Currie P J, Coscina D V, Fletcher P J
Department of Psychology, Barnard College, Columbia University, New York 10027, USA.
Brain Res. 1998 Jul 27;800(1):62-8. doi: 10.1016/s0006-8993(98)00497-1.
Drugs that enhance serotonergic neurotransmission reduce food intake by directly or indirectly activating serotonergic receptors. In contrast drugs that inhibit serotonergic neurotransmission such as the 5-HT1A agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) stimulate food intake. The present study examined the effects of 8-OH-DPAT on the feeding suppressant action of the indirect 5-HT agonists fenfluramine (FEN; 0.63-2.5 mg/kg) and fluoxetine (FLU; 2.5-10 mg/kg), as well as the 5-HT1B/2C agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP; 0.5-2 mg/kg). 8-OH-DPAT (62.5-250 microg/kg) was administered 5 min prior to FEN, FLU or TFMPP, injected 30 min before food access. While FEN, FLU and TFMPP dose-dependently reduced 2 h food intake, 8-OH-DPAT stimulated eating behavior. 8-OH-DPAT (62.5-250 microg/kg) pretreatment reversed the anorectic action of FEN (1.25 mg/kg) and FLU (5 mg/kg) but not TFMPP (1 mg/kg). Separate groups of rats were injected with 5,7-dihydroxytryptamine (5,7-DHT; 3 microg free base) into both the dorsal and median raphe, which resulted in extensive 5-HT depletion in hypothalamus (80%), striatum and hippocampus (90%). In both 5, 7-DHT and vehicle-injected rats, FEN (1.25 mg/kg) and FLU (5 mg/kg) suppressed feeding. In 5,7-DHT treated rats, however, the ability of 8-OH-DPAT (125 microg/kg) to block FEN and FLU induced anorexia was attenuated. That is, 8-OH-DPAT pretreatment did not reverse the feeding inhibitory effects of either FEN or FLU. Further, the ability of FEN and FLU to suppress food intake was not altered by the 5,7-DHT lesion. These findings suggest that the reversal of FEN and FLU anorexia by 8-OH-DPAT is partially dependent on the integrity of brain 5-HT systems since their disruption compromises the ability of this 5-HT1A agonist to antagonize the feeding suppressant action of either FEN or FLU. However, the ability of treatments which impair 5-HT neurotransmission to reverse FEN and FLU induced suppression of food intake may depend upon whether this impairment is acute and reversible (8-OH-DPAT), or chronic and irreversible (5,7-DHT).
增强5-羟色胺能神经传递的药物通过直接或间接激活5-羟色胺能受体来减少食物摄入量。相比之下，抑制5-羟色胺能神经传递的药物，如5-HT1A激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT），会刺激食物摄入。本研究考察了8-OH-DPAT对间接5-羟色胺激动剂芬氟拉明（FEN；0.63 - 2.5毫克/千克）、氟西汀（FLU；2.5 - 10毫克/千克）以及5-HT1B/2C激动剂1-（3-三氟甲基苯基）哌嗪（TFMPP；0.5 - 2毫克/千克）的摄食抑制作用的影响。在给予FEN、FLU或TFMPP前5分钟注射8-OH-DPAT（62.5 - 250微克/千克），FEN、FLU或TFMPP在给予食物前30分钟注射。虽然FEN、FLU和TFMPP剂量依赖性地减少了2小时食物摄入量，但8-OH-DPAT刺激了进食行为。8-OH-DPAT（62.5 - 250微克/千克）预处理可逆转FEN（1.25毫克/千克）和FLU（5毫克/千克）的厌食作用，但不能逆转TFMPP（1毫克/千克）的厌食作用。将单独的几组大鼠双侧背侧和中缝核注射5,7-二羟基色胺（5,7-DHT；3微克游离碱），这导致下丘脑（80%）、纹状体和海马体（90%）中5-羟色胺大量耗竭。在5,7-DHT注射组和注射溶媒组大鼠中，FEN（1.25毫克/千克）和FLU（5毫克/千克）均抑制进食。然而，在5,7-DHT处理的大鼠中，8-OH-DPAT（125微克/千克）阻断FEN和FLU诱导的厌食的能力减弱。也就是说，8-OH-DPAT预处理不能逆转FEN或FLU的摄食抑制作用。此外，5,7-DHT损伤并未改变FEN和FLU抑制食物摄入的能力。这些发现表明，8-OH-DPAT对FEN和FLU厌食作用的逆转部分依赖于脑5-羟色胺系统的完整性，因为其破坏会损害该5-HT1A激动剂拮抗FEN或FLU摄食抑制作用的能力。然而，损害5-羟色胺神经传递的处理逆转FEN和FLU诱导的食物摄入抑制的能力可能取决于这种损害是急性且可逆的（8-OH-DPAT）还是慢性且不可逆的（5,7-DHT）。
