Biomedical subjects

W R Buckett

Publications and source records attributed to W R Buckett.

At least 19 recordsLinked to original sources

PubMed1992

A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine.

Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1-3 mg/kg PO) and methamphetamine (0.3-30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED50 values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10-100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [3H]-dopamine from preloaded rat striatal slices was not altered by 10(-7)-10(-5) M concentrations of sibutramine, BTS 54,354, BTS 54,505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10(-8)-10(-4) M) caused a significant concentration-dependent increase in [3H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 30 mg/kg PO) did not alter 3-methoxytyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3-10 mg/kg IP or 0.42-4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10-100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

A comparison of various antidepressant drugs demonstrates rapid desensitisation of alpha 2-adrenoceptors exclusively by sibutramine hydrochloride.

The functional status of presynaptic and postsynaptic alpha 2-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate alpha 2-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the alpha 2-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS; 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic alpha 2-adrenoceptors. ECS down-regulated postsynaptic alpha 2-adrenoceptors when given for 3 days, but required 5 days to desensitise both alpha 2-adrenoceptor populations.

Adrenergic alpha-Antagonists↗

PubMed1991

Membrane stabilising properties of the selective 5-HT2 receptor agonist, (+/-)-DOI.

The effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2 receptor agonist, on nerve conduction in the isolated frog sciatic nerve trunk were examined. Compound action potential amplitude was concentration dependently decreased by (+/-)-DOI (EC50 = 1.2 mM), an effect that was not altered by the presence of ketanserin and with a similar potency to lignocaine. (+/-)-propranolol and disopyramide. The results indicate that (+/-)-DOI has membrane stabilising properties, in addition to its reported 5-HT2 agonist actions.

Action Potentials↗

PubMed1991

Effects of antidepressant drugs and electroconvulsive shock on pre- and postsynaptic alpha 2-adrenoceptor function in the brain: rapid down-regulation by sibutramine hydrochloride.

Clonidine (0.1 mg/kg IP)-induced hypoactivity and mydriasis responses were respectively used as functional indices of pre- and postsynaptic alpha 2-adrenoceptors in mouse brain. A single injection of various antidepressant drugs had no effect on either response when measured 24 h later. However, 14 days' treatment with sibutramine HCl (3 mg/kg IP), dothiepin (50 mg/kg IP), amitriptyline (10 mg/kg IP), desipramine (10 mg/kg IP) or tranylcypromine (10 mg/kg IP) markedly attenuated both clonidine-induced hypoactivity and mydriasis. Repeated administration of zimeldine (10 mg/kg IP), mianserin (10 mg/kg IP) or clenbuterol (5 mg/kg IP) had no effect on either response. Subchronic treatment with sibutramine HCl (3 mg/kg IP; 3 days) also attenuated pre- and postsynaptic alpha 2-adrenoceptor function. Five ECS (200 V, 2 s) spread over 10 days, but not a single shock, reduced the hypoactivity and mydriasis responses to clonidine. Together, the results indicate that pre- and postsynaptic alpha 2-adrenoceptor function is attenuated by repeated treatment with those antidepressants which acutely increase synaptic levels of noradrenaline. These adrenergic receptor populations are also desensitized by ECS, although this effect is probably mediated via a different mechanism. Finally, the rapid down-regulation observed with sibutramine HCl is not confined to beta-adrenoceptors alone, because pre- and postsynaptic alpha 2-adrenoceptor function is also attenuated by 3 days of treatment with this novel antidepressant drug.

Animals↗

PubMed1991

Determination of the role of noradrenergic and 5-hydroxytryptaminergic neurones in postsynaptic alpha 2-adrenoceptor desensitization by desipramine and ECS.

1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment.

Animals↗

PubMed1990

Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl.

Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5-20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [3H]-noradrenaline (NA) by rat cortical synaptosomes, [3H]-5-hydroxytryptamine (5HT) by human platelets and [14C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [3H]-NA greater than [3H]-5HT greater than [14C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4-6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [3H]-NA and [3H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.

Animals↗

PubMed1990

An investigation of the role of 5-hydroxytryptamine in the attenuation of presynaptic alpha 2-adrenoceptor-mediated responses by antidepressant treatments.

Changes in the function of presynaptic alpha 2-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 micrograms ICV) or administration of p-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11-15 days produced 62-77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT2 receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this alpha 2-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic alpha 2-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.

5,7-Dihydroxytryptamine↗

PubMed1990

A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detection. Studies with drugs which alter dopamine metabolism in the brain.

