Liu Y P, Wilkinson L S, Robbins T W
Department of Psychiatry, University of Cambridge, Cambridge, UK.
Psychopharmacology (Berl). 2004 Apr;173(1-2):175-85. doi: 10.1007/s00213-003-1726-1. Epub 2004 Jan 15.
Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT(1A) agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats.
Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT(1A) antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats.
In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex.
Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT(1A) receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition.
These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT(1A) receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.
中枢5-羟色胺（5-HT）活性降低与冲动选择行为有关，但对于这些影响的确切性质尚无共识。丁螺环酮等5-HT（1A）激动剂的行为和神经化学作用严重依赖于剂量和治疗持续时间。因此，我们对急性和慢性丁螺环酮对大鼠延迟满足测试表现以及皮质和皮质下区域5-羟色胺和多巴胺（DA）流出的影响进行了参数研究。
三项实验研究了（i）急性丁螺环酮对冲动选择的影响以及这种影响如何因先前长期接触丁螺环酮而改变；（ii）慢性丁螺环酮对冲动选择的影响；（iii）单独测试以及与丁螺环酮联合测试的选择性5-HT（1A）拮抗剂WAY-100635对冲动选择的影响；（iv）慢性和急性丁螺环酮对麻醉大鼠5-HT和DA流出的影响。
在实验1中，对先前接受延迟满足任务训练的大鼠用急性丁螺环酮（0.5、1和2mg/kg）进行测试。然后在接下来的65天里，对同一批大鼠用慢性丁螺环酮（每天1mg/kg）进行治疗，并在慢性治疗的第20、45和65天重新测定急性丁螺环酮（1mg/kg）的效果。在实验2中，两组接受延迟满足任务训练的大鼠，在连续用生理盐水或丁螺环酮（每天1mg/kg）治疗65天后，再用急性丁螺环酮（1mg/kg）、WAY-100635（0.08mg/kg）或两种药物的组合进行测试。在实验3中，大鼠接受与实验2相同的丁螺环酮给药方案，然后在腹侧海马体、伏隔核和内侧前额叶皮质进行5-HT和DA的体内微透析。
急性丁螺环酮剂量依赖性地增加了对小的即时强化物的选择（冲动选择），但在长期给予丁螺环酮后，1mg/kg剂量的效果发生了逆转。这种对大的延迟强化物的选择增加，且在基线（未用药）表现上没有任何变化，被5-HT（1A）受体拮抗剂WAY-100635阻断。慢性丁螺环酮给药方案并未改变丁螺环酮引起的海马体中5-HT流出的减少，但确实导致急性丁螺环酮在内侧前额叶皮质产生不同的效果，慢性丁螺环酮组和生理盐水组的流出分别减少和增加。在任何情况下，DA流出均无系统性变化。
这些发现表明，急性丁螺环酮对冲动选择的影响在慢性治疗后会逆转，且由5-HT（1A）受体介导，此外还表明行为影响可能涉及内侧前额叶皮质中5-HT功能的变化。
