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Characterization of behavioral responses to a 5-HT releasing drug, p-chloroamphetamine, in mice and the involvement of 5-HT receptor subtypes in p-chloroamphetamine-induced behavior

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Behavioral effects of a serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine (PCA) were investigated in mice. We found that PCA elicited 5-HT syndrome including head weaving, hindlimb abduction and tremor and increased locomotor activity in mice. PCA-induced 5-HT syndrome was strongly reduced by both the 5-HT depleter p-chlorophenylalanine (pCPA) and the 5-HT transporter inhibitor fluoxetine. pCPA and fluoxetine significantly reduced PCA-induced hyperactivity. PCA-induced 5-HT syndrome and hyperactivity were antagonized by the 5-HT1A receptor antagonist WAY100635. Furthermore, 5-HT syndrome was also reduced by the 5-HT2A/2B/2C receptor antagonist LY 53857 and the 5-HT2B/2C receptor antagonist, SB 206553. However, the 5-HT2A receptor antagonist ketanserin was without effect. The 5-HT2 receptor antagonists did not affect hyperactivity elicited by PCA. Since PCA can elicit dopamine release, the involvement of dopamine in PCA-induced behavior was also studied. The dopamine depleter α-methyl-p-tyrosine did not affect PCA-induced 5-HT syndrome, although it strongly reduced PCA-induced hyperactivity. These results suggest that PCA is incorporated into nerve terminals via 5-HT transporter and that PCA facilitates 5-HT release, which induces 5-HT syndrome and hyperactivity. The 5-HT syndrome elicited by PCA is caused by stimulation of the 5-HT2B/2C receptor in addition to the 5-HT1A receptor. It also suggests that PCA-induced dopamine releasing effects are not related to the 5-HT syndrome in mice, while dopamine is related to hyperactivity induced by PCA.


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