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N R Swerdlow

Publications and source records attributed to N R Swerdlow.

At least 19 recordsLinked to original sources
PubMed2005

Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats.

BACKGROUND: Sensorimotor gating, as measured by prepulse inhibition of the startle reflex, is deficient in schizophrenia patients, and in rats after specific manipulations of limbic cortico-striato-pallido-thalamic circuitry. For example, prepulse inhibition in rats is disrupted after D1 blockade in the medial prefrontal cortex, and after N-methyl-D-aspartate infusion into the ventral hippocampus. In the present study, we examined whether these two substrates form part of an integrated circuit regulating sensorimotor gating, which might contribute to the loss of prepulse inhibition in patient populations. METHODS: Prepulse inhibition was assessed in male Sprague-Dawley rats after systemic or intra-medial prefrontal cortex administration of the D1 antagonist, SCH 23390. Separate rats received intra-medial prefrontal cortex infusion of the retrograde transported label Fluoro-Gold. In rats with sham or electrolytic lesions of the medial prefrontal cortex, prepulse inhibition was tested after infusion of N-methyl-D-aspartate or vehicle into ventral hippocampus regions that were determined to send projections to the medial prefrontal cortex. RESULTS: Prepulse inhibition was disrupted after systemic SCH 23390 treatment and after infusion of SCH 23390 into medial prefrontal cortex sites within the prelimbic and cingulate cortices. Fluoro-Gold infusion into these medial prefrontal cortex sites labeled cells in the ventral hippocampus complex, including regions CA1 and entorhinal cortex. N-methyl-D-aspartate infusions into these ventral hippocampus regions disrupted prepulse inhibition in rats after sham but not electrolytic lesions of the medial prefrontal cortex. CONCLUSIONS: Prepulse inhibition appears to be regulated by interacting substrates within the ventral hippocampus and MPFC. Specifically, NMDA activation of the ventral hippocampus appears to disrupt prepulse inhibition in a manner that is dependent on the integrity of infralimbic or cingulate cortical regions that also support a D1-mediated regulation of prepulse inhibition. Conceivably, dysfunction within these hippocampal-frontal circuits may contribute to sensorimotor gating deficits in schizophrenia.

Acoustic Stimulation↗
PubMed2004

The ventral hippocampal regulation of prepulse inhibition and its disruption by apomorphine in rats are not mediated via the fornix.

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is impaired in schizophrenia. We have reported that PPI is regulated by the ventral hippocampus (VH) and that the PPI disruptive effects of the dopamine agonist apomorphine are enhanced 4 weeks after excitotoxic lesions of the VH. The mechanisms responsible for the VH influence on PPI are not understood, but have been ascribed to interactions between the VH and nucleus accumbens. In the present study, we examined whether the VH influence on PPI and its dopaminergic regulation is dependent on the integrity of the VH-accumbens projection via the fornix. First, the PPI-disruptive effects of intra-VH NMDA infusion were assessed after sham or electrolytic transection of the fornix. Second, the PPI-disruptive effects of apomorphine were assessed 1 month after excitotoxic or electrolytic lesions of the VH, or after fornix transection. Intra-VH N-methyl-D-aspartate infusion significantly disrupted PPI; this effect was unaffected by fornix lesions. The PPI-disruptive effects of apomorphine were significantly enhanced by excitotoxic or electrolytic lesions of the VH, but not by fornix transection. The influence of the VH on PPI and its dopaminergic regulation does not appear to be mediated via the fornix. The enhanced sensitivity to the PPI-disruptive effects of apomorphine after VH lesions is not dependent on excitotoxin-induced changes in the VH or its downstream projections.

Animals↗
PubMed2003

Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats.

