TY - JOUR
T1 - Effects of the l isomer of fenfluramine on dopamine mechanisms in rat brain
T2 - further studies
AU - Invernizzi, Roberto
AU - Bertorelli, Rosalia
AU - Consolo, Silvana
AU - Garattini, Silvio
AU - Samanin, Rosario
PY - 1989/5/19
Y1 - 1989/5/19
N2 - Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg.kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5-20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the 1 isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.
AB - Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg.kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5-20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the 1 isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.
KW - Acetylcholine release in vivo
KW - Dopamine metabolism
KW - l-Fenfluramine
KW - l-Norfenfluramine
KW - Nucleus accumbens
KW - Striatum
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U2 - 10.1016/0014-2999(89)90464-0
DO - 10.1016/0014-2999(89)90464-0
M3 - Article
C2 - 2759175
AN - SCOPUS:0024392097
VL - 164
SP - 241
EP - 248
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2
ER -