Changes In Prepulse Inhibition Research Articles

Age-related changes in prepulse inhibition of the startle response.

Acoustic prepulse inhibition of the startle response (PPI) is a phenomenon characterized by the reduction in the startle reflex caused by the presence of weak and brief stimulus before an intense and sudden stimulus (pulse). These phenomena can be observed in several species, but in humans it is commonly measured by the eyeblink using electromyography. PPI works as an operational measure of sensorimotor gating, which is the ability to suppress motor responses for sensory stimulus. Healthy aging is marked by several changes in neural processing, like inhibitory functioning decline. In this line, PPI measure can be a potential biomarker for changes related to the aging process. In this research we aim to investigate if PPI is reduced with aging and if this reduction would be associated with cognitive functioning of older adults. To this aim, we compared PPI levels of older adults (over 60 years old) with PPI levels of young adults (from 18 to 28 years old). With that, we found, significantly lower PPI level (F[1,25] = 7.44 p = 0.01) and lower startle amplitude startle amplitude: (U = 26.000 p = 0.001) in older adults than in young adults. However, we did not find differences in levels of habituation (T = -1.1 p = 0.28) and correlation between PPI and cognition within the sample of healthy older adults. Our results demonstrate that aging is a factor that affects PPI and that it does not seem to predict cognition, however, future studies should explore the potential of using PPI for monitoring cognitive changes associated with techniques such as cognitive training.

A novel allosteric modulator of the cannabinoid CB1 receptor ameliorates hyperdopaminergia endophenotypes in rodent models

The endocannabinoid system (eCBs) encompasses the endocannabinoids, their synthetic and degradative enzymes, and cannabinoid (CB) receptors. The eCBs mediates inhibition of neurotransmitter release and acts as a major homeostatic system. Many aspects of the eCBs are altered in a number of psychiatric disorders including schizophrenia, which is characterized by dysregulation of dopaminergic signaling. The GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice are models of hyperdopaminergia, which display abnormal psychosis-related behaviors, including hyperlocomotion and changes in pre-pulse inhibition (PPI). Here, we investigate the ability of a novel CB1 receptor (CB1R) allosteric modulator, ABM300, to ameliorate these dysregulated behaviors. ABM300 was characterized in vitro (receptor binding, β-arrestin2 recruitment, ERK1/2 phosphorylation, cAMP inhibition) and in vivo (anxiety-like behaviors, cannabimimetic effects, novel environment exploratory behavior, pre-pulse inhibition, conditioned avoidance response) to assess the effects of the compound in dysregulated behaviors within the transgenic models. In vitro, ABM300 increased CB1R agonist binding but acted as an inhibitor of CB1R agonist induced signaling, including β-arrestin2 translocation, ERK phosphorylation and cAMP inhibition. In vivo, ABM300 did not elicit anxiogenic-like or cannabimimetic effects, but it decreased novelty-induced hyperactivity, exaggerated stereotypy, and vertical exploration in both transgenic models of hyperdopaminergia, as well as normalizing PPI in DATKO mice. The data demonstrate for the first time that a CB1R allosteric modulator ameliorates the behavioral deficits in two models of increased dopamine, warranting further investigation as a potential therapeutic target in psychiatry.

The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17β-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2–6 weeks) with 17β-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17β-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17β-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17β-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17β-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

Cell‐type specific expression of GluN2C and GluN2D subunits and their role in schizophrenic phenotypes

