D-amphetamine and antipsychotic drug effects on latent inhibition in mice lacking dopamine D2 receptors.

Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (Drd2-/-), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes.

Appetitive overshadowing is disrupted by systemic amphetamine but not by electrolytic lesions to the nucleus accumbens shell.

There is evidence that the indirect dopamine (DA) agonist amphetamine (AMP) can disrupt selective learning in an aversive overshadowing task, consistent with a role for the DA system in this form of salience manipulation. In the following experiments we assessed in the male Wistar rat: (1) whether amphetamine disruption of overshadowing extends to an appetitively motivated overshadowing task; and (2) whether selective electrolytic lesions to the n.acc (shell versus core subfields) disrupt appetitively motivated overshadowing. The experiments used sucrose reward pellets as the unconditioned stimulus (UCS). In each case, a conditioned stimulus (CS, light) was either conditioned alone or in compound together with a more intense CS (noise or tone). The presence of overshadowing was demonstrated as reduced conditioning to the light when it had been previously conditioned in compound compared to when it had been conditioned alone. It was predicted that AMP and lesions to the n.acc shell would disrupt overshadowing. AMP was found to abolish overshadowing at 0.5 mg/kg, but not at 1 mg/kg. Contrary to prediction, the shell lesioned animals did not differ from shams. The results of Experiment 1 add to the evidence that the DA system can moderate salience processing of weaker predictors, also in cases where CS salience is manipulated directly via the physical intensities of the stimuli, as here. However, in terms of the brain structures involved, Experiment 2 suggests that, overshadowing is moderated by projections of the DA system without n.acc.

Abnormal prediction error is associated with negative and depressive symptoms in schizophrenia.

Prediction error in learning is where learning occurs to the degree to which an outcome consequent to a stimulus is surprising. It has been suggested that abnormal use of prediction error in schizophrenia may underlie the formation of inappropriate associations giving rise to psychotic symptoms. Kamin blocking is a phenomenon that demonstrates prediction error. Kamin blocking is shown where prior learning about a stimulus A paired with an outcome retards learning about a stimulus B when presented subsequently as part of a stimulus compound AB paired with the same outcome. Prior studies have indicated reduced Kamin blocking in schizophrenia specifically in non-paranoid patients. It is however unclear how reduced Kamin blocking is associated with specific symptoms in schizophrenia. The present study examined Kamin blocking performance in a high functioning community-based sample of 34 people with schizophrenia and 48 controls closely matched for pre-morbid IQ. In these patients we measured Kamin blocking and symptoms using positive and negative symptom scales (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS). Results confirmed that people with schizophrenia had significantly reduced Kamin blocking. Kamin blocking performance was associated with negative and depressive symptoms. These associations with symptoms were crucially not found with baseline associative learning or unblocking measures, confirming specificity to the Kamin blocking effect. These data demonstrate first that abnormal prediction error as assessed in the Kamin blocking task is associated with negative and depressive symptoms rather than positive symptoms in high functioning schizophrenia patients. Second this strongly suggests that reduced Kamin blocking may be useful as an animal model of specific relevance to negative and depressive symptoms in schizophrenia.

Measuring memory impairment in community-based patients with schizophrenia. Case-control study.

BACKGROUND: The majority of memory impairment studies in schizophrenia are cohort studies using laboratory-based tests, which make it difficult to estimate the true extent and relevance of memory impairment in patients with schizophrenia in the community. AIMS: To examine the extent of memory impairment in community-based patients with schizophrenia using a clinically relevant test. METHOD: All patients with schizophrenia (n=190) in one catchment area were identified, of whom 133 were potentially eligible for the study; 73 patients volunteered to take part. They were assessed using the Rivermead Behavioural Memory Test (RBMT), the National Adult Reading Test, the Positive and Negative Syndrome Scale, the Health of the Nation Outcome Scales and the Scales and the Office for National Statistics Classification of Occupation. Their performance on the memory test was compared with that of matched controls (n=71). RESULTS: Patients as a group performed significantly worse (P<0.001) than controls on the RBMT. Using the RBMT normative scores, 81% of patients were found to have impaired memory compared with 28% of controls. CONCLUSIONS: Using a clinically relevant test, the majority of community-based patients with schizophrenia may have memory impairment.

