Effects of microinjections of apomorphine and haloperidol into the inferior colliculus on the latent inhibition of the conditioned emotional response

Electrical or chemical stimulation of the inferior colliculus (IC) induces fear-like behaviors. More recently, consistent evidence has shown that electrical stimulation of the central nucleus of the IC supports Pavlovian conditioning and latent inhibition (Li). LI is characterized by retardation in conditioning and also by an impaired ability to ignore irrelevant stimuli, after a non-reinforced pre-exposure to the conditioned stimulus. LI has been proposed as a behavioral model of cognitive abnormalities seen in schizophrenia. The aim of the present study was to determine whether dopaminergic mechanisms in the IC are involved in LI of the conditioned emotional response (CER). To induce LI, a group of rats was pre-exposed (PE) to six tones in two sessions, while rats that were not pre-exposed (NPE) had two sessions without tone presentations. The conditioning consisted of two tone presentations to the animal, followed immediately by a foot shock. PE and NPE rats received IC microinjections of physiological saline, the dopaminergic agonist apomorphine (9.0 mu g/0.5 mu L/side), or the dopaminergic antagonist haloperidol (0.5 mu g/0.5 mu L/side) before both pre-exposure and conditioning. During the test, the PE rats that received saline or haloperidol had a lower suppression of the licking response compared to NPE rats that received vehicle or haloperidol, indicating that latent inhibition was induced. There was no significant difference in the suppression ratio in rats that received apomorphine injections into the IC, indicating reduced latent inhibition. These results suggest that dopamine-mediated mechanisms of the IC are involved in the development of LI. (C) 2008 Elsevier Inc. All rights reserved.

Latent inhibition and autonomic responses: a psychophysiological approach

Latent inhibition, retarded learning after preexposure to the to-be-conditioned stimulus, has been implied as a tool for the investigation of attentional deficits in schizophrenia and related disorders. The present paper reviews research that used Pavlovian conditioning as indexed by autonomic responses (electrodermal, vasomotor, cardiac) to investigate latent inhibition in adult humans. Latent inhibition has been demonstrated repeatedly in healthy subjects in absence of a masking task that is required in other latent inhibition paradigms. Moreover, latent inhibition of Pavlovian conditioning is stimulus-specific and increases with an increased number of preexposure trials which mirrors results from research in animals. A reduction of latent inhibition has been shown in healthy subjects who score high on questionnaire measures of psychosis proneness and in unmedicated schizophrenic patients. The latter result was obtained in a within-subject paradigm that holds promise for research with patient samples. (C) 1997 Elsevier Science B.V.

Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses

Latent inhibition (LI) is an important model for understanding cognitive deficits in schizophrenia, Disruption of LI is thought to result from an inability to ignore irrelevant stimuli. The study investigated LI in schizophrenic patients by using Pavlovian conditioning of electrodermal responses in a complete within-subject design. Thirty-two schizophrenic patients, ( 16 acute. unmedicated and 16 medicated patients) and 16 healthy control subjects (matched with respect to age and gender) participated in the study. The experiment consisted of two stages: preexposure and conditioning. During preexposure two visual stimuli were presented, one of which served as the to-be-conditioned stimulus (CSp +) and the other one was the not-to-be-conditioned stimulus (CSp -) during the following conditioning ( = acquisition). During acquisition. two novel visual stimuli (CSn + and CSn -) were introduced. A reaction time task was used as the unconditioned stimulus (US). LI was defined as the difference in response differentiation observed between proexposed and non-preexposed sets of CS + and CS -. During preexposure. the schizophrenic patients did not differ in electrodermal responding from the control subjects, neither concerning the extent of orienting nor the course of habituation. The exposure to novel stimuli at the beginning of the acquisition elicited reduced orienting responses in unmedicated patients compared to medicated patients and control subjects, LI was observed in medicated schizophrenic patients and healthy controls. but not in acute unmedicated patients. Furthermore LI was found to be correlated with the duration of illness: it was attenuated in patients who had suffered their first psychotic episode. (C) 2002 Elsevier Science B.V. All rights reserved.

