The ameliorating effects of 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one, an oroxylin A derivative, against memory impairment and sensorimotor gating deficit in mice.

We previously reported that oroxylin A, a γ-aminobutyric acid A (GABAA) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-D-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 µM) inhibited intracellular Cl(-) influx induced by muscimol, a selective GABAA receptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system.

The effect of pregabalin on sensorimotor gating in 'low' gating humans and mice.

Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a "Low" or "High" gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the "low gating" group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.

Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder.

Functional and structural imaging studies suggest that obsessive-compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.

Disruption of prepulse inhibition by 3,4-methylenedioxymethamphetamine (MDMA): comparison between male and female wild-type and 5-HT(1A) receptor knockout mice.

The aim of this study was to investigate the involvement of serotonin-1A (5-HT(1A)) receptors in the effects of 3,4-methylenedioxymetamphetamine (MDMA) on prepulse inhibition of acoustic startle (PPI) by comparing male and female wild-type (WT) mice and 5-HT(1A) receptor knockout (1AKO) mice. MDMA dose-dependently decreased PPI in male and female mice although female mice were more sensitive at the 100-ms inter-stimulus interval (ISI). In male mice, 10 mg/kg MDMA disrupted PPI in 1AKO but not in WT controls. There was no genotype difference at higher or lower doses of MDMA. In female mice, there was no difference between genotypes at any dose of MDMA. Average startle was reduced by 10 mg/kg and 20 mg/kg MDMA similarly in male and female mice and all genotypes. These results show an involvement of 5-HT(1A) receptors in the effect of MDMA on PPI in male, but not female mice.

Age-associated improvements in cross-modal prepulse inhibition in mice.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe preattentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.

CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD.

Post traumatic stress disorder (PTSD) is a chronic anxiety disorder initiated by an intensely threatening, traumatic event. There is a great need for more efficacious pharmacotherapy and preventive treatments for PTSD. In animals, corticotropin-releasing factor (CRF) and the CRF1 receptor play a critical role in behavioural and neuroendocrine responses to stress. We tested the hypothesis that CRF1 activation is required for initiation and consolidation of long-term effects of trauma on anxiety-like behaviour in the predator exposure (predator stress) model of PTSD. Male C57BL6 mice were treated with the selective CRF1 antagonist CRA0450 (2, 20 mg/kg) 30 min before or just after predator stress. Long-term effects of stress on rodent anxiety were measured 7 d later using acoustic startle, elevated plus maze (EPM), light/dark box, and hole-board tests. Predator stress increased startle amplitude and delayed startle habituation, increased time in and decreased exits from the dark chamber in the light/dark box test, and decreased risk assessment in the EPM. CRF1 antagonism had limited effects on these behaviours in non-stressed controls, with the high dose decreasing risk assessment in the EPM. However, in stressed animals CRF1 antagonism blocked initiation and consolidation of stressor effects on startle, and returned risk assessment to baseline levels in predator-stressed mice. These findings implicate CRF1 activation in initiation and post-trauma consolidation of predator stress effects on anxiety-like behaviour, specifically on increased arousal as measured by exaggerated startle behaviours. These data support further research of CRF1 antagonists as potential prophylactic treatments for PTSD.

Spontaneous nicotine withdrawal potentiates the effects of stress in rats.

Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-beta-erythroidine hydrobromide (DHbetaE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.

Anxiogenic treatments do not increase fear-potentiated startle in mice.

BACKGROUND: In rodents, the fear-potentiated startle paradigm (FPS; exaggerated startle as a measure of the conditioned fear response to cues associated with footshock) has demonstrated predictive validity for anxiolytic drugs. The predictive validity of the model for anxiogenic drugs, however, remains unclear. Therefore, we evaluated the bi-directionality of the FPS model for anxiety-modulating compounds in mice. METHODS: The clinical anxiogenics FG-7142 (1-20 mg/kg), yohimbine (.1-10 mg/kg), and m-Chlorophenylpiperazine (mCPP; .3-3 mg/kg), and the putative anxiogenics atipamezole (.3-3 mg/kg) and corticotropin-releasing factor (h/r-CRF; .03-1 microg) were tested in DBA/1J mice trained for FPS. RESULTS: Contrary to predictions, FG-7142 (10 and 20 mg/kg) and yohimbine (10 mg/kg) reduced FPS in mice without affecting baseline startle. Atipamezole (3 mg/kg), mCPP (3 mg/kg), and h/r-CRF (.3, 1 microg) did not affect FPS, but increased startle independently from the presence of the cue. FG-7142 and h/r-CRF had similar effects in 129SvEv mice. CONCLUSIONS: Murine FPS is not bi-directionally predictive for anxiety-modulating compounds, although murine baseline startle may have some utility as a bi-directional model of anxiety. These data corroborate the recent hypothesis that systems mediating FPS are independent from systems mediating increased startle from unconditioned and putatively anxiogenic stimuli.