The childhood experience of care and abuse questionnaire (CECA.Q): validation in a community series.

BACKGROUND: Childhood neglect and abuse, as measured by retrospective interview, is highly predictive of psychiatric disorder in adult life and has an important role in aetiological models. However, such measures are labour-intensive, costly, and thus restricted to relatively modest sample sizes. A compact self-report assessment of childhood experience is invaluable for research screening purposes and large-scale survey investigation. METHOD: A self-report questionnaire (CECA.Q) was developed to mirror an existing validated interview measure: the childhood experience of care and abuse (CECA). The questionnaire assessed lack of parental care (neglect and antipathy), parental physical abuse, and sexual abuse from any adult before age 17. A high-risk series of 179 London women were interviewed using the CECA together with the PSE psychiatric assessment, and completed the CECA.Q at later follow-up. Repeat CECA.Qs were returned for 111 women and 99 women additionally completed the parental bonding instrument (PBI; Parker, Tupling, & Brown, 1979). RESULTS: Satisfactory internal scale consistency was achieved on the CECA.Q for antipathy (alpha = .81) and neglect (alpha = .80) scales. There was satisfactory test-retest for both care and abuse scales. Significant associations were found between CECA.Q scales and the parallel interview scales with cut-offs determined for high sensitivity and specificity. CECA.Q neglect and antipathy scales were also significantly related to PBI parental care. CECA.Q scales were significantly related to lifetime history of depression. Optimal cut-off scores revealed significant odds ratios (average of 2) for individual scales and depression. When indices were compiled to reflect peak severity of each type of adversity across perpetrator, odds-ratios increased (average 3). A dose-response effect was evident with the number of types of neglect/abuse and rate of lifetime depression. CONCLUSION: The CECA.Q shows satisfactory reliability and validity as a self-report measure for adverse childhood experience. The merits of having parallel questionnaire and interview instruments for both research and clinical work are discussed.

Enhancement of latent inhibition by two 5-HT2A receptor antagonists only when given at both pre-exposure and conditioning.

RATIONALE: Clozapine-like atypical antipsychotic drugs, such as olanzapine, risperidone and sertindole, bind most strongly to 5-HT(2A) receptors, which may contribute to their antipsychotic effects. Antipsychotic drugs, such as clozapine and haloperidol, have been found to enhance latent inhibition (LI) in humans and rats. LI is a process of learning to ignore irrelevant stimuli that is disrupted in acute, positive-symptom schizophrenia, and can be modelled in animals. OBJECTIVES: The aim of this study was to determine the effects of two selective 5-HT(2A) receptor antagonists, SR 46,349B and ICI 169,369, on LI, as a test of their antipsychotic potential. METHODS: Doses of the 5-HT(2A) receptor antagonists that were sufficient for receptor blockade were determined in 5-HT behavioural syndrome tests. SR 46,349B and ICI 169,369 were then tested for enhancement of LI and reversal of amphetamine-induced attenuation of LI in a conditioned suppression paradigm. RESULTS: SR 46,349B (0.6-2.4 mg kg(-1) i.p.) and ICI 169,369 (10-40 mg kg(-1) i.p.) antagonised 5-hydroxytryptophan (5-HTP)-induced head twitches and wet dog shakes, which are mediated by 5-HT(2A) receptors, but had no effect on mCPP-induced hypolocomotion, which is mediated by 5-HT(2C) receptors. Neither SR 46,349B (1.2 mg kg(-1) i.p.) nor ICI 169,369 (40 mg kg(-1) i.p) affected 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT)-induced forepaw treading, suggesting that they were not in vivo 5-HT(1A) receptor antagonists. SR 46,349B (2.4 mg kg(-1) i.p.) and ICI 169,369 (40 mg kg(-1) i.p.) enhanced LI when given at both the pre-exposure and conditioning stages of the paradigm, but not when given at either pre-exposure or conditioning only. Both drugs also reversed the disruption of LI induced by D-amphetamine (1 mg kg(-1) i.p.). CONCLUSIONS: The profile of SR 46,349B and ICI 169,369 in LI differs from that of clozapine and haloperidol in LI, which both enhance LI when given only at the conditioning stage of the paradigm.

The Vulnerable Attachment Style Questionnaire (VASQ): an interview-based measure of attachment styles that predict depressive disorder.

