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W R Buckett

Publications and source records attributed to W R Buckett.

At least 37 records · Page 2Linked to original sources
PubMed1989

Measurement of 3-methoxytyramine by in vivo voltammetry: evidence for differences in central dopamine function in BALB/c and CBA mice.

Differential pulse voltammetry (DPV) combined with carbon fibre electrodes allows selective detection of electroactive dopamine and serotonin metabolites in vivo. While usually employed in rats, we have now applied this in vivo technique in two inbred strains of mice: BALB/c and CBA. Three distinct oxidation peaks were recorded in vivo in the striatum of either BALB/c or CBA mice with a small shoulder occurring after the third peak at approximately +400 mV. Pargyline (150 mg/kg i.p.) potentiated this voltammetric shoulder into an easily measurable peak (Peak 4). In addition, Peak 4 was 2-3 times larger in BALB/c than in CBA mice. Homovanillic acid (HVA) and 3-methoxytyramine (3-MT), both catabolites of dopamine, oxidised at approximately +400 mV in vitro. Brain tissue levels of HVA and 3-MT, measured by high-performance liquid chromatography (HPLC) with electrochemical detection, demonstrated that pargyline treatment reduced striatal HVA, but increased 3-MT. These results support the view that Peak 4 recorded in the striatum of pargyline-treated mice in vivo is due to the oxidation of extracellular 3-MT. Thus, Peak 4 may be a useful index of dopamine release in situations where dopamine itself cannot be detected. Local infusion of KCl (2 microliters, 0.1 M) further increased the size of Peak 4 in the striatum of both BALB/c and CBA mice. However, the increase was approx. 3 times greater in BALB/c mice, supporting previous evidence of greater dopaminergic function of BALB/c compared with CBA mice. In addition these two inbred strains of mice provide model systems for investigating the comparative functional roles of nigrostriatal pathways.

Animals↗
PubMed1989

The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride.

Sibutramine HCl is an inhibitor of the reuptake of monoamines with a pharmacological profile in rodents indicative of antidepressant activity. The secondary (BTS 54 354) and primary (BTS 54 505) amine metabolites of the tertiary amine sibutramine HCl exhibit similar in vivo pharmacological activity to the parent compound. Thus, each compound displays potent activity in acute behavioural models predictive of antidepressant effects and a comparable ability to inhibit the uptake of monoamines in vivo. In addition, BTS 54 354 and BTS 54 505 induce an equally rapid and potent down-regulation of cortical beta-adrenoceptors in the rat as sibutramine HCl. The secondary and primary amines are, however, considerably more active than sibutramine HCl as inhibitors of the uptake of noradrenaline, dopamine and 5-hydroxytryptamine in vitro. The potent inhibition of the reuptake of noradrenaline by the secondary and primary amine metabolites probably contributes to the rapid and potent down-regulation of beta-adrenoceptors in the rat, induced by the putative antidepressant sibutramine HCl.

Animals↗
PubMed1989

Antidepressant treatments, including sibutramine hydrochloride and electroconvulsive shock, decrease beta 1- but not beta 2-adrenoceptors in rat cortex.

The beta 1- and beta 2-adrenoceptor populations in rat cortex were individually quantified by labelling all of the receptors with [3H]dihydroalprenolol and displacing with isoprenaline (200 microM) or CGP 20712A (1-(2-[(3-carbamoyl-4-hydroxy)phenoxy]ethylamino)-3-[4-(1-methyl-4- trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol methanesulphonate; 100 nM) to define total beta-adrenoceptors and beta 1-adrenoceptors, respectively. Binding parameters for beta 2-adrenoceptors were calculated by the difference. Oral administration of the monoamine reuptake inhibitors sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg), or zimeldine (10 mg/kg) for 10 days decreased the total number of beta-adrenoceptors present in rat cortex. This effect was entirely due to a reduction in the number of beta 1-adrenoceptors. Similarly, 10 days of treatment with the monoamine oxidase inhibitor tranylcypromine (10 mg/kg p.o.) or five electroconvulsive shocks (ECSs; 200 V, 2 s) spread over this period also down-regulated beta-adrenoceptors by reducing the content of the beta 1-subtype. By contrast, treatment with clenbuterol (5 mg/kg p.o.) for 10 days reduced the number of cortical beta-adrenoceptors by an effect on the beta 2-adrenoceptor population. The effects of short-term treatment with these drugs were also investigated, and, using the doses shown above, the results of 3 days of administration or a single ECS were determined. Sibutramine HCl and desipramine were alone in producing a reduction in number of beta-adrenoceptors after 3 days. Once again, this was exclusively due to a loss of beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1989

Measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by h.p.l.c. with electrochemical detection, as an index of noradrenaline utilisation and presynaptic alpha 2-adrenoceptor function.

1. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with electrochemical detection is described. This technique incorporates an ethyl acetate purification procedure and uses 3-hydroxy-4-methoxyphenylglycol (iso-MHPG) as the internal standard. 2. Inhibition of monoamine oxidase by injection of tranylcypromine (5 and 10 mg kg-1) or pargyline (50 and 100 mg kg-1) markedly decreased brain MHPG concentrations. After injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (200 mg kg-1), there were time-dependent linear decreases in the concentrations of noradrenaline and MHPG in mouse brain. In addition, a very good correlation (r = 0.95, n = 30; P less than 0.001) was found between the concentrations of noradrenaline and MHPG present in the brains of the same mice after alpha-methyl-p-tyrosine treatment. 3. Mouse brain MHPG concentrations were dose-dependently reduced after administration of the alpha 2-adrenoceptor agonist, clonidine (1-3000 micrograms kg-1), and elevated by the antagonists, idazoxan (1 and 5 mg kg-1), and yohimbine (1 and 5 mg kg-1). Intracerebroventricular injection of the alpha 1-adrenoceptor agonist, phenylephrine (5-50 micrograms) dose-dependently increased MHPG levels. The alpha 1-adrenoceptor antagonist, prazosin, had no effect at the moderate dose of 1 mg kg-1, but increased MHPG concentrations at 5 mg kg-1. The beta-adrenoceptor agonist, clenbuterol (10-1000 micrograms kg-1) and the antagonist, pindolol (1 and 5 mg kg-1), were both without effect. 4. The decrease in brain MHPG concentrations induced by clonidine (100 micrograms kg-1) was prevented by prior injection of 1 mg kg-1 of idazoxan or yohimbine, but not by prazosin or pindolol. 5. MHPG levels were decreased after administration of the noradrenaline reuptake inhibitor desipramine (5 and 10 mg kg-1) and the non-selective monoamine reuptake inhibitors, sibutramine HCl (BTS 54 524; 1 and 3 mg kg-1) and amitryptyline (5 mg kg-1). However, the selective 5-hydroxytryptamine reuptake inhibitor, zimeldine (5 and 10 mg kg-1), was without effect. Dexamphetamine (1 and 5 mg kg-1) and methamphetamine (1 and 5 mg kg-1) both decreased brain MHPG concentrations in a dose-related fashion. 6. Overall the data show that MHPG can be used as a functional index of both presynaptic alpha 2-adrenoceptor activity and noradrenaline turnover and utilisation.

Animals↗
PubMed1989

Sex-related differences in central adrenergic function and responsiveness to repeated administration of desipramine or electroconvulsive shock.

1. Clonidine induces hypoactivity in rodents. Male rats were found to be markedly more susceptible to the sedative effects of this alpha 2-adrenoceptor agonist than females. Thus to obtain identical hypoactivity responses for subsequent experiments, clonidine was administered to male and female rats at doses of 0.2 and 0.5 mg kg-1, respectively. 2. The clonidine-induced hypoactivity response of female rats was not affected by the oestrous cycle. 3. Repeated injection of desipramine (DMI; 5 mg kg-1 b.d.) for up to 14 days progressively attenuated clonidine-induced hypoactivity in both male and female rats. However, in males the attenuation was more rapid in onset and a greater overall reduction was obtained. This alpha 2-adrenoceptor-mediated response was also progressively reversed by repeated daily administration of an electroconvulsive shock (ECS; 110 V, 1 s). In this case, although the maximum decrease was greater in males, the time of onset was identical in both sexes. 4. There were no sex-related differences in either the number or affinity of alpha 2- and beta-adrenoceptors in rat cortex. Cortical alpha 2-adrenoceptors were decreased by 14 days of DMI injection or 10 days of ECS treatment (ECS x 10) and these effects were identical in both sexes. These receptors were not altered by 2 days administration of DMI or ECS. Cortical beta-adrenoceptors were reduced in male and female rats by 2 and 14 days of DMI injection and by ECS x 10, but not ECS x 2. 5. Viewed overall, the data show differences in alpha 2-adrenoceptor function between the sexes, as determined by clonidine-induced hypoactivity and the responsiveness of this paradigm to repeated administration of DMI and ECS. In contrast, no differences were observed in complementary alpha 2- and beta-adrenoceptor binding experiments using rat cortical tissue.

