Prepulse Inhibition Of Acoustic Startle Research Articles

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.

Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia.

Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia. To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia. Family-based heritability study. Seven sites across the United States. At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes. Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article. All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable (P < or = .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures. This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia.

Patients with Premenstrual Dysphoric Disorder have Increased Startle Response Across both Cycle Phases and Lower Levels of Prepulse Inhibition During the Late Luteal Phase of the Menstrual Cycle

Patients with premenstrual dysphoric disorder (PMDD) experience their most intense symptoms during the late luteal phase. The aim of the current study was to compare acoustic startle response and prepulse inhibition in PMDD patients and controls during the follicular and late luteal phases of the menstrual cycle. Following two months of prospective daily ratings on the Cyclicity Diagnoser scale, 30 PMDD patients and 30 asymptomatic controls, between the ages of 20 and 46, were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. orbicularis oculi. Twenty pulse-alone trials (115 dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115 dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB. PMDD patients had a significantly higher startle response than controls during both phases of the menstrual cycle (p<0.05). PMDD patients exhibited lower levels of prepulse inhibition with 78 dB and 86 dB prepulses compared to control subjects in the luteal (p<0.01) but not in the follicular phase. Whereas control subjects displayed increased PPI during the late luteal phase compared to the follicular phase (p<0.01), PPI magnitude remained unchanged in PMDD patients between cycle phases. Relative to controls, PMDD patients displayed increased startle reactivity across both menstrual cycle phases and deficits in prepulse inhibition of acoustic startle during the late luteal phase. These findings are consistent with an altered response to ovarian steroids among PMDD patients.

Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia

Prepulse inhibition (PPI) of acoustic startle reflex has been suggested as a neurophysiologic measure of information processing abnormalities in schizophrenia. However, there has been little information on PPI and related measures in Asian patients with schizophrenia. We examined startle response to acoustic stimuli, its habituation, and PPI in 20 Japanese patients with chronic schizophrenia under antipsychotic medication and 16 healthy controls matched for age and sex. We measured PPI with 115 dB of pulse (40 ms), 82, 86, or 90 dB of prepulse (20 ms) and 30, 60, or 120 ms of lead interval (LI). The startle response to pulse alone trials was significantly smaller in schizophrenics than in controls, which may be due, at least in part, to medication. There was no significant difference in habituation of startle response during the test session between the two groups. PPI differed significantly between the two groups when LI was 120 ms. No significant relationship was found on startle response or PPI with age of onset, number of previous admission, medication dosages, or symptom scores assessed with the Positive and Negative Syndrome Scale (PANSS). Our results confirm impaired PPI in chronic schizophrenia patients compared with controls in Japanese.

Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy

Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational age at time of administration have varied. The objective of the present study was to compare the effects of prenatal challenge with different immune agents given at different time windows during gestation on behavioral outcomes in offspring. For this, pregnant rats were administered bacterial endotoxin (lipopolysaccharide, LPS), the viral mimic polyinosinic: polycytidylic acid (poly I:C), or turpentine, an inducer of local inflammation, at doses known to produce fever, at three different stages in pregnancy: embryonic day (E)10–11, E15–16 and E18–19. Prepulse inhibition of acoustic startle (PPI) was later measured in male adult offspring. PPI was significantly decreased in offspring after prenatal LPS treatment at E15–16 and E18–19. Intramuscular injection of pregnant dams with turpentine at E15–16 also decreased PPI in adult offspring. Maternal poly I:C administration had no significant effect on PPI in offspring. In contrast to prenatal LPS exposure, acute LPS administration to naive adult males had no effect on PPI. Thus, prenatal exposure both to a systemic immunogen and to local inflammation at brief periods during later pregnancy produced lasting deficits in PPI in rat offspring. These findings support the idea that maternal infection during critical windows of pregnancy could contribute to sensorimotor gating deficits in schizophrenia.