BACKGROUND: The Vulnerable Attachment Style Questionnaire (VASQ) was developed to provide a brief self-report tool to assess adult attachment style in relation to depression and validated against an existing investigator-based interview (Attachment Style Interview--ASI). This paper describes the development and scoring of the VASQ and its relationship to poor support and major depression. METHOD: Items for the VASQ reflected behaviours, emotions and attitudes relating to attachment relationship style, drawn directly from the ASI. The VASQ was validated against the ASI for 262 community-based subjects. Test-retest was determined on 38 subjects. RESULTS: Factor analysis derived two factors, labelled 'insecurity' and 'proximity-seeking'. The VASQ insecurity dimension had highest mean scores for those with interview-based Angry-dismissive and Fearful styles and was significantly correlated with degree of interview-based insecurity. The proximity-seeking VASQ scores had highest mean for those with Enmeshed interview attachment style and was uncorrelated with ASI insecurity. VASQ scores were highly correlated with a well-known self-report measure of insecure attachment (Relationship Questionnaire) and text-retest reliability of the VASQ was satisfactory. The total VASQ score and the insecurity subscale proved highly related to poor support and to depressive disorder. This was not the case for the proximity-seeking subscale. CONCLUSION: The VASQ is a brief self-report measure that distinguishes individuals with attachment styles vulnerable for depressive disorder. The use of the measure for screening in research and clinical contexts is discussed.

The effect of amphetamine on Kamin blocking and overshadowing.

Schizophrenic patients show deficits on stimulus salience tasks such as latent inhibition and blocking, which measure the ability to disregard irrelevant stimuli. Amphetamine-treated animals show similar deficits in analogous tasks, thereby providing a model of the stimulus-selection deficits observed in schizophrenia. In two experiments, the effect of the indirect dopamine (DA) agonist D-amphetamine sulphate (1.0 mg/kg, i.p.) on Kamin blocking and overshadowing were examined and compared, in the rat, using the conditioned lick suppression procedure. The aim was to provide some insight into the behavioural and pharmacological mechanisms underlying amphetamine effects in both paradigms. In experiment 1, it was shown that amphetamine selectively disrupted Kamin blocking, when given either at stage 2 alone, or at both stages of the task. In experiment 2, amphetamine treatment significantly abolished Kamin blocking and overshadowing, when administered prior to compound conditioning in both tasks. These data suggest that dopamine may play a critical role in mediating performance in tasks measuring stimulus salience processes. The results are discussed in the framework of the role of DA in stimulus-selection performance.

An investigation into age and gender differences in human Kamin blocking, using a computerized task.

Kamin blocking (KB) is a function within selective attention found to be deficient in schizophrenia. Disparate results in the KB literature, specifically regarding age and gender effects, suggest that we do not yet have a comprehensive understanding of KB in normal human development. The aim of this study is to provide a thorough investigation into the development and occurrence of KB in a normal population. The design replicated and extended a study by Oades, Roepcke, and Schepker (1996). KB is measured using a computer game called the "mouse in the house." Participants must use a joystick to move an icon around a set floor plan, to find a hidden location. These locations are cued by sets of colors, which denote the KB paradigm. Data was collected on 222 participants across 5 age groups (6-8 years; 9-12 years; 13-17 years; 18-21 years; 22+ years). Comparisons were carried out for age and gender effects. KB was observed in all age groups, but there was no significant effect of age on mean KB score. A measure of frequency of participants who showed KB did show a significant increase with age. A significant difference was found between males and females, with females having higher KB score than males. The gender difference was present from the earliest age tested. Our findings suggest significant age and gender differences in the manifestation of selective attention and information processing abilities. This has implications for understanding the development of attention and the understanding of the age and gender dependence of the development of schizophrenia.

Reduced Kamin blocking in non paranoid schizophrenia: associations with schizotypy.

