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PubMed2004

The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia?

The prenatal methylazoxymethanol acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia.

Acoustic Stimulation↗

PubMed1993

Auditory behaviour and brainstem histochemistry in adult rats with characterized ear damage after neonatal ossicle ablation or cochlear disruption.

Binaural and monaural ossicle ablation in neonate rats before the time of onset of auditory input resulted in hearing deficits as detected by behavioural responses to sound stimuli in these rats as young adults. Cochlear disruption at the same neonatal age similarly resulted in the absence of startle reflexes in many of the rats. When the middle and inner ears of the rats were analysed postmortem in serial sections, it was observed that most ears after neonatal ossicle ablation contained only small remnants of the malleus-incus unit, separated from the stapes; in other ears an apparent continuity of ossicles had been restored. The rats with blind-ending ear canals and ossicle atrophy were those that had shown little response to sound stimuli. In the cochlear-disrupted rats, those with modiolar damage and loss of most spiral ganglion cells had shown substantial impairment of sound perception, even in some rats with only monaural modiolar loss. The chronic conduction deficit caused by neonatal ossicle removal did not result in detectable differences in relative cytochrome oxidase activity in the dorsal cochlear nuclei and central nucleus of the inferior colliculus. For monaurally ossicle-ablated rats, quantitation of the average intensity of enzyme reaction product in sections of dorsal or ventral cochlear nuclei, or central nucleus, did not reveal a difference between operated and non-operated sides. However, in binaurally ossicle-ablated rats, the relative enzyme activity in the anteroventral cochlear nuclei was reduced in comparison to this nucleus in control rats. The volume of the anteroventral cochlear nucleus in rats that had had neonatal binaural cochlear disruption was reduced relative to the volume in control rats or in rats that had had binaural ossicle ablation (P < 0.001); the latter procedure did not result in a statistically significant difference from controls in AVCN volume. In cochlear-operated rats with monaural modiolar damage, the AVCN contralateral to the damaged cochlea had a lower mean level of cytochrome oxidase activity in its neurons measured individually than that for neurons in the ipsilateral AVCN. These results suggested the importance during development of input from contralateral cochlear neurons.

Acoustic Stimulation↗

PubMed1999

Effects of neurotensin administered into the ventral tegmental area on prepulse inhibition of startle.

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. Both locomotor activity and PPI are regulated by mesolimbic dopamine activity. Neurotensin is a neuropeptide, which coexists with dopamine in mesolimbic neurons. Neurotensin receptors have been identified in the nucleus accumbens (NAC) and ventral tegmental area (VTA). Previous studies have shown that neurotensin administered into the NAC differentially modulates PPI and locomotor activity. In this study we tested the effects of neurotensin administered into the VTA on PPI and locomotor activity. Consistent with previous studies, intra-VTA administered neurotensin significantly increased spontaneous locomotor activity. However, intra-VTA administered neurotensin did not have any significant effect on PPI. These results suggest that PPI and locomotor activity may have dissociable mesolimbic substrates and that neurotensin in the VTA does not play an important role in regulating PPI.

Animals↗

PubMed2002

Effect of lesions in the lateral nucleus of the amygdala on fear conditioning using auditory and visual conditioned stimuli in rats.

The lateral nucleus of the amygdala (LA) is believed to be the site of auditory conditioned stimulus (CS) relay in classical fear conditioning. The present study attempts to determine whether the LA is specifically involved in fear conditioning using an auditory CS. Seven rats with lesions in the LA (Tone-Lateral group) and eight sham-operated rats in the control group were trained using an auditory CS (overtone based on an 800 Hz fundamental tone, 70 dB, 3.7 s) paired with foot shock (1.0 mA, 0.5 s). Five rats with lesions in the LA (Light-Lateral group) and eight unoperated rats in the control group were trained using a visual CS (25 W light, 3.7 s). The behavioral index of fear conditioning was a potentiation of the startle reflex in the presence of CS. All rats in the control group and Light-Lateral group showed this potentiation, whereas those in the Tone-Lateral group did not. These results suggest that the LA is an input site of auditory CS information into the amygdala, and that it is not a site of visual CS information input in fear conditioning. Thus, each modality of CS may have a specific subnucleus of the amygdala that mediates fear conditioning.

Acoustic Stimulation↗

PubMed1997

The modulation of sensorimotor gating deficits by mesolimbic cholecystokinin.

The effects of cholecystokinin (CCK) in an animal model of sensorimotor-gating deficits with strong face, construct and predictive validity for schizophrenia were investigated. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus inhibits the startle response to a loud startling stimulus. Infusions of sulfated CCK-8 in the posterior nucleus accumbens potentiated apomorphine-induced disruption of PPI but had no effect on baseline PPI or the amplitude of acoustic startle reflex itself. The results provide evidence that mesolimbic CCK may play a role in regulating sensorimotor gating deficits but contradict earlier notions that CCK agonists may have antipsychotic properties and upon which clinical trials of CCK agonists in schizophrenia were based. Rather, these results suggest that antagonists of CCK may display neuroleptic-like actions on deficits in PPI and may hold greater promise as antipsychotics.