IntroductionFunctional deficit in NMDA‐receptors on parvalbumin (PV)‐positive interneurons (PV‐NMDARs) is central to the pathophysiology of schizophrenia. NMDA channel blockers like ketamine and MK‐801 have shown to produce psychosis by inhibiting GluN2C and GluN2D subunits with greater affinity than other subunits. Recent neuroanatomical and electrophysiological studies have reported expression of GluN2D subunit in PV positive interneurons in corticolimbic regions but the precise distribution of GluN2C subunit especially in PV interneurons remains unknown.Hence, the objective of the study was to identify the expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population and to perform a side‐by‐side comparison of the effect of partial and complete ablation of GluN2C and GluN2D subunit on pure C57BL/6N mouse strain.Methods and ResultsImmunohistochemistry was used to determine the heterogenous expression of GluN2C using a novel eGFP reporter mouse model. We found the expression of EGFP (GluN2C) with PV positive neurons in nucleus reticularis of the thalamus, globus pallidus externa and interna, ventral pallidum and substantia nigra. Interestingly, EGFP (GluN2C) showed co‐localization with astrocytic marker in the striatum, cortex, hippocampus and amygdala but not with PV positive neurons. GluN2C was found to be enriched in several thalamic relay nuclei including first order and higher order nuclei. GluN2D knockout mouse exhibited hypo‐locomotion and anxiety‐like behavior in the open field test. We found a significant increase in startle amplitude in GluN2C HET but not GluN2C KO and no change in prepulse inhibition (PPI) in either genotype was observed. Increase in startle response was found for GluN2D heterozygous and GluN2D knockout along with lower prepulse inhibition at some decibels. We also found CIQ, a selective positive allosteric modulator for GluN2C/GluN2D subunit, reversed the MK801 induced impairment in PPI in GluN2C wildtype and heterozygous mice but not in GluN2C KO mice. Furthermore, we observed that GluN2C knockout mice but not GluN2D knockout mice were less sensitive to phencyclidine‐induced hyperlocomotion, a model of psychosis. The cell‐type specific expression of both GluN2C and GluN2D subunit may provide more insights into schizophrenia‐like behaviors. Hence, we will confirm psychotic and sensorimotor deficits by selectively deleting GluN2D subunit from PV‐positive interneurons and GluN2C subunit from astrocytes using Cre‐lox strategy.ConclusionTogether, these results identify the unique expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population. It also demonstrates the preferential involvement of GluN2C‐ containing receptors in phencyclidine‐induced hyperlocomotion and that facilitation of GluN2C subunit may reverse the schizophrenic phenotypes.Support or Funding InformationR21 NS104705This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Behavior of Adult 5-HT1A Receptor Knockout Mice Exposed to Stress During Prenatal Development

Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the offspring. An understanding of the mechanisms responsible for mediating these effects is essential for devising therapeutic interventions. Here, we examined whether serotonin 1A receptor (5-HT1AR) mediates the effects of maternal stress on the behavioral outcomes of the offspring as adults. Heterozygous (HET) mouse dams were bred with HET males and were randomly assigned to stress or control groups. Pregnant dams in the stress group were exposed to a regime of chronic unpredictable stress from embryonic day 7 to 18. At two months of age, groups of male and female wildtype (WT), HET, and knockout (KO) offspring underwent a comprehensive behavioral test battery that included tests of social behavior, memory, aggression, anxiety, sensorimotor information processing, and exploratory and risk assessment behaviors. Independent of genotype, prenatal stress resulted in a change in locomotor activity and fear memory in male mice and a change in prepulse inhibition in female animals. 5-HT1AR KO affected anxiety in male mice, and fear memory and prepulse inhibition in female mice. 5-HT1AR genotype moderated the effects of maternal prenatal stress exposure on social behavior of male offspring and on activity levels of female offspring. Our findings indicate that 5-HT1A receptor availability can affect outcomes of the offspring resulting from maternal prenatal stress exposure, and that these effects are sex-specific.