Rearing rats in social isolation from weaning into adulthood leads to deficits in prepulse inhibition and alterations in monoamine systems that modulate prepulse inhibition. For example, rats reared in social isolation have elevated dopamine levels in the nucleus accumbens. Previous studies in rats have shown that nucleus accumbens dopamine depletion with 6-hydroxydopamine blocks the prepulse inhibition-disruptive effects of amphetamine, an indirect dopamine agonist. We tested the hypothesis that prepulse-inhibition deficits in isolation-reared rats are dependent on elevated dopamine levels in the nucleus accumbens. Specifically, we examined whether nucleus accumbens dopamine depletion would attenuate the isolation-induced disruption of prepulse inhibition. Isolation-housed female Long-Evans rats exhibited deficient prepulse inhibition. At 9 weeks post weaning, bilateral injections of 6-hydroxydopamine (8 microg/side) or ascorbic acid vehicle (0.1%) into the nucleus accumbens of social and isolation-reared rats were performed (8-10 rats per group). One week after surgery, prepulse inhibition deficits were exhibited by isolation-reared rats that received vehicle infusion into the nucleus accumbens, but not by those that received 6-hydroxydopamine infusions into the nucleus accumbens. 6-Hydroxydopamine infusions did not significantly change prepulse inhibition in socially reared rats. Behavioral and neurochemical evidence of nucleus accumbens dopamine depletion included: 1) a blockade of amphetamine-stimulated locomotor activity in nucleus accumbens 6-hydroxydopamine-infused isolated and socially reared rats; and 2) high performance liquid chromatography measurements demonstrating a significant depletion of accumbens dopamine and its major metabolites, in addition to decreases in dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the frontal cortex and anterior caudate. These data indicate that dopamine in the nucleus accumbens plays an essential role in the prepulse inhibition deficits associated with isolation rearing in female Long-Evans rats. The implication of a central role of nucleus accumbens dopamine in prepulse inhibition deficits in an animal model provides further evidence for a link between overactive dopamine function and sensorimotor-gating deficits in patients with schizophrenia.

Acoustic Stimulation↗
PubMed2001

Tactile prepuff inhibition of startle in children with Tourette's syndrome: in search of an "fMRI-friendly" startle paradigm.

BACKGROUND: Functional magnetic resonance imaging (fMRI) studies in neuropsychiatric populations will be enhanced by "on-line" tasks that assess brain activation linked to neurocognitive and psychophysiological functions. In some cases, task modifications may be required for use in an fMRI environment. Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in specific neuropsychiatric disorders, including schizophrenia, Huntington's disease, and Tourette's syndrome (TS). This study examined whether a modified "fMRI-friendly" PPI paradigm is suitable for use in children and adequately sensitive to detect PPI deficits in TS. METHODS: Bilateral eyeblink PPI was measured in children using chin air puffs to elicit startle and prepuffs to the dorsal hand surface as inhibiting stimuli. This paradigm involved no metallic objects or acoustic stimuli, making it suitable for an fMRI environment that is magnetically sensitive and acoustically complex. Children were also assessed in a "standard" acoustic PPI paradigm. RESULTS: Robust startle was elicited via either puffs or noise bursts, and these responses were inhibited by prepuffs and prepulses, respectively. Compared to control subjects, children with TS exhibited comparable startle magnitude and habituation but significantly reduced prepuff inhibition and acoustic PPI. CONCLUSIONS: Sensorimotor gating can be assessed in an "fMRI-friendly" paradigm that detects inhibitory deficits in TS.

Acoustic Stimulation↗
PubMed2001

Lesion size and amphetamine hyperlocomotion after neonatal ventral hippocampal lesions: more is less.

Neonatal hippocampal lesions in rats produce behavioral and neurochemical abnormalities post-puberty that are used in animal models for developmentally linked pathology in schizophrenia. In one model, adult rats exhibit enhanced sensitivity to the locomotor-activating effects of amphetamine, if they had sustained excitotoxic lesions of the ventral hippocampus on post-natal day 7. The hippocampal elements responsible for these lesion-induced developmental changes have not been fully characterized. The present study assessed the locomotor-activating effects of amphetamine in adult rats that on day 7 had sustained either sham or ibotenic acid lesions of the ventral hippocampus alone ("standard lesions"), or the ventral hippocampus plus surrounding portions of entorhinal cortex and dorsal hippocampus ("large lesions"). "Standard lesions" produced the expected "supersensitive" locomotor response to amphetamine, while "large lesions" did not. No differences between these lesion groups were observed in baseline levels of locomotor activity or habituation. These data suggest that models of enhanced behavioral sensitivity to dopamine agonists after neonatal hippocampal lesions require functionality in the entorhinal cortex and/or dorsal hippocampus. It is possible that the behavioral abnormalities in the "neonatal hippocampal lesion model" reflect, at least in part, aberrant function within spared elements of the hippocampal complex.