Kamin blocking (KB) is an attentional phenomenon whereby prior learning about a stimulus (A) retards learning about a new stimulus (B) when later presented in compound (AB) with the original stimulus A. KB has been shown to be reduced in patients with schizophrenia. Using Oades' KB paradigm it has been suggested that drug treatment may influence the expression of KB abnormalities in patients. It is therefore unclear whether Reduced KB are due to drug treatment or to the illness itself. One experimental approach that circumvents drug treatment confounds is to study schizotypal traits in healthy volunteers. In the present study we investigated KB using the Oades paradigm in 27 healthy volunteers and 21 schizophrenic patients. We additionally investigated the relationship between KB performance and measures of schizotypal traits and a number of factors relevant to the experience of schizophrenia using the O-LIFE questionnaire. Our results indicate first a clear negative relationship between general schizotypy and more specifically, Unusual experiences (UNEX) and cognitive disorganisation (COGDIS) and KB performance. This relationship was qualitatively and quantitatively similar in both healthy volunteers and schizophrenic patients. Second we have independently replicated reduced KB in non-paranoid patients and no change in KB in paranoid patients using the Oades KB task. This study also confirms that reduced KB in non-paranoid patients is confined to early test trials (3-4) while the negative relationships with schizotypy scales UNEX and COGDIS that we have found are also confined to these early test trials confirming the psychological relevance of this specificity.

Latent inhibition is attenuated by noise and partially restored by a 5-HT2A receptor antagonist.

Latent inhibition (LI) is a model of attention, which is a cognitive process that can be modulated by stressors such as chronic intermittent broadband noise, e.g. caused by building work, which is particularly stressful to rats. The aim of this study was to analyse the effect of chronic noise stress, caused by a building project, on LI, and its interaction with SR 46,349B, a 5-HT2A receptor antagonist. Control groups from LI experiments conducted during periods of chronic intermittent noise were compared with control groups from LI experiments conducted in normal quiet conditions. The interaction of SR 46,349B with the effects of chronic noise stress was then tested. Chronic intermittent noise attenuated LI, an effect which was partially reversed by SR 46,349B, 2.4 mg/kg i.p. Attenuation of LI by chronic intermittent noise and reversal of this effect by SR 46,349B support suggestions that stress can modulate attention and that 5-HT2A receptors are involved in mediating the effects of chronic stress.

Childhood adversity, parental vulnerability and disorder: examining inter-generational transmission of risk.

BACKGROUND: An investigation of intergenerational factors associated with psychiatric disorder in late adolescence/early adulthood was undertaken to differentiate influences from maternal disorder, maternal poor psychosocial functioning and poor parenting, on offspring. METHOD: The sample comprised an intensively studied series of 276 mother-offspring pairs in a relatively deprived inner-city London area with high rates of lone parenthood and socio-economic disadvantage. The paired sample was collected over two time periods: first a consecutively screened series of mothers and offspring in 1985-90 (n = 172 pairs) and second a 'vulnerable' series of mothers and offspring in 1995-99 (n = 104 pairs). The vulnerable mothers were selected for poor interpersonal functioning and/or low self-esteem and the consecutive series were used for comparison. Rates of childhood adversity and disorder in the offspring were examined in the two groups. Maternal characteristics including psychosocial vulnerability and depression were then examined in relation to risk transmission. RESULTS: Offspring of vulnerable mothers had a fourfold higher rate of yearly disorder than those in the comparison series (43% vs. 11%, p < .001). They were twice as likely as those in the comparison series to have experienced childhood adversity comprising either severe neglect, physical or sexual abuse before age 17. Physical abuse, in particular, perpetrated either by mother or father/surrogate father was significantly raised in the vulnerable group. Analysis of the combined series showed that maternal vulnerability and neglect/abuse of offspring provided the best model for offspring disorder. Maternal history of depression had no direct effect on offspring disorder; its effects were entirely mediated by offspring neglect/abuse. Maternal childhood adversity also had no direct effect. CONCLUSIONS: Results are discussed in relation to psychosocial models of risk transmission for disorder. Maternal poor psychosocial functioning needs to be identified as a factor requiring intervention in order to stem escalation of risk across generations.

Evidence for dopamine D(1) receptor involvement in the stimulus selection task: overshadowing in the rat.