Standardized extract of Ficus platyphylla reverses apomorphine-induced changes in prepulse inhibition and locomotor activity in rats

Preparations of Ficus platyphylla are used in Nigeria’s folk medicine to manage a plethora of diseases including, insomnia, psychoses, depression, epilepsy, pain and inflammation. In this study, we examined the effects of the standardized methanol extract of F. platyphylla stem bark (FP) on apomorphine-induced changes in prepulse inhibition and locomotor activity in rats, as well as on the retrieval of a conditioned reaction in one-way active avoidance in mice. FP did not affect basal prepulse inhibition, but significantly reduced locomotor activity. The apomorphine-induced prepulse inhibition deficit and hyperactivity were significantly reversed by co-administration of clozapine or FP. Furthermore, FP inhibited the retrieval of a conditioned avoidance reaction. Our results revealed that FP contains psychoactive ingredients with neuroleptic-like properties, thus supporting the isolation and development of the biologically active components of this medicinal plant as antipsychotic agents.

Deletion of α-neurexin II results in autism-related behaviors in mice.

Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.

Effect of alarm therapy on conditioning of central reflex control in nocturnal enuresis: pilot study on changes in prepulse inhibition (PPI)

Alarm therapy is a long-established first-line therapy for nocturnal enuresis (NE). Desamino-arginine vasopressin (dDAVP) as alternative first-line therapy was shown to increase the prepulse inhibition (PPI) of startle reflexes, thus supporting the hypothesis of a maturational delay of reflex inhibition in NE. Effects of alarm therapy on PPI have not yet been investigated. The PPI of startle reflexes was measured in 20 children with NE (13 boys, 7 girls, median age 8.5 years, range 5-13) before and after at least 6 weeks of alarm treatment and compared with repeated PPI measurements in 11 healthy controls (7 boys, 4 girls, median age 8 years, range 6-13). In the NE patients, PPI increased from a median baseline of 20-46% under alarm therapy (p = 0.005), with a reduction from a median of 7 to 2 wet nights per week (p = 0.002). The controls showed no difference in PPI (52% median at first, 40% at second measurement, p = 0.966). The increase of PPI trough alarm therapy was comparable with that under dDAVP, suggesting an analogous method of action and explaining the alternative or synergistic effect of both therapies. In addition, it further substantiates the hypothesis of a maturational delay of reflex control in NE.

Do social statuses affect the startle reflex in male mice?

Usual housing conditions lead to dominance hierarchy forming between male mice. The situation produces physiological and behavioural differences between dominants and subordinates. The goal of the present study was to assess stress responses, and possible changes in prepulse inhibition (PPI) of the startle reflex in dominant and subordinate male mice. Three weeks of daily social interactions led to stable aggressive dominance in 11 pairs of male NMRI mice. Stress levels were assessed by measuring faecal corticosterone metabolites (FCM), a non-invasive technique for monitoring hormonal changes in response to specific situations, with repeated sampling of each animal. The analysis of FCM levels showed greater stress in subordinate males at the beginning of the experiment, as the hierarchy was being established, but by the end of the experiment, FCM levels were reduced and similar in both dominants and subordinates. No significant differences were found in the startle response or PPI.

Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

N-methyl-D-aspartate receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in humans and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits, and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast-firing interneurons. These neurons are critical for gamma oscillations, indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n = 5; NVP-AAM077, n = 18), NR2B-selective (ifenprodil, n = 6; threo-ifenprodil, n = 4; Ro25-6985, n = 13), and NR2C/D-selective (n = 8) antagonists, along with vehicle and nonselective NMDA-R antagonists (ketamine, n = 10; MK801, n = 12). Changes in prepulse inhibition of startle was tested after MK-801 (n = 6), NVP-AAM077, and Ro-6891 (n = 5) injection. Strong increase in gamma power was induced by nonselective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low-frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects. Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.