Sensorimotor gating in manic and mixed episode bipolar disorder

Few studies have examined acoustic startle sensorimotor gating in bipolar disorder (BPD) despite the fact that patients with BPD have exhibited inhibitory dysfunctions on a variety of early information processing tasks. The present study aimed to expand the current literature through the investigation of electromyographic (EMG) measures of acoustic startle prepulse inhibition (PPI) in manic and mixed episode BPD. Fourteen manic and 21 mixed episode BPD patients were compared to 32 healthy controls on acoustic startle measures of PPI using a 120-ms lead interval. Prepulse inhibition did not significantly differ across diagnostic groups (manic, mixed, control), and the presence of psychosis in the patient sample was not significantly related to PPI levels. With respect to startle response characteristics, patients in the mixed phase of the disorder showed prolonged prepulsed startle latency and attenuated responses to both probe-alone and prepulsed probes, though no differences in startle habituation were found across diagnostic groups. Although PPI deficits were not observed in either BPD sub-group, attenuated probe-alone and prepulsed startle magnitudes and reduced prepulse-induced latency facilitation in the mixed episode group is consistent with evidence that the mixed phase of BPD is associated with a more severe clinical outlook than other stages of the disorder. The absence of attenuated PPI in the patient sample may be due to the low incidence of psychosis in the BPD groups, though further studies are required to systematically assess the effects of symptom factors and clinical phase on sensorimotor gating in BPD.

Impact of stimulus signal‐to‐noise ratio on prepulse inhibition of acoustic startle

Prepulse inhibition (PPI) of the human acoustic startle response is reduced in the presence of background noise of a sufficient intensity, possibly due to a reduction in signal-to-noise ratio (prepulse intensity relative to background noise). We examined this hypothesis by varying prepulse intensity and background noise intensity in order to hold three different signal-to-noise ratios constant (5, 15, and 25 dB(A) above background noise intensity). The results showed that signal-to-noise ratio proved to be a more important factor than absolute stimulus intensity in determining the degree of PPI of startle eyeblink response magnitude. Therefore, the effectiveness of a prepulse is determined by prepulse salience, not intensity, and this effectiveness is equivalent across a range of physical intensities.

Medication status affects the relationship of symptoms to prepulse inhibition of acoustic startle in schizophrenia

Inhibition of the acoustic startle response by a smaller preliminary nonstartling stimulus is termed prepulse inhibition (PPI). Schizophrenia patients have impairments in PPI that may not fully normalize even when they are clinically stable on medication, particularly typical antipsychotics. There is evidence that more severe symptoms are associated with more severe PPI abnormalities, but the effect of antipsychotics on this relationship is not clear. Seventy-three male schizophrenia patients underwent acoustic startle and PPI testing. Symptom ratings were performed using the Brief Psychiatric Rating Scale (BPRS) and its subscales. Fifty-two subjects were treated with antipsychotic medication at time of testing; 21 were unmedicated. For all subjects, PPI was negatively correlated with the BPRS psychological discomfort subscale but not with BPRS total symptoms, BPRS positive symptoms or BPRS negative symptoms. For medicated subjects analyzed separately, there were no correlations with BPRS total scores or any subscales. For the unmedicated subjects analyzed separately, there were significant correlations of lower PPI with greater severity of BPRS total symptoms, positive symptoms and the psychological discomfort subscale. These data indicate that more severe symptoms are associated with lower PPI, but that medication status is an important factor in the relationship between symptom severity and sensorimotor gating.