Animals↗
PubMed1988

The pharmacology of sibutramine hydrochloride (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation.

1. Sibutramine hydrochloride (BTS 54 524) has been evaluated in a range of behavioural and biochemical models predictive of potential antidepressant activity. 2. BTS 54 524 exhibited potent activity in acute behavioural tests for detecting potential antidepressants. 3. BTS 54 524 rapidly and potently down-regulated rat cortical beta-adrenoceptors, being effective after only three days of oral administration. 4. BTS 54 524 showed very little activity in a range of experiments predictive of side-effect potential. 5. BTS 54 524 possesses a pharmacological profile which suggests that it may be a potent antidepressant with a rapid onset of action, and with a low potential for causing side-effects.

Adenylyl Cyclases↗
PubMed1985

Decreased 5-HT2 but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin. Application of the Woolf plot to analysis of binding parameters.

Prolonged administration of the antidepressant drug, dothiepin hydrochloride (30 mg/kg orally twice daily for 24 days), resulted in a significant decrease in the population of serotonin2 (5-HT2) binding sites in the frontal cortex of rats whereas serotonin1 (5-HT1) binding sites remained unaltered. No significant differences in affinity constants for either ligand-binding site interaction were observed. Analyses of the binding parameters was performed using linear transformation methods of the specific binding isotherms according to Scatchard (1949) [Ann. N.Y. Acad. Sci. 51: 660-672] or Woolf (see Haldane, 1957: Nature 179: 832). The resulting parameter estimates generated in each analysis were compared. Although both methods demonstrated the decreased Bmax for 5-HT2 binding sites with no change in 5-HT1 sites after prolonged administration of dothiepin, Woolf analyses gave reliably better estimates of the binding parameters as judged by examination of the respective correlation coefficients for best fit linear regression lines.

Animals↗
PubMed1984

Chronic antidepressant administration fails to attenuate apomorphine-induced decreases in rat striatal dopamine metabolites.

The responsiveness of the rat striatal dopamine (DA) receptor system to apomorphine (APO) was assessed after 10 days of antidepressant administration. Desipramine (DMI), dothiepin (DOTH), iprindole (IPR) and nomifensine (NOM) were administered intra-peritoneally, twice daily, to rats for 10 days and 42 h after the last drug dose, animals were injected with APO (25 or 200 micrograms/kg s.c., 15 min) or vehicle. Striatal content of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), assayed using a recently developed high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method, showed that prolonged administration of all four antidepressant drugs failed to modify the effect of APO on DA metabolism. The results of these experiments therefore do not provide evidence to support the suggestion that subsensitivity in presynaptic DA 'autoreceptors' is a significant biochemical correlate of chronic antidepressant drug administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

An automated method to measure monoamines and metabolites using elevated temperature reversed phase HPLC with electrochemical detection. Application to striatal dopamine and hippocampal serotonin turnover.

High pressure liquid chromatography with electrochemical detection has been successfully used for the analysis of noradrenaline, dopamine(DA), serotonin(5-HT), and selected metabolites in brain. Automated sample injection allows up to 100 samples per day to be analyzed; precise thermostatic control of the chromatography at 45 degrees C increases both method reproducibility and separation efficiency while increasing column life. The method requires minimal sample pretreatment and is rapid and inexpensive. It has been applied to the analysis of rat and mouse whole brain and, in particular, to milligram samples of rat striatum and hippocampus, thus permitting the measurement of regional DA and 5-HT turnover. Effects of selected psychotropic drugs on these processes illustrate the value of the method to either DA or 5-HT turnover studies.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Pharmacological studies on stimulation-produced analgesia in mice.

