Ginsenoside Rg1 modulates medial prefrontal cortical firing and suppresses the hippocampo-medial prefrontal cortical long-term potentiation.

BACKGROUND: Panax ginseng is one of the most commonly used medicinal herbs worldwide for a variety of therapeutic properties including neurocognitive effects. Ginsenoside Rg1 is one of the most abundant active chemical constituents of this herb with known neuroprotective, anxiolytic, and cognition improving effects. METHODS: We investigated the effects of Rg1 on the medial prefrontal cortex (mPFC), a key brain region involved in cognition, information processing, working memory, and decision making. In this study, the effects of systemic administration of Rg1 (1 mg/kg, 3 mg/kg, or 10 mg/kg) on (1) spontaneous firing of the medial prefrontal cortical neurons and (2) long-term potentiation (LTP) in the hippocampal-medial prefrontal cortical (HP-mPFC) pathway were investigated in male Sprague-Dawley rats. RESULTS: The spontaneous neuronal activity of approximately 50% the recorded pyramidal cells in the mPFC was suppressed by Rg1. In addition, Rg1 attenuated LTP in the HP-mPFC pathway. These effects were not dose-dependent. CONCLUSION: This report suggests that acute treatment of Rg1 impairs LTP in the HP-mPFC pathway, perhaps by suppressing the firing of a subset of mPFC neurons that may contribute to the neurocognitive effects of Rg1.

Role of phospholipase A(2) in prepulse inhibition of the auditory startle reflex in rats.

High levels of calcium-independent phospholipase A(2) (iPLA(2)) are present in the striatum and cerebral cortex [W.Y. Ong, J.F. Yeo, S.F. Ling, A.A. Farooqui, Distribution of calcium-independent phospholipase A(2) (iPLA(2)) in monkey brain, J. Neurocytol. 34 (2005) 447-458], and several clinical investigations have suggested a possible role of altered iPLA(2) activity in neurodegenerative and psychiatric disorders. The present study was carried out to elucidate a possible effect of PLA(2) on prepulse inhibition (PPI) of the acoustic startle reflex. Rats that received intraperitoneal injection of the non-specific PLA(2) inhibitor, quinacrine, showed significantly decreased PPI at 76, 80, and 84dB, compared to saline injected controls. In addition, rats that received intrastriatal injection of antisense oligonucleotide to iPLA(2) showed significant reduction in PPI at prepulse intensities of 76 and 84dB compared to scrambled sense injected controls. Together, these findings point to a role of PLA(2) in PPI of the auditory startle reflex and sensorimotor gating.

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition.

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.

The chakragati mouse: a mouse model for rapid in vivo screening of antipsychotic drug candidates.

The chakragati (ckr) mouse is a serendipitously discovered insertional transgenic mutant that exhibits circling and hyperactivity. Studies of social behavior, sensorimotor gating and ventricular anatomy suggest that the ckr mouse models aspects of schizophrenia. The underlying genetic and neurodevelopmental mechanisms remain to be elucidated but appear to result in a hemispheric asymmetry in striatal D(2)-like dopamine receptors. The circling is inhibited by administration of antipsychotic drugs and so lends itself to in vivo prospective screening for novel molecules with antipsychotic-like activity. Using the ckr mouse we have applied an in vivo first approach to screening for antipsychotic drug candidates. This offers the advantage of early indication of central nervous system bioavailability and potential toxicological concerns. Additionally, in vivo first screening in the ckr mouse is not biased by any particular neurotransmitter hypothesis of the disease, and so has the potential to identify compounds modifying the behavioral output by novel mechanisms of interaction with the underlying brain circuitry. Thus, in contrast to the classical strategy of hypothesis-driven in vitro screening for drugs fitting a "receptor model" of the disease, the ckr mouse screen has greater potential to identify lead molecules for a new generation antipsychotics with novel mechanisms of action.

Chronic high-dose haloperidol has qualitatively similar effects to risperidone and clozapine on immediate-early gene and tyrosine hydroxylase expression in the rat locus coeruleus but not medial prefrontal cortex.

Acute administration of clozapine has been reported to activate the locus coeruleus (LC) and beta-adrenoceptor-dependent Fos immunoreactivity in the medial prefrontal cortex (mPFC) in rodents. Haloperidol is reported to exhibit a similar acute effect on LC firing and beta-adrenoceptor dependent Fos immunoreactivity in the mPFC but only at high doses. We compared the effects of chronic 4-week treatment with risperidone (1mg/kg/day s.c.), clozapine (10mg/kg/day s.c.) or a high dose of haloperidol (4mg/kg/day s.c.) on immediate-early gene protein (c-Fos, Egr-1 and Egr-2) and tyrosine hydroxylase (TH) expression. In the mPFC, haloperidol decreased, whereas clozapine increased, c-Fos immunoreactivity. Only haloperidol increased Egr-1 immunoreactivity. There was no significant effect on Egr-2 immunoreactivity. In the LC, both Egr-1 and Egr-2 expression was down regulated by all three antipsychotics. Clozapine and risperidone increased TH immunoreactivity in both mPFC and LC. Haloperidol caused a smaller increase in TH expression in the LC, but did not alter expression in the mPFC. In conclusion, despite qualitatively similar effects in the LC, chronic treatment with haloperidol had different effects to clozapine and risperidone in the mPFC. This may relate to the reported advantage of clozapine and risperidone over haloperidol against prefrontal cortical-dependent cognitive and negative symptoms.