Facilitated acquisition of the classically conditioned eyeblink response in females is augmented in those taking oral contraceptives

Sex differences in attentional processing and new motor learning remain controversial, and are complicated by the influence of endogenous and exogenous gonadal hormones. Facilitated acquisition of a classically conditioned eyeblink response in oral contraceptive-using women has been reported, as have menstrual cycle-dependent changes in pre-pulse inhibition (PPI). The current study sought to replicate and extend these findings by comparing acquisition of the conditioned eyeblink response and PPI in women currently taking oral contraceptives (OCs), women not taking OCs, as well as men. Women were assigned to participate either during their follicular or luteal menstrual cycle phase. Acquisition was assessed in a two-tone discrimination delay paradigm (500-ms conditional stimulus (CS); 100-ms airpuff unconditional stimulus (US)). PPI was lower in males and OC-users depending on stimulus intensity. Consistent with early classical conditioning research, females acquired an eyeblink conditioned response faster than males. Faster acquisition was associated with larger unconditional responses. Women taking OCs demonstrated accelerated conditioned response acquisition compared to women not taking OCs and males although unconditional responses were comparable to males. Facilitated acquisition of new motor learning in OC-users was replicated in a college-aged population of women and was not secondary to enhanced reactivity to sensory stimuli.

Pramipexole effects on startle gating in rats and normal men

BackgroundDopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague–Dawley rats.Materials and MethodsAcoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague–Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans.ResultsPramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10–20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude.ConclusionThe preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating.

Mice deficient in the alpha subunit of Gz show changes in pre-pulse inhibition, anxiety and responses to 5-HT1A receptor stimulation, which are strongly dependent on the genetic background

G(z), a member of the G(i) G protein family, is involved in the coupling of dopaminergic and serotonergic receptors. In the present study, we investigated behaviour of mice deficient in the alpha subunit of G(z) and focused on pre-pulse inhibition (PPI) and anxiety-like responses and the role of serotonin-1A (5-HT(1A)) receptors. We compared male and female wild-type and knock-out mice on either a C57Bl/6 or Balb/c background. We used automated startle boxes to assess startle and PPI and elevated plus maze to assess anxiety-like behaviours. Balb/c mice showed higher baseline PPI than C57Bl/6 mice, and there was no difference between the genotypes. The 5-HT(1A) receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), had no effect on PPI in C57Bl/6 mice but markedly increased PPI in Balb/c mice, with the effect being attenuated in Galpha(z) knock-outs. On the elevated plus maze, there was little effect of the knock-out or 8-OH-DPAT in C57Bl/6 mice, whereas in Balb/c mice, Galpha(z) knock-outs showed a phenotype of high levels of anxiety-like behaviour. 8-OH-DPAT was anxiogenic in Balb/c mice, but this effect was attenuated in Galpha(z) knock-outs. 5-HT(1A) receptors couple to G(z). In a strictly background strain-dependent manner, Galpha(z) knock-out mice display high levels of anxiety-like behaviour and are less sensitive to the action of 8-OH-DPAT. Balb/c mice show much more clear effects of the Galpha(z) knock-out than C57Bl/6 mice, which are often considered the standard background strain for genetic modifications. Therefore, our results suggest caution when studying the behavioural effects of genetic modifications only in C57Bl/6 mice.

Effects of haloperidol and clozapine on sensorimotor gating deficits induced by 5-hydroxytryptamine depletion in the brain.

Evidence is increasing for a role of brain 5-hydroxytryptamine (5-HT) systems in schizophrenia. We previously showed that brain 5-HT depletion causes disruption of prepulse inhibition, a measure of sensorimotor gating that is deficient in schizophrenia. Antipsychotic treatment has been reported to reverse these deficits in patients with schizophrenia. The present study was designed to investigate the ability of antipsychotic drugs to reverse prepulse inhibition deficits caused by lesions of the brain 5-HT system in rats. In male Sprague-Dawley rats, selected parts of the brain 5-HT systems were lesioned by micro-injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN). The effects of antipsychotic drugs on lesion-induced changes in prepulse inhibition were examined 2 weeks after the surgery. There was significant disruption of prepulse inhibition in the MRN-lesioned group compared to sham-operated controls. This deficiency in prepulse inhibition was restored by clozapine (1 and 5 mg kg(-1)) treatment, and by treatment with a relatively high dose of haloperidol (0.25 mg kg(-1)). There was no significant effect of the DRN lesions on prepulse inhibition compared with sham-operated controls. These results indicate that 5-HT depletion in MRN-innervated brain structures leads to disruption of prepulse inhibition. Treatment with both antipsychotic drugs, haloperidol and clozapine, significantly increased prepulse inhibition in these animals back to the level seen in sham-operated controls. The present findings highlight the importance of the 5-HT systems in cognitive models of schizophrenia.

