Nicotine effect on prepulse inhibition and prepulse facilitation in schizophrenia patients.

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

The acoustic startle reflex in Sprague-Dawley rats is altered by permanent middle cerebral artery occlusion.

The startle reflex is an unconditioned, quantifiable behavior used to study sensory modalities. We examined whether the acoustic startle reflex (ASR) was sensitive to lesions induced by focal cerebral ischemia. Sprague-Dawley rats were pre-screened for startle reflex responses 3-6 days prior to surgery and there were no differences in mean startle amplitude across groups. Animals were subjected to permanent middle cerebral artery occlusion (pMCAo) or a sham surgical procedure. Twenty-four hours later rats were evaluated for ASR prior to sacrifice. Infarct volumes were subsequently determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride-stained brain sections. Infarct volumes of rats undergoing pMCAO ranged from 0 to 48%. Data were divided into three groups based upon percent infarction: mild (0-20%), moderate (21-35%), and severe (>35%). A within-subject analysis revealed a significant decrease in mean startle amplitude of only severely infarcted rats relative to their pre-surgery startle responses. Furthermore, the lesioned brain areas observed in these animals provide an anatomical basis for these results. Our findings demonstrate that ASR is affected in a model of stroke. Further work is needed to characterize this behavioral test and to determine whether it may have application as a surrogate endpoint for clinical stroke studies.

Electrical stimulation of the hippocampus disrupts prepulse inhibition in rats: frequency- and site-dependent effects.

Prepulse inhibition (PPI) is a normal reduction in the startle response produced when a brief, low intensity stimulus is presented prior to a startle-evoking stimulus. PPI is often disrupted in humans diagnosed with schizophrenia. As similar stimuli elicit PPI in rodents and humans, interventions in rodents that disrupt PPI may reveal aspects of neuronal dysfunction relevant to schizophrenia. Stimulation of the ventral hippocampus (vHip) with NMDA significantly increases dopamine (DA) efflux in the nucleus accumbens (NAc) and disrupts PPI, whereas NMDA infusion into the dorsal hippocampus (dHip) fails to alter PPI. Our previous research shows that brief periods of 20 Hz electrical vHip stimulation also significantly increase NAc DA efflux. The present experiments assessed the effects of stimulating the vHip or dHip on PPI and NAc DA efflux. As predicted, 20 Hz stimulation (10 s, 300 microA) of the vHip, but not the dHip, reversibly disrupted PPI. In contrast, 2 Hz stimulation (100 s, 300 microA) of the vHip failed to affect PPI. Microdialysis experiments revealed that 20 Hz stimulation of the vHip increased NAc DA efflux only in the hemisphere ipsilateral to the stimulating electrode, whereas 20 Hz stimulation of the dHip failed to affect NAc DA efflux. These data demonstrate the regional specificity and frequency-dependent effects of hippocampal activity on PPI. Additionally, it is intriguing that both chemical and electrical stimulation of the vHip disrupt PPI and increase NAc DA efflux, however, the relevance of these changes in NAc DA efflux to the disruption of PPI remains to be determined.

Anxiety and cognition in histamine H3 receptor-/- mice.

Histamine H(3) receptors (H3Rs) were first characterized as autoreceptors modulating histamine release and synthesis via negative feedback. Acute H3R stimulation or blockade with selective agonists and antagonists suggests a role for H3R in anxiety and cognition. However, little is known about the long-term effects of H3R blockade on brain function. In the current study, mice lacking H3 receptors (H3R(-/-)) were used to investigate the role of H3R-mediated signalling in anxiety and cognition. H3R(-/-) mice showed enhanced spatial learning and memory in the Barnes maze. In addition, H3R(-/-) mice showed reduced measures of anxiety in the elevated plus and zero mazes involving exploratory behaviour and avoidable anxiety-provoking stimuli, but enhanced acoustic startle responses involving unavoidable anxiety-provoking stimuli. These behavioural alterations were associated with higher arginine vasopressin levels in the central and basolateral nuclei of the amygdala. These findings support a role for H3Rs in mediating histamine effects on spatial learning and memory and measures of anxiety.

Attentional modulation of prepulse inhibition: a new startle paradigm.

There is increasing evidence for an influence of directed attention on prepulse inhibition (PPI) of the acoustic startle reflex. However, the existing paradigms for the assessment of this effect have methodological problems and pitfalls. In particular, most previous studies used a paradigm which directed the attention of subjects to the prepulse only. In the present study, we used a modified paradigm which directed the attention of the subjects both to the prepulse and the pulse. Twenty healthy male subjects were instructed trial by trial either to relax or to attend to the startle stimulus and decide whether it was a 'simple' (prepulse alone or pulse alone) or a 'composite' trial (pulse plus a prepulse or postpulse). Directed attention enhanced PPI at the lead interval of 240 ms, but not at the lead interval of 100 ms. This finding is in line with the idea that attention contributes to PPI when there is enough time for the attentional mechanisms to exert an influence. This new paradigm offers a valuable tool for the study of attentional modulation of sensorimotor gating in humans.

Intraretinal grafting restores visual function in light-blinded rats.

In seeing rats light flashes inhibit acoustic startle reflexes at short lead times. In contrast, visually impaired (light-blinded) rats show an early phase of exaggerated reflex expression, revealing the presence of pathological visual processing, and then an aberrant late phase of delayed inhibition. Grafting fetal retinal cells into the damaged retina entirely removed reflex facilitation and restored a modest degree of properly timed and statistically significant reflex inhibition. This restoration of visually-mediated behaviour, observed in two independent groups, reveals that intraretinal grafts provide useful information to blinded hosts.