3-Methoxytyramine (3-MT) is a minor metabolite of dopamine which is suggested to reflect the turnover and utilization of dopamine. A novel, isocratic HPLC method has been developed which can be used to analyse 3-MT in homogenates of rat brain without the need for additional purification procedures. Furthermore, the coulometric electrochemical detection system is sensitive enough to measure 3 pg of 3-MT (equivalent to 0.6 ng/g tissue wet weight). 3-Methoxytyramine was measured in the striatum and n. accumbens after decapitation and rapid freezing, using 3-methoxy-4-hydroxybenzylamine as the internal standard. The effects of dopaminergic and other drugs on this metabolite were examined using this method. alpha-Methyl-p-tyrosine (200 mg/kg i.v.) produced parallel linear decreases in dopamine and 3-MT in naive rats, but not those pretreated with tranylcypromine (5 mg/kg i.p.). Methamphetamine (0.3-10 mg/kg i.p.) and amphetamine (0.3-10 mg/kg i.p.) both dose-dependently increased 3-MT in naive and tranylcypromine-pretreated rats. In naive animals, 3-MT was not altered by intraperitoneal injection of the dopamine reuptake inhibitors, bupropion (10 mg/kg) and nomifensine (10 mg/kg) or by sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg) and zimeldine (10 mg/kg). 3-Methoxytyramine was decreased by apomorphine (5 mg/kg i.p.) and also by large doses of the selective D2 antagonist, BRL 34778 (5 mg/kg i.p.) or L-DOPA (50 mg/kg i.p.). The selective D1 antagonist, SCH 23390 (0.1 or 5 mg/kg i.p.) was without effect. In tranylcypromine-pretreated rats, 3-MT was dose-dependently reduced and increased by apomorphine (0.01-5 mg/kg i.p.) and BRL 34778 (0.1-5 mg/kg i.p.), respectively. The drug SCH 23390 (0.1-5 mg/kg i.p.) produced much smaller increases in 3-MT which were probably mediated through the striatonigral pathway. Overall, the data suggest that measurement of 3-MT, after inhibition of monoamine oxidase, is a useful index of the release and utilization of dopamine. However, after substantial and prolonged depletion of dopamine, levels of 3-MT in naive animals are a better index. Also, the formation of 3-MT in naive rats rats provides a sensitive method for distinguishing between dopamine releasing agents and reuptake inhibitors.

Animals↗

PubMed1990

Biochemical and in vivo voltammetric evidence for differences in striatal dopamine levels in inbred strains of mice.

High performance liquid chromatography with electrochemical detection and differential pulse voltammetry were used to provide a direct measurement of tissue content of dopamine and its metabolites and extracellular dopamine levels, respectively, in the striata of BALB/c and CBA inbred strains of mice. We found that levels of striatal dopamine and its metabolite, dihydroxyphenylacetic acid, were significantly higher in the CBA strain than in the BALB/c strain, whereas levels of homovanillic acid were not significantly different between the strains. Levels of the dopamine metabolite 3-methoxytyramine, on the other hand, were higher in the BALB/c mice. Dopamine turnover rates were significantly higher in the CBA strain when the homovanillic acid/dopamine ratio was used as an index of dopamine activity. Voltammetric recording showed that the local infusion of K+ in pargyline-treated mice resulted in the immediate appearance of a peak at +85 mV, which has been shown to correspond to extracellular dopamine in the rat. The mean height of this peak detected in vivo following K+ stimulation corresponds to in vitro dopamine concentrations of 25 +/- 8 microM for BALB/c mice and 7 +/- 2 microM for CBA mice. K(+)-stimulated dopamine release in the BALB/c mice could be evoked every 10-15 min with similar magnitude. In contrast, very little dopamine release in CBA mice could be evoked after the first stimulation. Since striatal dopamine levels are higher in CBA mice, these data suggest that (a) BALB/c strain may have more dopamine in the readily releasable pool, whereas the CBA mice have a larger storage pool of dopamine, and/or (b) that dopamine uptake in the CBA mice is much more avid than in BALB/c.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Clonidine produces mydriasis in conscious mice by activating central alpha 2-adrenoceptors.

Intraperitoneal (i.p.) injection of the alpha 2-adrenoceptor agonist clonidine (1-3000 micrograms/kg) produced dose-dependent pupil dilatation in conscious C57/Bl/6 mice with an ED50 of 54 micrograms/kg (95% confidence limits 40-74 micrograms/kg). This response was rapid in onset and of approximately 30 min duration. The alpha 2-adrenoceptor antagonists idazoxan (1 or 3 mg/kg i.p.) and yohimbine (1 or 3 mg/kg i.p.) both produced dose-related miosis, but the alpha 1- and beta-adrenoceptor antagonists prazosin (1 or 3 mg/kg i.p.) and pindolol (1 or 3 mg/kg i.p.) were without effect. These doses of idazoxan and yohimbine potently reversed the mydriasis induced by clonidine (100 micrograms/kg i.p.), while prazosin and pindolol were again ineffective. Clonidine-induced mydriasis was also unaltered by the 5-HT antagonists, methysergide (2.5 mg/kg i.p.) and ketanserin (0.1 mg/kg i.p.) or 0.1 mg/kg i.p. of the dopamine antagonists, haloperidol, SCH 23390 and BRL 34778. A dose of 0.25 microgram clonidine, which was ineffective when administered i.p., produced marked mydriasis after intracerebroventricular (i.c.v.) injection. In addition, the mydriasis produced by i.p. injection of clonidine (100 micrograms/kg) was abolished by i.c.v. dosing of 2.5 micrograms idazoxan or yohimbine, but again not by prazosin or pindolol. Together, these data provide strong evidence to indicate that clonidine-induced mydriasis is exclusively mediated via central alpha 2-adrenoceptors and that this response provides a useful model for studying the function of these receptors.

Adrenergic alpha-Agonists↗

PubMed1989

Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic alpha 2-adrenoceptors in the brain.

Since brain alpha 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1-3000 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.

Animals↗

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↗