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Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes.
Synapse. 2003 Dec 01; 50(3):212-22.S

Abstract

Fenfluramine releases serotonin (5-HT) via the 5-HT transporter (SERT). Previous work has shown that amphetamine increases particulate protein kinase C (PKC) activity in striatal synaptoneurosomes. The increased PKC activity is linked to the outward transport of dopamine, and when release is diminished, the inward transport of amphetamine inhibits PKC instead. Since there is homology among monoamine transporters, this study was undertaken to determine if D-fenfluramine has similar effects on PKC. The role of 5-HT receptors and endogenous 5-HT were also examined. Naive rats and rats pretreated with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, were sacrificed. Cortical synaptoneurosomes were prepared and incubated with fenfluramine. PKC activity was determined by thiophosphorylation of endogenous substrates. It was found that 5-HT, D/L-fenfluramine, and D-fenfluramine increased PKC activity in a time- and dose-dependent manner. The 5-HT-mediated increase in PKC activity was attenuated by pretreatment with the 5-HT(2) antagonist ketanserin, but not with the SERT inhibitor fluoxetine. The D-fenfluramine-induced increase in PKC activity was completely prevented, however, by pretreatment with SERT inhibitors and partially with ketanserin. It was also attenuated by pretreatment with PCPA, resulting in a dose-dependent inhibition of PKC instead. Thus, when 5-HT release was diminished the uptake of D-fenfluramine inhibited PKC. Similar effects have been observed with amphetamine. Unlike D-fenfluramine, the D/L-fenfluramine-induced increase in PKC activity was partially resistant to PCPA pretreatment but was attenuated with bupropion, a dopamine transporter (DAT) inhibitor. SERT inhibitors (sertraline, paroxetine, citalopram, and fluoxetine) also increased PKC activity. Nefazodone and bupropion increased PKC activity, but mirtazapine was relatively inactive. The SERT inhibitor-induced increase in PKC was unaffected by pretreatment with PCPA but was inhibited by calcium. Similar effects on PKC activity have been observed with DAT inhibitors. These results, showing that D-fenfluramine altered PKC activity similar to D-amphetamine, suggest that the topographic homology between DAT and SERT may extend to their effects on PKC activity.

Authors+Show Affiliations

Rhode Island Psychiatric Research Center, Eleanor Slater Hospital, Cranston, Rhode Island 02920, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14515339

Citation

Giambalvo, Cecilia T., and Lawrence H. Price. "Effects of Fenfluramine and Antidepressants On Protein Kinase C Activity in Rat Cortical Synaptoneurosomes." Synapse (New York, N.Y.), vol. 50, no. 3, 2003, pp. 212-22.
Giambalvo CT, Price LH. Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes. Synapse. 2003;50(3):212-22.
Giambalvo, C. T., & Price, L. H. (2003). Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes. Synapse (New York, N.Y.), 50(3), 212-22.
Giambalvo CT, Price LH. Effects of Fenfluramine and Antidepressants On Protein Kinase C Activity in Rat Cortical Synaptoneurosomes. Synapse. 2003 Dec 1;50(3):212-22. PubMed PMID: 14515339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes. AU - Giambalvo,Cecilia T, AU - Price,Lawrence H, PY - 2003/9/30/pubmed PY - 2004/1/7/medline PY - 2003/9/30/entrez SP - 212 EP - 22 JF - Synapse (New York, N.Y.) JO - Synapse VL - 50 IS - 3 N2 - Fenfluramine releases serotonin (5-HT) via the 5-HT transporter (SERT). Previous work has shown that amphetamine increases particulate protein kinase C (PKC) activity in striatal synaptoneurosomes. The increased PKC activity is linked to the outward transport of dopamine, and when release is diminished, the inward transport of amphetamine inhibits PKC instead. Since there is homology among monoamine transporters, this study was undertaken to determine if D-fenfluramine has similar effects on PKC. The role of 5-HT receptors and endogenous 5-HT were also examined. Naive rats and rats pretreated with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, were sacrificed. Cortical synaptoneurosomes were prepared and incubated with fenfluramine. PKC activity was determined by thiophosphorylation of endogenous substrates. It was found that 5-HT, D/L-fenfluramine, and D-fenfluramine increased PKC activity in a time- and dose-dependent manner. The 5-HT-mediated increase in PKC activity was attenuated by pretreatment with the 5-HT(2) antagonist ketanserin, but not with the SERT inhibitor fluoxetine. The D-fenfluramine-induced increase in PKC activity was completely prevented, however, by pretreatment with SERT inhibitors and partially with ketanserin. It was also attenuated by pretreatment with PCPA, resulting in a dose-dependent inhibition of PKC instead. Thus, when 5-HT release was diminished the uptake of D-fenfluramine inhibited PKC. Similar effects have been observed with amphetamine. Unlike D-fenfluramine, the D/L-fenfluramine-induced increase in PKC activity was partially resistant to PCPA pretreatment but was attenuated with bupropion, a dopamine transporter (DAT) inhibitor. SERT inhibitors (sertraline, paroxetine, citalopram, and fluoxetine) also increased PKC activity. Nefazodone and bupropion increased PKC activity, but mirtazapine was relatively inactive. The SERT inhibitor-induced increase in PKC was unaffected by pretreatment with PCPA but was inhibited by calcium. Similar effects on PKC activity have been observed with DAT inhibitors. These results, showing that D-fenfluramine altered PKC activity similar to D-amphetamine, suggest that the topographic homology between DAT and SERT may extend to their effects on PKC activity. SN - 0887-4476 UR - https://www.unboundmedicine.com/medline/citation/14515339/Effects_of_fenfluramine_and_antidepressants_on_protein_kinase_C_activity_in_rat_cortical_synaptoneurosomes_ L2 - https://doi.org/10.1002/syn.10262 DB - PRIME DP - Unbound Medicine ER -