P.3.046 Change in prepulse inhibition after switching schizophrenic patients from zuclopenthixol to long-acting injectable risperidone

La seudoobstrucción crónica del colon se caracteriza por una dilatación crónica del colon de causa no mecánica. Es una entidad poco frecuente que puede ser desencadenada por múltiples causas, entre ellas las farmacológicas. Presentamos el caso de una paciente psiquiátrica de 74 años que tras recibir tratamiento con un neuroléptico (decanoato de zuclopentixol) presentó distensión abdominal, diarrea, alteraciones electrolíticas intensas e importante dilatación radiográfica del colon. Tras descartar obstrucción orgánica y otras causas, el diagnóstico final fue de seudoobstrucción colónica crónica secundaria al uso de neurolépticos. Se observó discreta mejoría sintomática con cisaprida 20 mg/8 h, persistiendo la dilatación de colon de forma permanente.Colonic pseudo-obstruction is characterized by non-mechanical chronic colonic dilatation. It is an infrequent entity that can be provoked by multiple causes, among them pharmacological. We present the case of a 74-year-old female psychiatric patient who presented abdominal bloating, diarrhea, intense electrolytic alterations and marked radiographic colonic dilatation after treatment with a neuroleptic (zuclopenthixol decanoate). Organic obstruction and other causes were ruled out and the final diagnosis was chronic colonic pseudo-obstruction secondary to the use of neuroleptics. Cisapride (20 mg/8 h) produced a slight improvement in symptoms but colonic dilatation was permanent.

Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition

Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP. The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus. Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10(-4) mol/l and 10(-3) mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, L: -NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP. These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.

Craving and startle modification during in vivo exposure to food cues

Rationale and objectives. Food craving and reactivity to food cues are related to food intake. Research has shown that both startle magnitude and prepulse inhibition of startle may be useful indices of cue reactivity and drug craving. The goal of this study was to assess the utility of these paradigms for the study of food craving in food-deprived participants. Methods. Twenty-nine non-smoking, food-deprived undergraduate participants were exposed to a counterbalanced series of food, cigarette, and neutral cues. During each 4.5-min cue, nine startle probes (102-dB white noise) were presented, and a prepulse (20-ms noise 8 dB above background) preceded 2/3 of the probes by 60 or 120 ms. Subjects were divided into those high and low in food-craving on the basis of subjective craving to food cues. Responses to food cues were compared to smoking cues to control for attention and arousal. Results. Both probe-alone startle magnitude and percent prepulse inhibition were significantly reduced during the food cue compared to the smoking cue among high food cravers, but not low food cravers. These processes seemed to be independent, as cue-induced changes in prepulse inhibition were uncorrelated with cue effects on probe-alone startle magnitude. Conclusions. Both probe-alone startle magnitude and prepulse inhibition are sensitive to cue-induced craving for food, but appear to assess separate processes. Startle methodologies may prove useful in understanding basic processes that regulate food intake.

Long-term effects of fluoxetine or vehicle administration during pregnancy on behavioral outcomes in guinea pig offspring.

