Blocking alpha2A adrenoceptors, but not dopamine receptors, augments bupropion-induced hypophagia in rats
Disclosures: Dr. Janhunen reports grant from TI Pharma, during the conduct of the study; other from Orion Pharma Orion Corp. (current employment), outside the submitted work. Dr. la Fleur and Prof. Adan report grant from TI Pharma, during the conduct of the study. The authors have no competing interests.
Funding agencies: This study was supported by TI Pharma project T2.105.
Author contributions: SJ, RA and SF designed the study, wrote protocol and managed literature searches and analyses. SJ undertook the statistical analyses and wrote the first draft of manuscript. All authors contributed to and have approved the final manuscript.
Anti-obesity drugs have adverse effects which limit their use, creating a need for novel anti-obesity compounds. We studied effects of dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (BUP), alone and after blocking α1- or α2-adrenoceptors (AR), D1/5, D2/3, or D4 receptors, to determine which receptors act downstream of BUP.
Design and Methods
Effects on caloric intake, meal patterning and locomotion were assessed, using an automated weighing system and telemetry in male rats with 18-h access to Western Human style diet.
BUP (30 mg/kg) induced hypophagia by reducing meal size and postponing meal initiation. WB4101 (α1-AR; 2 mg/kg) and imiloxan (α2B-AR; 5 mg/kg) attenuated BUP's effect on meal size, while WB4101 and BRL 44408 (α2A/D-AR; 2 mg/kg) counteracted effect on meal initiation. Atipamezole (α2-AR; 1 mg/kg) and imiloxan further postponed initiation of meals. SKF 83566 (D1/5; 0.3 mg/kg), raclopride (D2/3; 0.5 mg/kg) and to a lesser extent FAUC 213 (D4; 0.5 mg/kg), attenuated BUP-induced hypophagia. BUP stimulated locomotion, which was blocked by all antagonists, except FAUC 213 or BRL 44408.
Alpha1-, α2A/D- and α2B-ARs, and DA receptors underlie BUP's effects on size and initiation of meals, while blocking pre-synaptic α2-ARs enhanced BUP-induced hypophagia. An inverse agonist of (pre-synaptic) α2A-ARs could enhance BUP-induced anorexia and treat eating disorders and obesity.