IngentaConnect Effects of fenfluramine on free-operant timing behaviour: evidenc...

Abstract:

Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT₂ receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T ₅₀. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation.

We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT_1A receptor antagonist n-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-n-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT_2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine.

Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T ₅₀, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT_1A and 5-HT_2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography.

Experiment 1: fenfluramine (2 mg/kg) reduced T ₅₀; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 μg/kg). Experiment 2: 8-OH-DPAT (100 μg/kg) and DOI (250 μg/kg) reduced T ₅₀ in both groups; fenfluramine reduced T ₅₀ only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected.

The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT_2A receptors.

Keywords: Fenfluramine; DOI; 8-OH-DPAT; Ketanserin; WAY-100635; 5-HT2A receptors; Temporal differentiation

Document Type: Research article

DOI: 10.1007/s00213-004-1871-1

Affiliations: 1: Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Nottingham, NG7 2UH, UK, 2: Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Nottingham, NG7 2UH, UK, Email: myho@mail.cgu.edu.tw 3: Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Nottingham, NG7 2UH, UK, Email: c.m.bradshaw@nottingham.ac.uk

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Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT2A receptors

Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT_2A receptors