Stimulation-produced analgesia (ESPA) was induced in mice by peripheral caudal electrostimulation and subsequently monitored on a 52 degrees C hot plate. The effects on ESPA of compounds modulating some neurotransmitter systems were studied at appropriate premedication times and at doses at which the compounds themselves did not exhibit antinociceptive actions. The manipulation of catecholaminergic, dopaminergic or GABAergic systems did not modify ESPA. It could be potentiated by an increase in serotoninergic activity following 5-hydroxy-D,L-tryptophan (80-120 mg/kg) and reduced, under certain circumstances, by serotonin depletion with p-chlorophenylalanine (3 x 132 mg/kg). However the serotonin reuptake inhibitors fluoxetine (5 mg/kg) and zimelidine (10 mg/kg) were without effect indicating a complex modulating role of the monoamine. As with morphine-tolerant mice, the induction of ESPA in mice tolerant to methadone and to meperidine has been demonstrated, while the analgesia was not enhanced by chronic naloxone treatment. Although the naloxone reversibility of ESPA has been confirmed, a second acute dose of naloxone (1 mg/kg) did not reverse the analgesia. ESPA could also be fully elicited in adrenalectomized mice. It is concluded that ESPA is a specific type of stimulation-produced analgesia, shorter in duration and pharmacologically more resistant to modulation than others, which might subserve a functional role in response to noxious stimuli.

Adrenalectomy↗
PubMed1981

The influence of a GABA transaminase inhibitor, gamma-vinyl GABA, on voluntary morphine consumption in the rat.

Morphine-dependent and control rats in an oral free-choice protocol were treated with gamma-vinyl GABA (GVG), 60, 120 and 240 mg/kg IP, for 3 days over three successive periods. Morphine dependence was assessed with naltrexone. Fluid intake of morphine-dependent rats was reduced during GVG treatment and the proportion of fluid taken as morphine was also decreased, but not sufficiently to induce withdrawal signs. Intake by controls was only affected by 240 mg/kg GVG, when body weight decreased. The attentuation of morphine consumption by GVG treatment may, within the limitations of this protocol, interfere with the positive reinforcing properties of morphine.

4-Aminobutyrate Transaminase↗
PubMed1981

Intravenous bicuculline test in mice: characterization with GABAergic drugs.

The effects of GABAergic drugs having diverse modes of action were studied in the myoclonic seizure syndrome induced by intravenous bicuculline in mice. The elicited syndrome can be antagonized dose-dependently by GABA-agonists, by GABA-transaminase inhibitors, by GABA neuronal uptake inhibitors, and by benzodiazepines stereospecifically after appropriate premedication times and routes. This test is proposed as a useful in vivo test for examination of compounds presumed to modify GABAergic function. It is pharmacologically relevant and warrants inclusion in any program involving GABAergic drugs.

4-Aminobutyrate Transaminase↗
PubMed1979

Peripheral stimulation in mice induces short-duration analgesia preventable by naloxone.

Peripheral stimulation was applied to mice by mild caudal electrostimulation, by mechanical pressure or by footshock for 30 sec, before testing on a 52 degrees C hot plate. Reaction times to paw lick and to escape from the hot plate were recorded. Analgesia could be elicited and measured by these procedures. It was of short duration, declining in a minute, and was antagonized by low doses of naloxone. The analgesia measured by the escape reaction time could be elicited after multiple caudal electrostimulation as well as in morphine-tolerant mice, and it could still be reversed by naloxone. An opioid link is thus involved in this phenomenon, which also supports the notion of more than one opioid pathway existing in the brain. The short period of analgesic cover afforded in the face of noxious stimuli would permit aversive action to be taken in nature and thus might represent the prime functional role of enkephalins in the brain.

Analgesia↗
PubMed1979

The actions of enkephalins are not modified by the "kininase-II" inhibitor captopril.

The "kininase-II" (EC 3.4.15.1) inhibitor captopril in concentrations up to 10(-4) M did not affect the actions of enkephalins on the isolated electrically stimulated guinea-pig ileum. Captopril (100 mg/kg i.p.) in mice did not influence stimulation-produced analgesia and did not show analgesic properties. It is concluded that "kininase-II" is not involved in enkephalin catabolism, since the pharmacological actions of enkephalins were not enhanced after inhibition of the enzyme by captopril.

Angiotensin-Converting Enzyme Inhibitors↗