1 Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotoninnoradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramineinduced hypophagia. 2 Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3 Sibutramine (10 mg kg 71 , p.o.) produced a signi®cant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the a 1 -adrenoceptor antagonist, prazosin (0.3 and 1 mg kg 71 , i.p.), and partially antagonized by the b 1 -adrenoceptor antagonist, metoprolol (3 and 10 mg kg 71 , i.p.) and the 5-HT receptor antagonists, metergoline (nonselective; 0.3 mg kg 71 , i.p.); ritanserin (5-HT 2A/2C ; 0.1 and 0.5 mg kg 71 , i.p.) and SB200646 (5-HT 2B/2C ; 20 and 40 mg kg 71 , p.o.). 4 By contrast, the a 2 -adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg 71 , i.p.) and the b 2 -adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg 71 , i.p.) did not reduce the decrease in food intake induced by sibutramine. 5 These results demonstrate that b 1 -adrenoceptors, 5-HT 2A/2C -receptors and particularly a 1 -adrenoceptors, are involved in the e ects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.

1 The e ects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI),¯uoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fen¯uramine. 2 Sibutramine (3 and 10 mg kg 71 , p.o.) and (+)-fen¯uramine (1 and 3 mg kg 71 , p.o.) produced a signi®cant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the ®rst 2 h following drug administration. 3 Fluoxetine (3, 10 and 30 mg kg 71 , p.o.), and nisoxetine (3, 10 and 30 mg kg 71 , p.o.) had no signi®cant e ect on food intake during the 8 h dark period. However, a combination of¯uoxetine and nisoxetine (30 mg kg 71 , p.o., of each) signi®cantly decreased food intake 2 and 8 h after drug administration. 4 Venlafaxine (100 and 300 mg kg 71 , p.o.) and duloxetine (30 mg kg 71 , p.o.) also signi®cantly decreased food intake in the 2 and 8 h following drug administration. 5 The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of¯uoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.

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)

1 The 5-hydroxytryptamine (5-HT),A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. ) and opiate receptors (naloxone; 3-100 mg kg-', p.o.) had no effect on the 8-OH-DPAT response. 5 Selective destruction of 5-HT neurones with 5,7-dihydroxytryptamine or inhibition of 5-HT synthesis with p-chlorophenylalanine did not change the 8-OH-DPAT response in the Porsolt test. This response was also unaltered by pretreatment with the noradrenergic neurotoxin, DSP-4. 6 Administration of 8-OH-DPAT (3 mg kg-', s.c.) twice-daily for 10 days attenuated the hypothermia, but not the increased mobility, induced by 8-OH-DPAT (3 mg kg-', s.c.). Similarly, repeated administration of amitriptyline (3-30 mg kg-'), desipramine (3-30 mg kg-') or dothiepin (10-I00 mg kg-) also attenuated the former, but not the latter, response. 7 We conclude that 8-OH-DPAT produces an antidepressant-like effect in the Porsolt test which is mediated via postsynaptic 5-HTA receptors.

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