Acoustic Stimulation↗

PubMed2003

Affective associative learning modifies the sensory perception of nociceptive stimuli without participant's awareness.

The present experiment examined the possibility to change the sensory and/or the affective perception of thermal stimuli by an emotional associative learning procedure known to operate without participants' awareness (evaluative conditioning). In a mixed design, an aversive conditioning procedure was compared between subjects to an appetitive conditioning procedure. Both groups were also compared within-subject to a control condition (neutral conditioning). The aversive conditioning was induced by associating non-painful and painful thermal stimuli - delivered on the right forearm - with unpleasant slides. The appetitive conditioning consisted in an association between thermal stimuli - also delivered on the right forearm - and pleasant slides. The control condition consisted in an association between thermal stimuli - delivered for all participants on the left forearm - and neutral slides. The effects of the conditioning procedures on the sensory and affective dimensions were evaluated with visual analogue scale (VAS)-intensity and VAS-unpleasantness. Startle reflex was used as a physiological index of emotional valence disposition. Results confirmed that no participants were aware of the conditioning procedure. After unpleasant slides (aversive conditioning), non-painful and painful thermal stimuli were judged more intense and more unpleasant than when preceded by neutral slides (control condition) or pleasant slides (appetitive conditioning). Despite a strong correlation between the intensity and the unpleasantness scales, effects were weaker for the affective scale and, became statistically non-significant when VAS-intensity was used as covariate. This experiment shows that it is possible to modify the perception of intensity of thermal stimuli by a non-conscious learning procedure based on the transfer of the valence of the unconditioned stimuli (pleasant or unpleasant slides) towards the conditioned stimuli (non-painful and painful thermal stimuli). These results plead for a conception of pain as a conscious output of complex informational processes all of which are not accessible to participants' awareness. Mechanisms by which affective input may influence sensory experience and clinical implications of the present study are discussed.

Adolescent↗

PubMed2002

A differential involvement of the shell and core subterritories of the nucleus accumbens of rats in attentional processes.

The nucleus accumbens comprises of two anatomically distinct subterritories: an inner core and an outer shell region. The distinct pattern of the core and shell input and output targets suggests that these two regions may mediate different behavioral processes. Using N-methyl-D-aspartate excitotoxic lesions in either the core or shell region, we investigated whether we can dissociate functionally these two subterritories. N-Methyl-D-aspartate-lesioned, sham-lesioned and non-operated animals were tested for locomotor activity in an open field and in two behavioral paradigms known to evaluate attentional deficits, namely the pre-pulse inhibition of the acoustic startle reflex and latent inhibition, measured in a two-way active avoidance paradigm. The shell-lesioned animals showed a small but significant hyperactivity in the open field when compared to the core-lesioned and to control animals. In the pre-pulse inhibition paradigm, core-lesioned animals demonstrated reduced pre-pulse inhibition to the two high pre-pulse intensities (80 dB[A], 84 dB[A]). In the active avoidance paradigm, whereas no lesion effects were detected in the non-pre-exposed groups, clear attenuation of latent inhibition was found in the shell-lesioned rats, in comparison to both core-lesioned and control rats, due to improved avoidance performance of the shell-pre-exposed group. From these results we suggest that the two subterritories of the nucleus accumbens are differentially involved in attention-related processes: the core lesion leads to significant disruption of pre-pulse inhibition while the shell lesion leads to heightened activity and significant attenuation of latent inhibition.

Acoustic Stimulation↗

PubMed2002

Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F(2) intercross of Roman rat strains.

Anxiety-related behaviours were evaluated across various tests in a 800 F(2)-intercross of the Roman high- and low-avoidance inbred rats. These tests either evoke unlearned (open field [OF]; plus-maze [PM]; hole-board [HB]; spontaneous activity [A]; and acoustic startle reflex [ASR]) or learned (classical fear conditioning [CFC]; and shuttlebox avoidance conditioning [SAC]), anxious/fearful responses. Using factor analysis (oblique rotation), we obtained a six-fold solution with 14 variables derived from all tests. These six factors represented SAC, CFC, PM anxiety, PM and OF activity, ASR anxiety, plus a mixed whole of anxious and activity variables (from OF and A), respectively. In searching for a smaller number of meaningful factors, we applied a three-factor solution that coherently corresponded with differentiated facets of fearfulness, rather than with the tests. Results showed that (1) measures of SAC and CFC strongly loaded onto Factor 1, labelled as "Learned Fear"; (2) a blend of almost all variables loaded onto Factor 2, called "Emotional Reactivity"; and (3) open arm behaviour in the PM loaded onto Factor 3, called "Fear of Heights." After discussing limitations of this apparently consistent behavioural map of anxiety, we advance some connections between those factors with quantitative trait loci candidates (genetic markers) as detected in the same sample.

