Abstract
Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function.
Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in
obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms
underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed
significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized
food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying
the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine
(0.5–3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED50 of 1.3 mg/kg. The hypophagic response
of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, a1 adrenoceptor antagonist)
and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D1 receptor antagonist). In contrast, tesofensine-induced
hypophagia was not affected by RX821002 (0.3 mg/kg, a2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D2 receptor antagonist),
NGB2904 (0.1 mg/kg, D3 receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT2A/C receptor antagonist). Hence, the mechanism
underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug’s ability to indirectly stimulate a1
adrenoceptor and DA D1 receptor function.
Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in
obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms
underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed
significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized
food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying
the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine
(0.5–3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED50 of 1.3 mg/kg. The hypophagic response
of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, a1 adrenoceptor antagonist)
and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D1 receptor antagonist). In contrast, tesofensine-induced
hypophagia was not affected by RX821002 (0.3 mg/kg, a2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D2 receptor antagonist),
NGB2904 (0.1 mg/kg, D3 receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT2A/C receptor antagonist). Hence, the mechanism
underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug’s ability to indirectly stimulate a1
adrenoceptor and DA D1 receptor function.
| Bidragets oversatte titel | Tesofensine, en ny triple monoamine optags hæmmer, inducerer sænkning af appetit ved indirekte stimulation af alpha1 adrenoceptor og dopamin D1 receptor signaleringsveje i en kost induceret fed rotte model |
|---|---|
| Originalsprog | Engelsk |
| Tidsskrift | Neuropsychopharmacology |
| Vol/bind | 35 |
| Udgave nummer | 7 |
| Sider (fra-til) | 1464-1476 |
| Antal sider | 13 |
| ISSN | 0893-133X |
| Status | Udgivet - jun. 2010 |
| Udgivet eksternt | Ja |
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