RATIONALE: A number of lines of evidence suggest that dopamine might play a role in stimulus selection, the process whereby specific cues are selected to guide action. OBJECTIVES: In order further to define the potential role for dopamine in stimulus selection, the present series of studies examined whether dopaminergic drugs modulate overshadowing, a paradigm that involves stimulus selection in rats. Overshadowing is where preferential learning occurs to one (usually the more salient) element of a stimulus compound. METHODS: Overshadowing was measured in rats using a thirst motivated conditioned emotional response paradigm (CER). Two simultaneously presented stimuli (light and tone) were paired with an aversive unconditioned stimulus (mild footshock); overshadowing is observed when learning to the less salient stimulus is weaker than learning to the same stimulus when it is conditioned alone. RESULTS: d-Amphetamine sulphate (1 mg/kg, IP) was found selectively to disrupt overshadowing, without affecting the CER in control animals. The dopamine (DA) D(2) receptor antagonists, haloperidol (0.2 mg/kg, IP) or raclopride (0.5 mg/kg, IP), failed to reverse amphetamine-induced disruption of overshadowing. In contrast, the selective DA D(1) antagonist SCH 23390 (0.05 mg/kg, IP) reversed amphetamine-induced disruption of overshadowing. The partial DA D(1) agonist SKF 38393 (5 mg/kg, IP) was found to abolish overshadowing when given alone. CONCLUSION: These data indicate a modulatory role for the DA D(1) receptor in the expression of stimulus selection and suggest that the DA D(1) receptor might play a role in salience allocation aspects of learning.

Adult attachment style. I: Its relationship to clinical depression.

BACKGROUND: Although there are an increasing number of studies showing an association of adult attachment style to depressive disorder, such studies have rarely utilised epidemiological approaches with large community-based series and have relied heavily on brief self-report measurement of both attachment style and symptoms. The result is a wide inconsistency in the type of insecure style shown to relate to disorder. The present study examined adult attachment style in a high-risk community sample of women in relation to clinical depression. It utilised an interview measure of adult attachment which allowed for an assessment of both type of attachment style and the degree of insecurity of attachment. A companion paper examines its relationship with other depressive-vulnerability (Bifulco et al. 2002). METHOD: Two hundred and twenty-two high-risk and 80 comparison women were selected from questionnaire screenings of London GP patient lists and intensively interviewed. A global scale of attachment style based on supportive relationships (with partner and very close others) together with attitudes to support-seeking, derived the four styles paralleling those from self-report attachment assessments (Secure, Enmeshed, Fearful, Avoidant). In order to additionally reflect hostility in the scheme, the Avoidant category was subdivided into 'Angry-dismissive' and 'Withdrawn'. The degree to which attitudes and behaviour within such styles were dysfunctional ('non-standard') was also assessed. Attachment style was examined in relation to clinical depression in a 12-month period. For a third of the series this was examined prospectively to new onset of disorder. RESULTS: The presence of any insecure style was significantly related to 12-month depression. However, when controls were made for depressive symptomatology at interview, only the 'non-standard' levels of Enmeshed, Fearful or Angry-dismissive styles related to disorder. Withdrawn-avoidance was not significantly related to disorder. CONCLUSION: The relationship of attachment style to clinical depression is increased by differentiating the degree of insecurity of style and differentiating hostile and non-hostile avoidance.

Adult attachment style. II: Its relationship to psychosocial depressive-vulnerability.

BACKGROUND: A range of studies show adult attachment style is associated with depressive-vulnerability factors such as low self-esteem, poor support and childhood adversity. However, there is wide inconsistency shown in the type of insecure style most highly associated. Few studies have examined attachment style in relation to clinical depression together with a range of such factors in epidemiological series. The present study uses an interview measure of adult attachment which differentiates type of attachment style and degree of insecurity of attachment, to see: (a) if it adds to other vulnerability in predicting depression and (b) if there is specificity of style to type of vulnerability. METHOD: Two hundred and twenty-two high-risk and 80 comparison women were selected from questionnaire screenings of London GP patient lists and intensively interviewed. The Attachment Style Interview (ASI) differentiated five styles (Enmeshed, Fearful, Angry-dismissive, Withdrawn and Standard) as well as the degree to which attitudes and behaviour within such styles were dysfunctional ('non-standard'). Attachment style was examined in relation to low self-esteem, support and childhood experience of neglect or abuse, and all of these examined in relation to clinical depression in a 12-month period. RESULTS: The presence of any 'non-standard' style was significantly related to poor support, low self-esteem and childhood adversity. Some specificity of type of style and type of vulnerability was observed. Logistic regression showed that non-standard Enmeshed, Fearful and Angry-dismissive styles, poor support and childhood neglect/abuse provided the best model for clinical depression. CONCLUSION: Non-standard attachment in the form of markedly Enmeshed, Fearful or Angry-dismissive styles was shown to be associated with other depressive-vulnerability factors involving close relationships, self-esteem and childhood adversity and added to these in modelling depression.