Animals↗

PubMed2002

Maternal dietary docosahexanoic acid content affects the rat pup auditory system.

Previous studies of the effects of dietary docosahexanoic acid (DHA), 22:6n3, on neurodevelopment have focused mainly on visual-evoked potentials and indices of visual activity, measures that may be confounded by effects on the retina rather than on neural pathways. We investigated the effect of pre- and postnatal maternal dietary DHA content on auditory brainstem conduction times (ABCTs), the appearance of the auditory startle reflex (ASR), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity in brainstem homogenates. Timed pregnant dams were fed, beginning on day 2 of gestation and throughout lactation, a purified diet containing one of three levels of DHA (0, 1, or 3% of total fatty acids, or 0, 0.4 or 1.2% of total energy). On postnatal day (PND) 3, pups were randomly crossfostered within diet groups to minimize litter effects and culled to 10 per litter. Cerebrums and milk from culled pups stomachs were collected for lipid analysis. The timing of appearance of the ASR was determined between PND 10 through 14 and ABCTs were measured in pups on PND 24 and 31. Pups were sacrificed on PND 31 and cerebrums were removed. In each of two replicated studies, pups in the 1% DHA group weighed significantly less on PND 3 and they gained significantly less weight from PND 3 to 31 compared with pups in the 0 or 3% groups (p<0.01). The auditory studies were not conducted on the 1% DHA group since measures of auditory function are in part a function of somatic growth. The tissue fatty acid data for the 1% DHA group did not show unexpected findings. Higher dietary DHA was reflected in milk and pup cerebrums, and levels of arachidonic acid were inversely related to levels of DHA. In the pups of dams fed diets containing 3% versus 0% DHA, the ASR appeared significantly later (p<0.001) and the ABCTs were longer (p<0.05) on PND 31. CNPase activity levels were not different between the 0 and 3% DHA groups. This study demonstrated that the auditory brainstem response is sensitive for identifying effects of diet on neurodevelopment, and that diets supplemented with high levels of DHA may exert a negative influence on central nervous system development, potentially through effects on myelin. This study suggests the need for further studies of pre- and postnatal long chain polyunsaturated fatty acid dietary supplementation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2002

Hyperekplexia: a treatable neurogenetic disease.

Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype-phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.

Animals↗

PubMed2001

Effects of MDMA (ecstasy) on prepulse inhibition and habituation of startle in humans after pretreatment with citalopram, haloperidol, or ketanserin.

Prepulse inhibition (PPI) of the acoustic startle response is an operational measure of sensorimotor gating that can be assessed in animals and in humans. Serotonin releasers such as MDMA disrupt PPI and reduce startle habituation in rodents. These effects are prevented by pretreatment with selective serotonin uptake inhibitors, indicating that the effect of MDMA on startle plasticity is largely due to carrier-mediated release of serotonin from presynaptic terminals. In contrast, MDMA has been shown to increase PPI in humans. It is unclear, however, whether the MDMA-induced increase in PPI in humans is also dependent on carrier-mediated serotonin release and which postsynaptic receptors are involved. We investigated the effects of three different pretreatments on the MDMA-induced effects on PPI and habituation in humans. Pretreatments were: (1) the highly selective serotonin uptake inhibitor citalopram (40 mg IV) in 16 subjects, (2) the D(2) antagonist haloperidol (1.4 mg IV) in 14 subjects, and (3) the 5-HT(2A/C) antagonist ketanserin (50 mg PO) in 14 subjects. Each of the three studies used a double-blind placebo-controlled design. All healthy volunteers were examined four times at 2-4-week intervals after placebo, pretreatment, MDMA (1.5 mg/kg PO), and pretreatment plus MDMA. MDMA increased PPI. Habituation was not altered by MDMA, although MDMA-induced individual differences on habituation and psychological symptoms were inversely correlated. Citalopram attenuated the MDMA-induced increase in PPI and most of the psychological effects of MDMA. Neither haloperidol nor ketanserin had any effect on PPI increases produced by MDMA, although each partially attenuated some MDMA-induced psychological effects. Results are consistent with the view that MDMA increases PPI of the acoustic startle reflex in humans via release of presynaptic serotonin.

Acoustic Stimulation↗

PubMed2002

Depletion of 5-HT disrupts prepulse inhibition in rats: dependence on the magnitude of depletion, and reversal by a 5-HT precursor.

The 5-HT(1A) agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3(rd) PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy-L-tryptophan reinstated PPI during retest. These data, together with recently published studies, provide strong evidence that pharmacologically-induced depletion of 5-HT disrupts PPI.

