Effect of γ-mangostin through the inhibition of 5-hydroxytryptamine(2A) receptors in 5-fluoro-α-methyltryptamine-induced head-twitch responses of mice

1. Intracerebronventricular (i.c.v.) injection of γ-mangostin (10–40 nmol/mouse), a major compound of the fruit hull of Garcinia mangostana Lin., like ketanserin (10, 20 nmol/mouse, i.c.v.) inhibited 5-fluoro-α-methyltryptamine (5-FMT) (45 mg kg(−1), i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (a 5-hydroxytryptamine (5-HT)-uptake inhibitor). 2. Neither the 5-FMT- nor the 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT(1A)-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by γ-mangostin or ketanserin. 3. The locomotor activity stimulated by 5-FMT through the activation of α(1)-adrenoceptors did not alter in the presence of γ-mangostin. 4. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. γ-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation. 5. γ-Mangostin caused a concentration-dependent inhibition of the binding of [(3)H]-spiperone, a specific 5-HT(2A) receptor antagonist, to mouse brain membranes. 6. Kinetic analysis of the [(3)H]-spiperone binding revealed that γ-mangostin increased the K(d) value without affecting the B(max) value, indicating the mode of the competitive nature of the inhibition by γ-mangostin. 7. These results suggest that γ-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-HT(2A) receptors not by blocking the release of 5-HT from the central neurone. γ-Mangostin is a promising 5-HT(2A) receptor antagonist in the central nervous system

Nociceptin-induced scratching, biting and licking in mice: involvement of spinal NK(1) receptors

1. Intrathecal (i.t.) injection of nociceptin at small doses (fmol order) elicited a behavioural response consisting of scratching, biting and licking in conscious mice. Here we have examined the involvement of substance P-containing neurons by using i.t. injection of tachykinin neurokinin (NK)(1) receptor antagonists and substance P (SP) antiserum. 2. Nociceptin-induced behavioural response was evoked significantly 5–10 min after i.t. injection and reached a maximum at 10–15 min. Dose-dependency of the induced response showed a bell-shaped pattern from 0.375–30.0 fmol, and the maximum effect was observed at 3.0 fmol. 3. The behavioural response elicited by nociceptin (3.0 fmol) was dose-dependently inhibited by intraperitoneal (i.p.) administration of morphine. 4. The NK(1) receptor antagonists, CP-96,345, CP-99,994 and sendide, inhibited nociceptin-induced behavioural response in a dose-dependent manner. A significant antagonistic effect of [D-Phe(7), D-His(9)]SP (6–11), a selective antagonist for SP receptors, was observed against nociceptin-induced response. The NK(2) receptor antagonist, MEN-10376, had no effect on the response elicited by nociceptin. 5. Pretreatment with SP antiserum resulted in a significant reduction of the response to nociceptin. No significant reduction of nociceptin-induced response was detected in mice pretreated with NKA antiserum. 6. The N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and D(−)-2-amino-5-phosphonovaleric acid (APV) (D-APV), and L-N(G)-nitro arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, failed to inhibit nociceptin-induced behavioural response. 7. The present results suggest that SP-containing neurons in the mouse spinal cord may be involved in elicitation of scratching, biting and licking behaviour following i.t. injection of nociceptin