Predicting onset of depression: the Vulnerability to Depression Questionnaire.

OBJECTIVES: The development of a self-report questionnaire capable of assessing cognitive and interpersonal vulnerability factors for clinical depression is described. The Vulnerability to Depression Questionnaire (VDQ) was developed to provide a brief, economical alternative to the Self-Evaluation and Social Support interview (SESS; O'Connor & Brown, 1984), assessing negative evaluation of self, negative interaction with partner or child and lack of a support figure. DESIGN: The VDQ was tested in a prospective study of community-based women who were contacted on three occasions over the course of approximately 1 year, to: (i) compare the VDQ's capacity to categorize vulnerability compared with the SESS interview, and (ii) to test the VDQ's prediction of onset of clinical depression during the follow-up. METHOD: Selected nondepressed respondents completed the VDQ and were interviewed to determine their vulnerability using the SESS. They were re-interviewed on two further occasions during the follow-up period, and the VDQ was also re-administered at the time of first follow-up. Onset of clinical depression during the follow-up was assessed by interview at each contact. RESULTS: Comparison of VDQ and SESS interview classification of participants' vulnerability at first contact indicated that the questionnaire had good sensitivity and specificity. Test-retest scores for the VDQ indicated satisfactory levels of reliability. VDQ scores also predicted onset of clinical depression in the follow-up period. CONCLUSIONS: Results suggest that the VDQ is an economical and effective means of screening large populations for the purposes of risk assessment, to aid future research into clinical depression and to facilitate the implementation of intervention strategies.

Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning.

Latent inhibition describes a process by which pre-exposure of a stimulus without consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that latent inhibition in rats is impaired by increased dopamine function and potentiated by reduced dopamine function. Previous evidence has suggested that these effects are modulated via the meso-accumbens dopamine projections. We have now undertaken three experiments to examine this issue directly, especially in the light of one study in which latent inhibition was reported to be unaffected by direct injection of amphetamine into the accumbens. Latent inhibition was studied using the effect of pre-exposure of a tone stimulus on the subsequent formation of a conditioned emotional response to the tone. 6-Hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens resulted in potentiation of latent inhibition. Bilateral local injections of the dopamine antagonist haloperidol into the nucleus accumbens (0.5 microg/side) before conditioning also potentiated latent inhibition. Moreover, such injections were able to reverse the disruptive effect of systemic amphetamine (1mg/kg, i.p.) on latent inhibition. Bilateral local injection of amphetamine (5 microg/side) into the nucleus accumbens before conditioning was able to disrupt latent inhibition, provided that it was preceded by a systemic injection of amphetamine (1mg/kg) 24h earlier.We conclude that the attenuation of latent inhibition by increased dopamine function in the nucleus accumbens is brought about by impulse-dependent release of the neurotransmitter occurring at the time of conditioning. The previously reported failure to disrupt latent inhibition with intra-accumbens amphetamine is probably due to impulse-independent release of dopamine. The implications of these conclusions for theories linking disrupted latent inhibition to the attentional deficits in schizophrenia, and to the dopamine theory of this disorder, are discussed.

The pharmacology of latent inhibition as an animal model of schizophrenia.

