p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission.

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT(2A)) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT(2A/2C) receptor antagonist) and MDL100,907 (a selective 5-HT(2A) receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT(2A) receptor.

Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: involvement of dopamine D2 and 5-HT2A receptors.

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D(2) antagonist sulpiride (40 mg/kg) and 5-HT(2A/2C) antagonist ketanserin (2 and 4 mg/kg) but not with the selective D(1) antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D(2) or 5-HT(2A) receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.

Suppressive effect of nantenine, isolated from Nandina domestica Thunberg, on the 5-hydroxy-L-tryptophan plus clorgyline-induced head-twitch response in mice.

We investigated the effects of nantenine (9,10-Methylenedioxy-1,2 dimethoxyaporphine), a major alkaloid isolated from the fruit of Nandina domestica Thunb (Berberidaceae), on the 5-HT2A receptor-mediated head-twitch response (HTR) in mice. Intraperitoneal (i.p.) injection of nantenine (13.3, 20 and 30 mg/kg) as well as the 5-HT2A receptor antagonist ketanserin (0.0625, 0.25 and 1 mg/kg) inhibited the 5-hydroxy-L-tryptophan (l-5-HTP; 75 mg/kg, i.p.) plus monoamine oxidase inhibitor, clorgyline (1 mg/kg, i.p.)-induced HTR in a dose-dependent manner. In contrast, neither l-5-HTP plus clorgyline nor 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 5 microg/mouse, i.c.v.)-induced head weaving was affected by nantenine or ketanserin. Furthermore, neither nantenine (up to 30 mg/kg) nor ketanserin (up to 1 mg/kg) affect on the locomotor activity. In the receptor binding studies, nantenine showed affinity to the 5-HT2A receptors (Ki = 0.4 microM), while it had less affinity toward alpha1-adrenergic (Ki = 2.1 microM) and D2-dopaminergic (Ki = 1.7 microM) receptors of the mouse brain. These results suggest that nantenine inhibits l-5-HTP plus clorgyline-induced head- twitch response by blocking 5-HT2A receptors in the central nervous system.