Adrenergic Uptake Inhibitors↗
PubMed2001

Regulation of sensorimotor gating in rats by hippocampal NMDA: anatomical localization.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating that is reduced in humans with certain neuropsychiatric disorders, including schizophrenia, and in rats after manipulations of limbic cortico-striato-pallido-pontine circuitry. We have reported that PPI is reduced after specific manipulations of the hippocampal complex (HPC) in rats, but the mechanisms for these effects remain poorly understood. For example, dopaminergic substrates clearly regulate PPI, but the PPI-disruptive effects of intra-HPC carbachol or NMDA are not reversed by D2 receptor antagonists. This study examined the anatomical specificity within the hippocampal complex of the PPI-disruptive effects of NMDA infusion. Startle magnitude and PPI were assessed after acute bilateral infusion of NMDA (0, 0.4 or 0.8 microg) into the dorsal subiculum (DS), region CA1, the ventral subiculum (VS), the rostral entorhinal cortex (ECr) and the caudal entorhinal cortex (ECc). A dorsal-ventral gradient for NMDA effects was observed, with a dose-dependent disruption of PPI after NMDA infusion into the VS or EC, but not the DS, and with intermediate level effects observed after NMDA infusion into CA1. A second set of studies confirmed that the failure of NMDA effects in the DS did not reflect site-related differences in startle magnitude or baseline levels of PPI. These findings demonstrate the importance of the ventral, but not the dorsal HPC, in the glutamatergic regulation of PPI.

Animals↗
PubMed2001

Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia.

Schizophrenia patients have prominent deficits in information processing that can be detected by measures of prepulse inhibition (PPI) of the startle response. Deficient PPI in schizophrenia is thought to reflect a failure of brain-based information 'protective' mechanisms that normally inhibit responsivity for 30-500ms after a weak prepulse stimulus. The relationship between specific prepulse stimulus characteristics and PPI deficits in this study was examined in 31 schizophrenia patients and 34 normal comparison subjects. Schizophrenia patients had overall deficits in PPI across four conditions where the prepulse was either discrete (abrupt) or continuous (sustained) and consisted of either white noise or a pure tone. On inspection and analysis of the data, it appears that the white noise conditions, rather than tone conditions, account for the group differences. Thus, the discrete white noise prepulse was most effective in eliciting PPI deficits, resulting in a large effect size between groups (d=0.85; P<0.01). Deficits in information-protective mechanisms in schizophrenia may be differentially sensitive to specific stimulus characteristics; this observation may be relevant both to the neurobiology of information processing deficits in schizophrenia and to the methodologies for studying these deficits experimentally.

Adult↗
PubMed2001

Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges.

RATIONALE: Sensorimotor gating of the startle reflex can be assessed across species, using similar stimuli to elicit similar responses. Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in patients with some neuropsychiatric disorders, and in rats after manipulations of limbic cortex, striatum, pallidum or pontine tegmentum ("CSPP" circuitry). OBJECTIVE: To review the current knowledge of the neural circuit regulation of PPI in rats, and to anticipate the future challenges facing this line of inquiry. METHODS: The published literature was reviewed and critically evaluated. RESULTS: Limbic CSPP circuitry has been studied in rats to reveal the neurochemical and neuroanatomical substrates regulating PPI at a high level of resolution. In translational cross-species research, this detailed circuit information is used as a "blueprint" to identify substrates that may lead to PPI deficits in psychiatrically disordered humans. Some human disorders with identifiable, localized lesions in CSPP circuitry may provide direct validation for the contribution of CSPP circuitry to this cross-species model. The rapid collection of experimental data supporting this cross-species PPI circuit "blueprint" has supported continuing advances in the development of theoretical models for understanding how this circuitry normally functions to regulate PPI. Such models are needed for building a conceptual framework for understanding the role of this circuitry in the regulation of sensorimotor gating in normal humans, and in the relative loss of sensorimotor gating, and the resulting clinical consequences, in individuals with particular neuropsychiatric disorders. CONCLUSIONS: Our understanding of the neural regulation of PPI has increased tremendously over the past 15 years. Progress has come in "broad strokes", and a number of important details and complex questions remain to be addressed. It is anticipated that this is a "work in progress", and that the precise models for the neural regulation of PPI will evolve substantially in the coming years.