Assessment of the benefits versus risks associated with antidepressant use during pregnancy must include an analysis of possible drug effects on fetal development. Human studies indicate that prenatal fluoxetine exposure is associated with adverse neonatal outcomes. Animal modeling may provide useful information concerning possible long-term effects of prenatal fluoxetine exposure. Limitations in previous such studies using rat models may be overcome using a guinea pig model in which fluoxetine is delivered by osmotic pump throughout pregnancy. Initial experiments measured the half-life of fluoxetine and dosing required to achieve human therapeutic blood levels in the guinea pig. In subsequent experiments, guinea pigs received fluoxetine or vehicle via osmotic pump or no treatment throughout pregnancy. Outcome measures included: pregnancy characteristics, weight gain, and, in offspring as adults, pain threshold, acoustic startle responses and prepulse inhibition. There was no effect of treatment group on gestation length, number of live-births or still-births, maternal or offspring weight gain, and acoustic startle responses. In adult offspring, pain threshold was decreased by vehicle treatment during gestation. Prenatal fluoxetine increased pain threshold, relative to vehicle controls. Prepulse inhibition of startle was increased in adult offspring treated prenatally with either vehicle or fluoxetine compared to no treatment. The guinea pig provides a practicable and clinically relevant model of prenatal fluoxetine exposure. Adult guinea pigs exposed to fluoxetine prenatally showed increased thermal pain thresholds but no change in prepulse inhibition, indicating selective long-term effects of prenatal fluoxetine on serotonin-modulated behaviors. Further studies on long-term effects of prenatal fluoxetine on nociception are warranted.

Prenatal protein deprivation in rats induces changes in prepulse inhibition and NMDA receptor binding

Epidemiological studies suggest that prenatal malnutrition increases the risk of developing schizophrenia. Animal models indicate that prenatal protein deprivation (PPD) affects many aspects of adult brain function. We tested the hypothesis that PPD in rats would alter prepulse inhibition (PPI), which is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Additionally, we examined dopaminergic and glutaminergic receptor binding in the striatum and hippocampus, which have been suggested to play a role in the etiology of schizophrenia. Rat dams were fed normal (25%) or low (6%) protein diets beginning 5 weeks prior to, and throughout pregnancy. The pups were tested at postnatal days (PND) 35 and 56 for PPI. Striatal and hippocampal NMDA receptor, and striatal dopamine receptor binding were quantified post-mortem in a subset of these rats. Female rats exposed to PPD had reduced levels of PPI at PND 56, but not PND 35, suggesting the emergence of a sensorimotor gating deficit in early adulthood. Striatal NMDA receptor binding was increased in PPD females. A decrease in initial startle response (SR) was also observed in all PPD rats relative to control rats. These results suggest that PPD causes age- and sex-dependent decreases in PPI and increases in NMDA receptor binding. This animal model may be useful for the investigation of neurodevelopmental changes that are associated with schizophrenia in humans.

Effects of acute tryptophan depletion on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effect of acute tryptophan depletion on prepulse inhibition of these responses. Thirteen males (21-52 years) participated in two sessions separated by 7 days, in which they ingested a drink containing a mixture of amino-acids, which either included (+ TP) or did not include (- TP) tryptophan, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 6 h after ingestion of the mixture. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Plasma tryptophan levels were measured from blood samples taken before and 7 h after each treatment. Under the + TP condition, both the EMG response and the N1/P2 complex showed > 60% prepulse inhibition. The - TP condition was associated with (i) significant suppression of prepulse inhibition of the EMG response, with no significant change in response amplitude and (ii) reduction of the amplitude of the N1/P2 potential, with no significant change in prepulse inhibition of this response. Tryptophan levels rose by 90+/-15% under the + TP condition and fell by 81+/-3% under the - TP condition. The suppression of prepulse inhibition of the acoustic startle response under the - TP condition suggests that central 5-hydroxytryptaminergic mechanisms may be involved in regulating prepulse inhibition of this response. The lack of effect of tryptophan depletion on prepulse inhibition of the N1/P2 potential suggests that different mechanisms are involved in prepulse inhibition of the startle response and the N1/P2 complex.