The acute effects of 3-nitropropionic acid on the behavior and spontaneous cortical electrical activity of rats

In this study, the acute effect of 3-nitropropionic acid was investigated on open field and startle behavior of rats, and on their cortical electrical activity. Spontaneous locomotor activity, acoustic startle response, and pre-pulse inhibition of acoustic startle were measured in male Wistar rats (10 weeks old, 180-200 g body weight) after a single dose of 10 or 20 mg/kg i.p. 3-nitropropionic acid. After the behavioral tests, the rats were anaesthetized, and spontaneous cortical electrical activity was recorded. The vertical, horizontal and local open field performance showed dose-dependent deterioration in the rats treated with 3-nitropropionic acid. The number of "noise-positive" startle responses showed non-significant changes, but the inhibition by pre-pulse was significantly reduced in the high dose animals. High dose also increased the proportion of low-frequencies in the cortical activity. 3-nitropropionic acid, known primarily to act in repeated doses (e.g., in animal models of Huntington's disease) had also some clear-cut acute effects on behavioral and electrophysiological parameters of the treated rats.

Salicylate induced tinnitus: Behavioral measures and neural activity in auditory cortex of awake rats

Neurophysiological studies of salicylate-induced tinnitus have generally been carried out under anesthesia, a condition that abolishes the perception of tinnitus and depresses neural activity. To overcome these limitations, measurement of salicylate induced tinnitus were obtained from rats using schedule induced polydipsia avoidance conditioning (SIPAC) and gap pre-pulse inhibition of acoustic startle (GPIAS). Both behavioral measures indicated that tinnitus was present after treatment with 150 and 250 mg/kg of salicylate; measurements with GPIAS indicated that the pitch of the tinnitus was near 16 kHz. Chronically implanted microwire electrode arrays were used to monitor the local field potentials and spontaneous discharge rate from multiunit clusters in the auditory cortex of awake rats before and after treatment with 150 mg/kg of salicylate. The amplitude of the local field potential elicited with 60 dB SPL tone bursts increased significantly 2 h after salicylate treatment particularly at 16–20 kHz; frequencies associated with the tinnitus pitch. Field potential amplitudes had largely recovered 1–2 days post-salicylate when behavioral results showed that tinnitus was absent. The mean spontaneous spike recorded from the same multiunit cluster pre- and post-salicylate decreased from 22 spikes/s before treatment to 14 spikes/s 2 h post-salicylate and recovered 1 day post-treatment. These preliminary physiology data suggest that salicylate induced tinnitus is associated with sound evoked hyperactivity in auditory cortex and spontaneous hypoactivity.

Changes in the amplitude and timing of the hemodynamic response associated with prepulse inhibition of acoustic startle

Disruption of the early stages of information processing in limbic brain circuits may underlie symptoms of severe neuropsychiatric disorders. Prepulse inhibition of acoustic startle (PPI) is diminished in many of these disorders and may reflect the disruption of this CNS function. PPI is associated with brain activity in many of the same regions in humans as it is in laboratory animals, suggesting that neuroimaging studies in humans may help localize deficits that can then be elucidated in animal models. In this article, we employed a rapid presentation event-related design during continuous EPI BOLD scanning to examine hemodynamic response functions (HRFs) associated with PPI. Fourteen healthy participants listened to 100 pulse alone and 100 prepulse combined with pulse (prepulse–pulse) trials. PPI is the normalized difference in the startle response to the two trial types. Following the prepulse–pulse trials, the amplitudes of the HRFs in auditory cortices and in the anterior insula were increased, while in the cerebellum, thalamus and anterior cingulate, they were decreased, relative to the pulse alone trials. In addition, the timing of the prepulse–pulse responses was delayed in the auditory cortices, anterior insula and cerebellum. Finally, PPI measured outside the scanner was predicted by the difference in BOLD responses between trial types in the anterior insula and in the cerebellum. The results suggest that prepulse inhibition, and by extension early stages of information processing, modulate both the amplitude as well as timing of neural activity.

