P-Hydroxyamphetamine causes prepulse inhibition disruption in mice: Contribution of serotonin neurotransmission

Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Behavioural brain research (Impact Factor: 3.03). 06/2011; 224(1):159-65. DOI: 10.1016/j.bbr.2011.06.002
Source: PubMed


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.

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    • "It should be noted that, in addition to dopaminergic effects, changes in serotonergic activity may also play a role in altered sensitivity to the disruptive effects of AMPH on PPI in male BDNF HETs. Although the psychotropic actions of AMPH appear to be largely mediated by increasing subcortical dopamine release (Sulzer et al., 2005), one group has recently reported major contributions of both serotonergic and dopaminergic signaling in the effects of the active AMPH metabolite p-hydroxyamphetamine on PPI in mice (Onogi et al., 2010, 2011). Alterations in serotonin levels and transporter function have also been described in BDNF HETs in the CA3 region and ventral hippocampus (Daws et al., 2007; Deltheil et al., 2008; Guiard et al., 2008). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET) has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the disorder.
    Full-text · Article · Jun 2013 · Frontiers in Cellular Neuroscience