during the peri-ovulatory period which appears to be independent from the hormonal changes.

Adult↗
PubMed1995

Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression.

OBJECTIVE: The incidence of depression in those with hypothyroidism is increased compared to healthy populations, though the mechanism for this is unclear. We tested the hypothesis that central 5-HT activity is reduced in hypothyroidism, and that this subsequently lowers the threshold for developing depression. PATIENTS: Twenty subjects entered the study: 10 drug free hypothyroid patients and 10 age, sex, weight and menstrual cycle matched controls. MEASUREMENTS: Patients were diagnosed as being depressed using DSM-IIIR criteria and rated using the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI). Cortisol and prolactin responses to dexfenfluramine, a centrally acting 5-HT releasing agent, were used as an index of central 5-HT responsivity. RESULTS: Both cortisol and PRL responses were reduced in the hypothyroid group relative to the controls. Peak cortisol responses were inversely correlated to TSH levels. Four of the 10 patients were clinically depressed. Depressed patients had higher TSH levels than their non-depressed counterparts, and TSH levels were positively correlated with HAM-D and BDI scores. CONCLUSIONS: These findings support animal work suggesting that hypothyroidism reduces central 5-HT activity. They also suggest a threshold effect in that higher TSH levels predicted both lower 5-HT mediated endocrine responses and the presence of clinical depression.

Adult↗