The nature of the primary symptoms of schizophrenia and our lack of knowledge of its underlying cause both contribute to the difficulty of generating convincing animal models of schizophrenia. A more recent approach to investigating the biological basis of schizophrenia has been to use information processing models of the disease to link psychotic phenomena to their neural basis. Schizophrenics are impaired in a number of experimental cognitive tasks that support this approach, including sensory gating tasks and models of selective attention such as latent inhibition (LI). LI refers to a process in which noncontingent presentation of a stimulus attenuates its ability to enter into subsequent associations, and it has received much attention because it is widely considered to relate to the cognitive abnormalities that characterise acute schizophrenia. Several claims have been made for LI having face and construct validity for schizophrenia. In this review of the pharmacological studies carried out with LI we examine its claim to predictive validity and the role of methodological considerations in drug effects. The data reviewed demonstrate that facilitation of low levels of LI is strongly related to demonstrated antipsychotic activity in man and all major antipsychotic drugs, both typical and atypical, have been shown to potentiate LI using a variety of protocols. Very few compounds without antipsychotic activity are active in this model. In contrast, disruption of LI occurs with a wide range of drugs and the relationship with psychotomimetic potential is less clear. Although reversal of disrupted LI has also been used as a model for antipsychotic acticity, mostly using amphetamine-induced disruption, insufficient studies have been carried out to evaluate its claim to predictive validity. However, like facilitation, it is sensitive to both typical and atypical antipsychotic agents. The data we have reviewed here demonstrate that facilitation of LI and, perhaps to a lesser extent, reversal of disrupted LI fulfil the criteria for predictive validity.

Lifetime stressors and recurrent depression: preliminary findings of the Adult Life Phase Interview (ALPHI).

BACKGROUND: The well-established association between stress and depression is explored in a lifespan context in relation to adverse childhood experience. A new retrospective interview instrument, the Adult Life Phase Interview (ALPHI) examined the number of chronic stressors (or 'adversities') experienced over the adult life course in relation to chronic or recurrent clinical depression. The role of such lifetime adversity in mediating the relationship between childhood neglect/ abuse and adult disorder was examined. METHOD: The ALPHI uses an investigator-based, contextual approach suited to retrospective and time-linked enquiries. Reliability of the instrument was found to be satisfactory. Its association with both lifetime clinical depression and childhood neglect or abuse was examined in a community series of 198 women, consisting of 99 sister pairs, where one-half of the series was selected for having had adverse childhood experience and the other for comparison. RESULTS: Adult adversity, both at settled/fixed times and at times of major life change, was significantly higher among those with prior childhood neglect or abuse. Both a high adult adversity score and childhood neglect or abuse were related to chronic or recurrent episodes of clinical depression, with logistic regression indicating both indices contributed independently to disorder. The same results held when controls were made for sister status, given possible familial bias in experience, and for age, since women under age 25 had fewer adult phases and less adversity. CONCLUSIONS: Characteristics of adult life phases and change-points are described and the relevance of the measure for intensive survey work seeking to investigate relationships between lifespan experience and depression is discussed.

Latent inhibition: the nucleus accumbens connection revisited.

It has been proposed that dopaminergic transmission in the nucleus accumbens plays a key role in regulating latent inhibition (LI), i.e. the retardation of conditioning that occurs if a to-be-conditioned stimulus is first presented a number of times ('preexposure') without other consequence. New evidence in support of this hypothesis is presented or reviewed here, showing that: (1) intra-accumbens injection of haloperidol at the time of conditioning potentiates LI; (2) destruction of dopaminergic terminals in the nucleus accumbens potentiates LI; (3) intra-accumbens haloperidol reverses the blockade of LI caused by systemic nicotine; (4) intra-accumbens haloperidol reverses the blockade of LI caused by systemic amphetamine; (5) after a single systemic injection of amphetamine (insufficient on its own to block LI), a subsequent intra-accumbens injection of amphetamine at the time of conditioning blocks LI; and (6) intra-accumbens (like systemic) amphetamine administered 15 min before conditioning, without prior systemic amphetamine, failed to block LI. The difference between the effects on LI of one and two administrations of amphetamine, respectively, is interpreted in terms of the need for sensitisation of the response to amphetamine, with the result that the response to the second administration includes a component of impulse-dependent dopamine release in the nucleus accumbens that is otherwise lacking. Data from dialysis experiments suggest that such impulse-dependent accumbens dopamine release also occurs at relatively long delays after a single systemic administration of amphetamine. It was accordingly predicted, and found, that, although LI is intact 15 min after an i.p. injection (confirming previous results), it is abolished at 90 min after the injection of amphetamine. This finding is consistent with the effects of amphetamine in human subjects, in whom LI is blocked 90 min after a single oral administration. Overall, these results strengthen the case that the blockade of LI by elevated, and potentiation of LI by decreased, dopaminergic transmission are both due specifically to actions in the nucleus accumbens; and also add to the similarities between LI studied in animal and human subjects, respectively.