P3-359: Reduction of mitochondrial superoxide dismutase modulates Alzheimer’s disease-like pathology in human amyloid precursor protein transgenic mice

Alzheimer's disease (AD) results in the accumulation of amyloid–β (Aβ) peptides in the brain, oxidative damage, degeneration of neuronal processes, gliosis, dementia, and death. Whether oxidative damage and mitochondrial decline contribute directly to the characteristic pathology or are a secondary effect of the disease process has not been fully established in vivo. We tested the hypothesis that the mitochondrial antioxidant enzyme superoxide dismutase–2 (Sod2) plays a critical role in defending against Aβ–induced AD–like alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2+/–) in human amyloid precursor protein (hAPP) transgenic mice. Levels of Sod2 mRNA, protein and activity in Sod2+/– mice were roughly 50% of those in Sod2 wild–type (Sod2+/+) mice. In the presence of normal Sod2 levels, hAPP/Aβ expression resulted in deposition of Aβ predominantly in the brain parenchyma, decreases in levels of the dendritic marker microtubule–associated protein–2 (MAP–2), neuritic dystrophy and behavioral alterations, including deficits in prepulse inhibition of acoustic startle. Sod2 reduction in hAPP mice caused a striking redistribution of amyloid deposits to the cerebrovasculature by middle age and a decrease in parenchymal amyloid plaques by old age, as well as an increased microgliosis and the presence of macrophages with abnormal accumulation of lipid vacuoles near some vessels. Compared with hAPP/Sod2+/+ mice, hAPP/Sod2+/– mice also had an earlier age of onset of behavioral deficits, a greater loss of MAP–2, and a more prominent and widespread neuritic dystrophy, much of which was plaque–independent. Hippocampi of hAPP/Sod2+/– mice had increased DNA binding activity of the injury–responsive transcription factor nuclear factor–κ–B (NFκB). These results suggest that Sod2 protects the aging brain against Aβ–induced impairments. While reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

Developmental Vitamin D Deficiency Alters MK 801-Induced Hyperlocomotion in the Adult Rat: An Animal Model of Schizophrenia

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice.

Alzheimer's disease (AD) is associated with accumulations of amyloid-beta (Abeta) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2(+/-)) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to approximately 50% of that in Sod2 wild-type (Sod2(+/+)) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/Abeta expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/Abeta-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor kappaB. These results suggest that Sod2 protects the aging brain against hAPP/Abeta-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.

Stuttering and sensory gating: A study of acoustic startle prepulse inhibition

It was hypothesized that stuttering may be related to impaired sensory gating, leading to overflow of superfluous disturbing auditory feedback and breakdown of the speech sequence. This hypothesis was tested using the acoustic startle prepulse inhibition (PPI) paradigm. A group of 22 adults with developmental stuttering were compared with controls regarding the degree of PPI. No significant differences were found between the stuttering adults and the control group; the groups showed similar means and distribution. Likewise, no relation between the degree of PPI and the effect of altered auditory feedback on stuttering was found. In summary, the results of the study indicate that there is no relation between stuttering and PPI.

Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle

Rearing rats in isolation produces perturbations in behavior and brain neurochemistry suggested to resemble those of schizophrenia. In particular, isolation-reared rats display deficits in prepulse inhibition of acoustic startle that in humans are associated with disorders including schizophrenia and are interpreted as abnormalities in sensorimotor gating. The prefrontal cortex is considered important in the regulation of prepulse inhibition of acoustic startle and postmortem studies suggest that neuropil and total volume, but not total number of neurons, are decreased in this region of the brains of schizophrenic patients. In this study we used design-based stereological techniques to examine the brains of Lister Hooded rats, reared in isolation and which displayed prepulse inhibition of acoustic startle deficits, for changes in morphology compared with the brains of their socially-reared littermates. Pooled data from three batches of animals revealed a significant 7% volume loss of the medial prefrontal cortex of isolation-reared rats whereas neuron number in this region was unchanged. In contrast, volume and total neuron number were unaffected in the rostral caudate putamen. The robust reduction in prefrontal cortical volume observed in isolation-reared rats, in the absence of reductions in total neuron number, suggest that there is a loss of volume of the neuropil. These changes parallel those reported in schizophrenia patients and therefore support the construct validity of this model.

