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21. Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by α2-adrenoceptors

Author

Wortley, K E, Heal, D J, and Stanford, S C

Subjects
Male, Hypothalamus, Imidazoles, Frontal Lobe, Rats, Rats, Sprague-Dawley, Norepinephrine, Idazoxan, Receptors, Adrenergic, alpha-2, Papers, Appetite Depressants, Animals, Dialysis, Adrenergic alpha-Antagonists, Cyclobutanes
Abstract

1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Published
1999

22. Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d-amphetamine: modulation by α2-adrenoceptors

Author

Wortley, K E, Hughes, Z A, Heal, D J, and Stanford, S C

Subjects
Cerebral Cortex, Male, Rats, Sprague-Dawley, Norepinephrine, Dextroamphetamine, Idazoxan, Receptors, Adrenergic, alpha-2, Papers, Appetite Depressants, Animals, Adrenergic alpha-Antagonists, Cyclobutanes, Rats
Abstract

1. The effects of sibutramine (0.25 - 10 mg kg-1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1 - 3 mg kg-1, i.p.) using in vivo microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha2-adrenoceptor antagonist, RX821002. 2. Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg-1. In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose. 3. Pretreatment with the alpha2-adrenoceptor antagonist, RX821002 (dose 3 mg kg-1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg-1) and reduced the latency of sibutramine to reach its maximum effect from 144 - 56 min. 4. RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg-1) and had no effect on the latency to reach maximum. 5. These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic alpha2-adreno-ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca2+-independent release of noradrenaline.

Published
1999

35. A comparison of the acute effects of zotepine and other antipsychotics on rat cortical dopamine release, in vivo.

Author

Rowley, H. L., Needham, P. L., Kilpatrick, I. C., and Heal, D. J.

Subjects
DOPAMINE, DRUG efficacy, ANTIPSYCHOTIC agents, OLANZAPINE, PERFUSION, BODY fluids
Abstract

The acute effects of systemic administration of the antipsychotic drug, zotepine, on extracellular dopamine (DA) in the frontal cortex of freely-moving rats were studied using in vivo microdialysis and compared with the actions of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.p.) resulted in a prolonged elevation of cortical DA levels for up to 180 min post-drug. A maximal rise of +333% was observed at 120 min post-zotepine treatment. Clozapine (10.0 mg/kg, i.p.) also evoked a rise in extracellular DA which was similar in duration (200 min) to that resulting from treatment with zotepine. A maximal rise of +223% was observed at 100 min post-clozapine treatment. Olanzapine (1.0 mg/kg, i.p.) resulted in an immediate increase in DA levels which was maximal 40 min post-treatment (+280%) with levels returning to pre-injection values by 100 min after dosing. In contrast, haloperidol (0.1 mg/kg, i.p.) had no measurable influence on cortical DA levels. Local perfusion with the NA uptake inhibitor, nisoxetine (10 µM), resulted in an increase in cortical DA levels which was maximal at 100 min post-onset of perfusion (+257% above baseline). Administration of zotepine (1.0 mg/kg, i.p.) during nisoxetine perfusion elevated DA levels to a maximum of +301% above baseline, 60 min post-zotepine. These results show that acute administration of each of three drugs with an atypical antipsychotic profile causes an elevation of cortical DA in freely-moving rats at doses relevant to those derived from animal models which predict antipsychotic activity. As a dysfunction in cortical DA is thought to be involved in both the negative symptoms of schizophrenia and cognitive deficits in schizophrenic patients, it is possible that zotepine's ability to elevate cortical DA levels may underlie its effectiveness in successfully treating these components of schizophrenia. Furthermore, the ability of zotepine to elevate cortical DA is more likely to derive from its inhibition of the NA transporter rather than DA receptor blockade in this region. [ABSTRACT FROM AUTHOR]

Published
2000
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43. D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists, but not by sibutramine hydrochloride, antidepressants or treatments which enhance central dopaminergic function

Author

Cheetham, S. C., Kettle, C. J., Martin, K. F., and Heal, D. J.

Abstract

Summary [3H]SCH 23390 is a selective high affinity ligand for D1 receptors in vitro. Using this ligand persistent blockade of D1 receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D1 receptor binding sites in rat striatum. In contrast, repeated administration of the D2-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D2-selective antagonist, haloperidol, the non-selective D1/D2 receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D1 receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D1 sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D1 receptor binding in rat striatum.

Published
1995
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