BEHAVIORAL AND NEUROENDOCRINE RESPONSES TO D-FENFLURAMINE IN RATS TREATED WITH NEUROTOXIC AMPHETAMINES

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-HT1A 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-HT1A 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.