Animals↗
PubMed2001

Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

RATIONALE: Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). OBJECTIVE: This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. METHODS: All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. RESULTS: The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. CONCLUSIONS: Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.

Humans↗
PubMed2001

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

RATIONALE: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. OBJECTIVE: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. METHODS: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. RESULTS: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. CONCLUSIONS: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.

Animals↗
PubMed2001

Effects of pergolide on sensorimotor gating of the startle reflex in rats.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders, including schizophrenia. This study was designed to assess the effects of the D2-family agonist pergolide in rats, in anticipation of human studies of the dopaminergic regulation of PPI. METHODS: The effects of pergolide (0.0001-0.5 mg/kg) on PPI of the acoustic startle reflex were studied in rats using a wide range of prepulse intensities [1-15 dB(A) over background] and prepulse intervals (5-100 ms, onset to onset). Studies also examined the effects of the D2 antagonist haloperidol on pergolide-induced changes in PPI. RESULTS: Pergolide exhibited dose- and stimulus-dependent effects on PPI. Pergolide increased PPI when startle stimuli were preceded by weak prepulses [1-5 dB(A) over background] at the longest prepulse interval (100 ms), or intense prepulses [15 dB(A) over background] at short prepulse intervals (5-20 ms). Pergolide (0.5 mg/kg) also decreased PPI elicited by intense prepulses at long intervals (60-100 ms). Both PPI-enhancing and PPI-disruptive effects of pergolide were reversed by the D2 antagonist haloperidol. CONCLUSIONS: These effects of pergolide suggest that D2 substrates mediate opposing influences on PPI under different stimulus conditions. The dopaminergic regulation of sensorimotor gating appears to interact with stimulus characteristics such as relative intensity and temporal separation, allowing for dynamic shifts in both the quantity and quality of "gated" information.

Animals↗
PubMed2001

Obsessive-compulsive disorder and tic syndromes.

The phenomenology of OCD and TS seem to match perfectly with the existing conceptualization of the functional relationship between frontal cortical and subcortical circuits. Failed editing of thoughts and impulses, perseverative patterns, and inhibitory deficits are the most convenient descriptors of the symptoms, and some operationalized measures can capture evidence for such deficits in TS and OCD patients. Beyond these expectations borne from conceptual models and some broad patterns of distributed metabolic disturbances in neuroimaging studies, a specific causal pathology within CSPT circuitry needs to be identified in these disorders. This is not a criticism of the existing studies of TS and OCD; to the contrary, the scarcity of pathologic material, the limits of resolution of existing technologies, and the heterogeneity of the phenotypes make the accomplishments of these studies more impressive. As clinicians strive to integrate clinical and scientific findings into coherent models for the pathophysiology of OCD and TS, it is useful to identify practical and effective strategies for therapeutic interventions.

Behavior Therapy↗
PubMed2001

Matching strategies for drug studies of prepulse inhibition in humans.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. Animal studies have revealed drug effects on PPI that may be relevant to understanding the biology of gating deficits in human populations. Recent efforts have examined similarities and differences in drug effects on PPI between rodents and humans. Experimental designs are needed that most effectively translate these drug studies across species. In the course of a larger set of studies of drug effects on startle in normal human subjects, we examined the potential utility of one design element that is utilized in rodent PPI drug studies: pre-testing to diminish variability across dose groups. Startle was measured during a screening session; 7-10 days later, 20 subjects were retested after consuming a placebo pill. Acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in five sessions over a period of 3 hours post-placebo. There were significant and robust correlations between levels of startle magnitude and PPI during pre-testing and testing, for both left and right eyeblink measures. Comparable correlations were evident for both unimodal and cross-modal testing. Pre-testing values were most predictive of test performance early in the 3-hour test session, and predictive strength diminished or disappeared towards the end of testing. The utility of a pre-testing design could be seen clearly by comparing groups 'matched', based on pre-test data, versus groups created by alternating or random group assignments. It is concluded that pre-test designs can effectively match groups with comparable levels of startle or PPI, and thereby diminish between-group variability in human PPI drug studies. For studies using repeated testing to assess drug time course, the predictive value of pre-testing is greatest in early test sessions.

