Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex
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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-HT1A 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-HT1A 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-HT1A 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-HT1A receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.
KeywordsDelayed reinforcement 5-HT Dopamine Buspirone 5-HT1A receptors WAY-100635 Microdialysis Chronic regime Hippocampus Accumbens Prefrontal cortex
We should like to thank Drs. Kendrick and Dyer for the facilities provided by the Neurobiology Programme at the Babraham Institute and Dr. R. Cardinal, Dr. T. Humby and Mr. C. de la Riva for their helpful advice and assistance. We also thank Drs. J.W. Dalley and C.A. Winstanley for their helpful comments on the manuscript. This research was supported by a Wellcome Trust programme grant to T.W.R. and by a scholarship from the government of Taiwan to Dr. Yia-Ping Liu. The work was completed within the MRC Cambridge Centre in Behavioural and Clinical Neuroscience.
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