5-Hydroxytryptophan↗

PubMed2002

Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia.

Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge- peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.

Animals↗

PubMed1999

Effects of sustained phencyclidine exposure on sensorimotor gating of startle in rats.

Phencyclidine (PCP), a non-competitive NMDA antagonist with actions at multiple other central nervous system receptors, can cause both acute and lasting psychoses in humans, and has also been used in cross-species models of psychosis. Acute exposure to PCP in rats produces behavioral changes, including a loss of prepulse inhibition (PPI) of the startle reflex, which parallels the loss of PPI observed in schizophrenia patients. Sustained exposure to PCP in rats produces neuropathological changes in several limbic regions and prolonged behavioral abnormalities that may parallel neuropsychological deficits in schizophrenia. It is unclear whether sustained PCP exposure will also produce a loss of prepulse inhibition which parallels the decrease observed in schizophrenia patients. In the present study, we examined changes in PPI during and after sustained PCP administration, using 5-day PCP exposure via subcutaneous osmotic minipumps, or 14-day PCP exposure via repeated intraperitoneal injections. In both forms of drug delivery, PPI was disrupted during, but not after, sustained drug exposure. PPI does not appear to be sensitive to neuropathological effects of sustained PCP exposure.

Animals↗

PubMed1998

Impaired sensorimotor gating in patients with non-epileptic seizures.

The aim of the study was to identify possible disturbances of sensorimotor gating and habituation of the eye blink startle response, in patients with non-epileptic seizures (NES). Prepulse inhibition (PPI) of the startle reflex, as an operational measure of sensorimotor gating and habituation was studied in 21 patients with NES and in 22 healthy control subjects. Six NES patients were taking antiepileptic drugs at the time of testing. PPI was significantly impaired in the NES group compared to the control group, with deficits being greater in unmedicated patients. There was a trend for medicated NES patients to show higher PPI than unmedicated patients, but this was not significant. Habituation was intact in both medicated and unmedicated NES patients. It is proposed that deficits of information processing related to sensorimotor gating in patients with NES may be associated with abnormalities within the limbic system-basal ganglia circuitry which has been shown to be the substrate of 'gating' assessed by PPI. It was also found that NES patients had greater psychopathology than the control group when rated by the Traumatic Symptom Checklist (TSC-40). Overall, the anxiety subscale was the only element that was negatively correlated with PPI. It is suggested that anxiety may contribute to impairment of PPI in patients with NES.

Acoustic Stimulation↗

PubMed2003

Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects.

Prepulse inhibition (PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibit the response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number of psychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neural correlates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of (i) healthy subjects and (ii) schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120 ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increased activation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateral inferior parietal lobe/supramarginal gyrus, and with decreased activation in the right cerebellum and left medial occipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenic patients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlie observations of reduced PPI in schizophrenia.

Adult↗

PubMedDate not supplied

Some physiological manifestations of the activity of the gene controlling the predisposition to pendulum-like movements in rats.

The physiological actions of the gene controlling the predisposition to stereotypic hyperkinesia in the form of pendulum-like movements (PM) and, probably, a form of spontaneous nystagmus in rats with albinism are manifest as a number of behavioral characteristics (total motor activity, emotionality, startle reflex intensity, sensitivity to serotonin 5-HT2 receptors as assessed in terms of the intensity of head twitching, and predisposition to cataleptic responses). A number of parameters showed differences between hybrids of gray handling-tolerant rats and carriers of the PM gene on the one hand, and between gray rats and animals not carrying the PM gene on the other. Some behavioral characteristics of rats with PM were closer to those of Wistar rats than to those of rats without PM. This, as well as the high frequency of PM in Wistar rats, indicates that the gene responsible for the manifestations of PM is not pathological, but controls a variety of adaptive features of the nervous system. The interaction between PM and the predisposition to catalepsy is biphasic in nature and is described by a curve in the form of an inverted U.

Animals↗

PubMed1995

The emotion probe. Studies of motivation and attention.

Emotions are action dispositions--states of vigilant readiness that vary widely in reported affect, physiology, and behavior. They are driven, however, by only 2 opponent motivational systems, appetitive and aversive--subcortical circuits that mediate reactions to primary reinforcers. Using a large emotional picture library, reliable affective psychophysiologies are shown, defined by the judged valence (appetitive/pleasant or aversive/unpleasant) and arousal of picture percepts. Picture-evoked affects also modulate responses to independently presented startle probe stimuli. In other words, they potentiate startle reflexes during unpleasant pictures and inhibit them during pleasant pictures, and both effects are augmented by high picture arousal. Implications are elucidated for research in basic emotions, psychopathology, and theories of orienting and defense. Conclusions highlight both the approach's constraints and promising paths for future study.

Affect↗