Acoustic Stimulation↗
PubMed2000

Distributed neurodegenerative changes 2-28 days after ventral hippocampal excitotoxic lesions in rats.

An enhanced sensitivity to the behavioral effects of dopamine (DA) agonists in adult rats occurs after cytotoxic lesions of the ventral hippocampus (vHPC). While some of these behavioral changes may model specific abnormalities in schizophrenia patients, little is known about the cellular events that underlie vHPC lesion-induced behavioral DA 'supersensitivity'. Neuropathological consequences of excitotoxin lesions of the vHPC were investigated in this study. Adult male rats received vehicle or ibotenic acid infusions into the vHPC, using parameters that produce an enhanced sensitivity to the prepulse inhibition-disruptive effects of the DA agonist apomorphine, 1 month post-lesion. A total of 27 rats were sacrificed, 2, 7, 14, 21 or 28 days post-lesion. Amino-cupric-silver staining demonstrated degenerative changes throughout the hippocampus, and in hippocampal efferent projections to forebrain structures, including the septal nucleus and nucleus accumbens (NAC), and within the olfactory tubercle (OT) and orbital cortex. Silver-impregnated fibers were identified in the substantia nigra reticulata (SNr), NAC, OT, septum and orbital cortex. Some degenerative changes were noted at the earliest time point (2 days post-lesion), while others were delayed in appearance. Adjacent sections stained for tyrosine hydroxylase (TH) immunocytochemistry revealed reduced TH labeling through forebrain DA terminal fields 28 days, but not 14 days after VH lesions. Excitotoxic lesions of the vHPC result in distributed neurotoxic changes in subcortical and cortical brain regions; these changes may contribute to the delayed emergence of DA-mediated behavioral abnormalities in these animals.

Animals↗
PubMed2000

Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Acoustic Stimulation↗
PubMed2000

Effects of caffeine on sensorimotor gating of the startle reflex in normal control subjects: impact of caffeine intake and withdrawal.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. This study was designed to assess caffeine effects on PPI in normal humans, as part of an effort to understand cross-species differences and similarities in the neurochemical regulation of PPI. METHODS: Startle was measured during a screening session; 7 days later, subjects were retested after placebo or caffeine (200 mg; double-blind design). Subjects were characterized as low versus high caffeine drinkers based on established scales (range 11-628 mg/day), and either maintained ad libitum caffeine intake (Ad lib study; n=18) or refrained from caffeine consumption for > or =15 h prior to testing (Withdrawal study; n=12). Autonomic and self-rating measures, acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in divided sessions for 3 h post-treatment. RESULTS: There were significant effects of caffeine and/or caffeine withdrawal on several self-rating and autonomic measures, and on startle reflex habituation, but not on acoustic or tactile startle magnitude or PPI. Difference scores of startle data from screening versus test days revealed no group effects on startle magnitude, but PPI difference scores revealed that caffeine had opposite effects on low versus high caffeine drinkers (means=57 versus 258 mg/day) in the two withdrawal states. In the absence of withdrawal, caffeine reduced PPI in heavy caffeine drinkers; during withdrawal, caffeine increased PPI in heavy caffeine drinkers. The opposite pattern was evident in low caffeine drinkers. CONCLUSIONS: While a physiologically active dose of caffeine has no simple effects on PPI in normal humans, both withdrawal states and normal levels of caffeine consumption may be important factors in understanding this drug's effects on sensorimotor gating.

Adolescent↗
PubMed2000

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats.

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.

Age Factors↗