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Biomedical subjects

D L Braff

Publications and source records attributed to D L Braff.

At least 91 records · Page 5Linked to original sources
PubMed1990

GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats.

Previous studies have demonstrated that increased mesolimbic dopamine (DA) activity disrupts sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Other behavioral changes following mesolimbic DA activation are mediated through GABAergic efferent projections from the nucleus accumbens (NAC) to the ventral pallidum (VP). In this experiment, we examined whether PPI deficits in rats following mesolimbic DA activation are mediated through these same GABAergic substrates. PPI was significantly disrupted in rats following infusion of DA (40 micrograms) into the NAC, and this effect was reversed by infusion of a low dose (10 ng) of the GABA agonist muscimol into the VP. In a second experiment, we tested the hypothesis and the loss of PPI following intra-NAC DA infusion results from a disruption of GABAergic activity within the VP. Consistent with this hypothesis, infusion of the GABA antagonist picrotoxin (0-0.2 micrograms) into the VP caused a significant loss of PPI. These findings strongly suggest that the accumbens-ventral pallidal GABAergic circuitry is a substrate for the decrease in sensorimotor gating induced by mesolimbic DA overactivity.

Acoustic Stimulation↗
PubMed1990

Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence.

The inability of schizophrenics to filter irrelevant information has often been implicated in the psychopathology of schizophrenia. Despite numerous attempts at characterizing the behavior of schizophrenics in the presence of distractors, evidence of increased distractibility has been equivocal due to the difficulty of assessing simultaneously the behavioral and neurophysiological effects of distracting stimuli. We report the results of an experiment in which event-related potential and performance measures were used to assess distractibility during reaction time tasks under different distracting conditions. The results supported the view of an increased distractibility in schizophrenic patients. Event-related potential data suggested that in schizophrenic patients, a reduced amount of processing resources is allocated to process external stimuli and attention is abnormally apportioned to task-irrelevant vs task-relevant stimuli.

Adolescent↗
PubMed1990

Sensorimotor gating and schizophrenia. Human and animal model studies.

Human and animal model studies of sensorimotor gating allow us to understand the functional significance of attentional abnormalities and monoaminergic alterations in patients with schizophrenic disorders. Clinically, schizophrenic patients report oversensitivity to sensory stimulation that theoretically correlates with stimulus overload and leads to cognitive fragmentation. Paradigms using cortical event-related potentials and the prepulse inhibition of startle responses show that schizophrenic patients also have impaired central nervous system inhibition (sensorimotor gating). Animal model studies demonstrate that increased systemic aminergic activity and increased nucleus accumbens dopamine tone causes sensorimotor gating failure, similar to that seen in schizophrenic patients. The time course of the observed schizophrenic and animal model deficits is compatible with the "temporal map" of monoaminergic neuron functions (le, several hundred milliseconds). Studies of sensorimotor gating allow investigators to comment on the spatial and temporal mapping of neurons, trait and state deficits, and vulnerability factors in the schizophrenic spectrum of disorders. By translating attentional theories into testable hypotheses, the neurobiology of schizophrenic disorders becomes clearer.

Animals↗
PubMed1990

Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens.

Previous studies have demonstrated that several dopamine agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Schizophrenic patients also exhibit deficits in PPI when the prepulse precedes the startle stimulus by less than 500 ms. In experiment 1, dopamine (0-40 micrograms) infused directly into the nucleus accumbens in rats caused a dose-dependent decrease in PPI at prepulse intervals shorter than 500 ms. In experiment 2, this effect of accumbens dopamine infusion on sensorimotor gating was found to vary with changes in prepulse intensity. These findings strongly suggest that increased mesolimbic dopamine activity is one substrate of the sensorimotor gating deficits in rats that are caused by treatment with dopamine agonists; similar substrates might mediate deficits in PPI exhibited by schizophrenic patients.

Animals↗
PubMed1990

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine.

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats.

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.

Acoustic Stimulation↗
PubMed1990

Startle response models of sensorimotor gating and habituation deficits in schizophrenia.

Studies of prepulse inhibition and habituation of startle responses elicited by intense stimuli provide some unusual opportunities for cross-species explorations of attentional deficits characteristic of schizophrenic patients. Schizophrenic patients exhibit deficits in both the prepulse inhibition of startle and the habituation of startle. The behavioral plasticity of startle responses and the comparability of the test paradigms used in rats and humans greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This review describes two such examples of parallel animal and human models, one involving sensorimotor gating and the other examining behavioral habituation. Evidence is presented supporting the involvement of mesolimbic dopaminergic systems in the modulation of prepulse inhibition or sensorimotor gating and the importance of central serotonergic systems in the habituation of startle.

Animals↗
PubMed1990

Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD.

One of the diagnostic criteria for posttraumatic stress disorder (PTSD) is an exaggerated startle response; however, this phenomenon has not been verified empirically. The authors compared 20 Vietnam combat veterans with PTSD and 18 combat veterans without PTSD on the eyeblink reflex electromyographic response of the startle reaction. Subjects in both groups who failed to show an eyeblink response to the startle stimuli were eliminated from further analyses. Among the remaining subjects, the 13 with PTSD had a significantly greater startle response amplitude than the 12 control subjects at intermediate intensities of acoustic stimuli. The relationship between startle responsivity and both negative and positive symptoms was also investigated.

Acoustic Stimulation↗
PubMed1990

A D2 dopamine receptor agonist disrupts sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia.

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Prepulse inhibition of the acoustic startle response is disrupted by N-ethyl-3,4-methylenedioxyamphetamine (MDEA) in the rat.

