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Behavioural and neuroendocrine responses to D-fenfluramine in rats treated with neurotoxic amphetamines

University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE, University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX

M. le Masurier

University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE

S.E. Gartside

University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE

M. Franklin

Psychopharmacology Research Unit, Department of Psychiatry, Littlemore Hospital, Oxford OX4 4XN, UK

T. Sharp

University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE

The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kgx2; MDMA 20 mg/kgx8; D-fenfluramine 12.5 mg/kgx8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT_1A and 5-HT₂ receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT_1A or 5-HT₂ receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.

Key Words: D-fenfluramine • MDMA • 3,4-methylenedioxymethamphetamine • Ecstasy • p-chloroamphetamine; prolactin • ACTH

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