Abnormal neurodevelopment, neurosignaling and behaviour in Npas3‐deficient mice

Npas3 is a member of the bHLH-PAS superfamily of transcription factors that is expressed broadly in the developing neuroepithelium. To study the function of this gene, mice deficient in Npas3 were generated and characterized. Npas3-/- mice were growth-retarded and exhibited developmental brain abnormalities that included a reduction in size of the anterior hippocampus, hypoplasia of the corpus callosum and enlargement of the ventricles. A number of behavioural abnormalities were identified in Npas3-/- mice including locomotor hyperactivity, subtle gait defects, impairment of prepulse inhibition of acoustic startle, deficit in recognition memory and altered anxiety-related responses. Characterization of neurosignaling pathways using several pharmacological agents revealed dysfunctional glutamate, dopamine and serotonin neurotransmitter signaling. Consistent with these findings, we identified a significant alteration in cortical PSD-95 expression, a PDZ-containing protein that has been shown to be involved in postsynaptic signal transduction. Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways.

Effects of phencyclidine on acoustic startle and prepulse inhibition in neuronal nitric oxide synthase deficient mice

Prepulse inhibition of acoustic startle is a behavioural response, which is used to estimate sensorimotor gating deficits in schizophrenia. Recent studies show that several behavioural effects of the psychotomimetic drug, phencyclidine (PCP), in rodents are blocked by nitric oxide synthase (NOS) inhibitors suggesting that NO plays an important role in the pharmacological effects of PCP. The present study was conducted to examine the effects of PCP on prepulse inhibition in neuronal NOS (nNOS) deficient mice. PCP treatment caused a significant and dose-related increase in prepulse inhibition in nNOS−/− mice whereas prepulse inhibition was not significantly affected in +/+ and ± mice. Basal prepulse inhibition level did not differ significantly between the groups. Furthermore, PCP caused a dose-related decrease in startle response reactivity in +/+ mice but did not significantly affect this measure in +/− and −/− mice. Basal startle response level did not differ between +/+ and +/− but was significantly lower in −/− mice. It is concluded that nNOS plays a role in the NO-sensitive effects of PCP.

Deletion of the α7 Nicotinic Receptor Subunit Gene Results in Increased Sensitivity to Several Behavioral Effects Produced by Alcohol

The finding that most people with alcoholism are also heavy smokers prompted several research groups to evaluate the effects of ethanol on neuronal nicotinic acetylcholine receptor (nAChR) function. Data collected in vitro indicate that physiologically relevant concentrations of ethanol inhibit the functional activation of homomeric alpha7 nAChRs, which are one of the most abundant nAChR subtypes expressed in the mammalian brain. The studies outlined here used alpha7 gene knockout (null mutant) mice to evaluate the potential role of alpha7 nAChRs in modulating selected behavioral and physiological effects produced by ethanol. Current evidence indicates that many responses to ethanol are not genetically correlated. Therefore, the authors measured the effects of acute administration of ethanol on several behaviors that are altered by both ethanol and nicotine: two tests of locomotor activity, acoustic startle, prepulse inhibition of acoustic startle, and body temperature. Ethanol-induced durations of loss of righting reflex and ethanol elimination rates were also determined. These studies used null mutant (alpha7(-/-)) and wild-type (alpha7(-/-)) mice. Relative to alpha7(+/+) mice, alpha7(-/-) mice were more sensitive to the activating effects of ethanol on open-field activity, ethanol-induced hypothermia, and duration of loss of the righting response. Deletion of the alpha7 gene did not influence the effects of ethanol on Y-maze crossing or rearing activities, acoustic startle, or prepulse inhibition of startle. Gene deletion did not alter ethanol metabolism. These results indicate that some but not all of the behavioral effects of ethanol are mediated in part by effects on nAChRs that include the alpha7 subunit and may help to explain the robust association between alcohol consumption and the use of tobacco.