N-Ethyl-3,4-methylenedioxyamphetamine (MDEA) is a derivative of methylenedioxyamphetamine (MDA), a substituted amphetamine with demonstrated abuse liability. MDA, MDEA and a third substituted amphetamine, methylenedioxymethamphetamine (MDMA), all produce a destructive action on central serotonin neurons and appear to induce some similar behavioral effects. The present study investigated the effects of racemic MDEA and its stereoisomers on prepulse inhibition of the acoustic startle response, a behavioral model of sensorimotor gating that is sensitive to psychostimulant drugs. Rats were subjected to 122 dB[A] acoustic noises, some of which were preceded by a weak 80 dB[A] prepulse noise. In vehicle-injected control rats, the prepulse induced a significant decrease in startle amplitude when compared to trials in which startle stimuli were not preceded by prepulses. Administration of racemic MDEA (0.3-10.0 mg/kg) and (+) MDEA (0.1-3.0 mg/kg) induced a significant attenuation in prepulse inhibition, while (-) MDEA (0.3-10.0 mg/kg) did not. Racemic MDMA (0.3-10.0 mg/kg) produced similar though not significant effects. These results confirm a stimulant-like behavioral effect of MDEA despite its relatively modest effects on dopamine markers, and support findings that the (+) stereoisomers of substituted amphetamines are more potent than tha (-) stereoisomers in producing psychostimulant-like biochemical and behavioral effects.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Sensory input deficits and negative symptoms in schizophrenic patients.

The information-processing correlates of positive and negative symptoms in schizophrenic patients are of increasing clinical research interest. The author tested 40 schizophrenic patients and 35 normal control subjects and reports on two major findings. First, patients with negative symptoms had dramatic inflations of stimulus recognition thresholds, similar to the deficits previously reported in patients with head injuries resulting in organic brain syndromes. Second, the schizophrenic patients had deficits in the time-dependent processing of information. Collectively, these data support the link between negative symptoms and multiple levels of information-processing abnormalities in patients with schizophrenic disorders.

Adult↗
PubMed1988

Methylphenidate-induced information processing dysfunction in nonschizophrenic patients.

To examine the relationship of aminergic overactivity to information processing, we gave methylphenidate hydrochloride, oxazepam, or placebo to 12 nonpsychotic patients in one-week blocks in a double-blind, randomized design. Methylphenidate induced a pattern of information processing dysfunction similar to that seen in schizophrenic patients, strengthening the linkage of the schizophrenia-information processing dysfunction-aminergic overactivity relationship. Further, the time course of the observed deficits in both schizophrenic and methylphenidate-induced states is strikingly compatible with the temporal mapping pattern of monoaminergic neuronal systems. More research is needed to identify definitively the aminergic influences on attentional functioning. A psychophysical task-pharmacologic probe strategy should prove useful.

Adult↗
PubMed1988

Dopaminergic stimulation disrupts sensorimotor gating in the rat.

Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125-4.0 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.

Animals↗
PubMed1988

The clinical significance of thought disorder across time in psychiatric patients.

The occurrence and clinical significance of thought disorder, as measured by general abstraction ability and idiosyncratic abstractions, remains a complex and ambiguous area of inquiry. We studied 49 subjects in a longitudinal design in which the effects of general psychopathology and depression on abstraction function were assessed. Results indicate that a) depressive patients have a generalized abstraction dysfunction not limited to specific content areas, b) some depressive patients have a residual abstraction deficit on discharge from the hospital, c) idiosyncratic abstractions are a characteristic but not pathognomonic marker for schizophrenia, and d) across all subjects, abstraction difficulties represent a seemingly state-dependent "final common pathway" that significantly correlates with general psychopathological impairment rather than level of depression.

Depressive Disorder↗
PubMed1987

Startle habituation and sensorimotor gating in schizophrenia and related animal models.

Studies of the habituation and sensorimotor gating of startle responses to strong exteroceptive stimuli provide some unique opportunities for cross-species explorations into information processing and attentional deficits in schizophrenia. The behavioral plasticity of startle paradigms greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This article reviews the promising findings of studies in which measures of startle have been used to clarify the importance of habituation and central inhibition deficits in schizophrenia. In addition, the development of closely related animal models of habituation and sensory gating of startle is discussed. Such animal model studies allow us to make strong inferences about the neurobiological substrate of schizophrenia. Recent evidence from animal studies of prepulse inhibition provides strong support for a schizophrenia-like loss of sensory gating with nucleus accumbens dopamine overactivity. These data are consistent with hypotheses regarding the significance of mesolimbic dopamine overactivity in schizophrenia. New results are also presented from animal model studies of the effects of serotonergic drugs on startle habituation, extending earlier findings of LSD-induced habituation deficits which are similar to those exhibited by schizophrenic patients. These new data indicate that the serotonergic system, working through serotonin-2 receptors, may play a pivotal role in the modulation of startle habituation. The relationship of serotonergic and catecholaminergic mechanisms is also discussed. Collectively, these studies demonstrate the utility of operationally defined measures of preattentive processes in the study of the neurobiological basis of the group of schizophrenias.

Animals↗
PubMed1986

Central dopamine hyperactivity in rats mimics abnormal acoustic startle response in schizophrenics.

Schizophrenic patients show loss of the normal inhibition of the acoustic startle response (ASR) when the startle stimulus is preceded by a weak prepulse stimulus. In rats experimentally induced to have locally supersensitive dopamine receptors within forebrain dopamine terminal regions, we find a similar deficit in "prepulse inhibition" of the ASR. Our results suggest that there are intriguing parallels between the aberrant sensory gating of the ASR demonstrated by schizophrenics and that demonstrated by rats during stimulation of supersensitive brain dopamine receptors. Thus, prepulse inhibition of the ASR provides a useful paradigm for investigating the bridge between mesolimbic dopamine overactivity and the specific time-dependent information processing-sensory gating disturbances that have been identified in schizophrenic patients.

Acoustic Stimulation↗