Overshadowing in conditioned taste aversion or in conditioned emotional response after neonatal ventral hippocampal lesions in rats

The neonatal hippocampus lesion thought to model schizophrenia should show the same modifications in behavioural tests as other models, especially pharmacological models. namely decreased latent inhibition, blocking and overshadowing. The present study is set out to evaluate overshadowing in order to complement our previous studies, which had tested latent inhibition. ""Overshadowing"" refers to the decreased conditioning that occurs when the to-be-conditioned stimulus is combined with another stimulus at the conditioning stage. We used the same two Pavlovian conditioning paradigms as in our previous works, namely conditioned taste aversion (CTA) and conditioned emotional response (CER). A sweet taste overshadowed a salty conditioned stimulus, and a tone overshadowed a flashing light. Totally different stimuli were used to counter possible sensory biases. The protocols were validated with two groups of Sprague Dawley rats. The same two protocols were then applied to a cohort of rats whose ventral hippocampus had been destroyed when they were 7 days old. Only rats with extended ventral hippocampus lesions were included. The overall effect of Pavlovian conditioning was attenuated, significantly so in the conditioned emotional response paradigm, but overshadowing appeared not to be modified in either the conditioned emotional response or the conditioned taste aversion paradigm. (C) 2008 Elsevier B.V. All rights reserved.

Rewarded associative and instrumental conditioning after neonatal ventral hippocampus lesions in rats

Sprague Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth. This corresponds to the Lipska and Weinberger`s procedure for modeling schizophrenia. The aim of the present work was to test the learning capacity of such rats with an associative Pavlovian and an instrumental learning paradigm, both methods using reward outcome (food, sucrose or polycose). The associative paradigm comprised also a second learning test with reversed learning contingencies. The instrumental conditioning comprised an extinction test under outcome devaluation conditions. Neonatally lesioned rats, once adults (over 60 days of age), showed a conditioning deficit in the associative paradigm but not in the instrumental one. Lesioned rats remained able to adapt as readily as controls to the reversed learning contingency and were as sensitive as controls to the devaluation of outcome. Such observations indicate that the active access (instrumental learning) to a reward could have compensated for the deficit observed under the ""passive"" stimulus-reward associative learning condition. This feature is compared to the memory management impairments observed in clinical patients. (c) 2008 Elsevier B.V. All rights reserved.

Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder.

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

Diethylpropion produces psychostimulant and reward effects

Diethylpropion (DEP) is a stimulant drug widely used for weight control in Brazil and other American countries. However, its effects on behavior and addiction potential are not yet well known. Data suggest that sensitization resulting from pre-exposure to psychostimulants could be a possible risk factor in subsequent drug addiction. The purpose of this investigation was to verify whether pre-exposure to DEP would sensitize rats to the motor activating effect and to the rewarding value of DEP. Two experiments were conducted. In both experiments rats were pre-exposed to DEP (20 mg/kg) or vehicle for 7 consecutive days. The acute effect of DEP (0.0, 1.0, 2.5 or 5.0 mg/kg) on motor activity (Experiment 1) and induction of Conditioned Place Preference-CPP (Experiment 2) were then measured. Results from Experiment 1 showed that 2.5 and 5.0 mg/kg DEP increased motor activity. Sensitization of this motor effect was observed. In Experiment 2, the doses of 2.5 and 5.0 mg/kg DEP induced CPP, indicating their rewarding value. However, no sensitization effect was observed. The results suggest that DEP at low doses has psychostimulant and rewarding properties. It is recommended that more effort should be dedicated to elucidating DEP abuse Potential. (c) 2008 Elsevier Inc. All rights reserved.

Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia. (c) 2005 Elsevier B.V. All rights reserved.

The immediate effects of atlanto-occipital joint manipulation and suboccipital muscle inhibition technique on active mouth opening and pressure pain sensitivity over latent myofascial trigger points in the masticatory muscles

DESIGN: A randomized controlled trial.OB JECTIVE: To investigate the immediate effects on pressure pain thresholds over latent trigger points (TrPs) in the masseter and temporalis muscles and active mouth opening following atlanto-occipital joint thrust manipulation or a soft tissue manual intervention targeted to the suboccipital muscles. BACKGROUND : Previous studies have described hypoalgesic effects of neck manipulative interventions over TrPs in the cervical musculature. There is a lack of studies analyzing these mechanisms over TrPs of muscles innervated by the trigeminal nerve. METHODS: One hundred twenty-two volunteers, 31 men and 91 women, between the ages of 18 and 30 years, with latent TrPs in the masseter muscle, were randomly divided into 3 groups: a manipulative group who received an atlanto-occipital joint thrust, a soft tissue group who received an inhibition technique over the suboccipital muscles, and a control group who did not receive an intervention. Pressure pain thresholds over latent TrPs in the masseter and temporalis muscles, and active mouth opening were assessed pretreatment and 2 minutes posttreatment by a blinded assessor. Mixed-model analyses of variance (ANOVA) were used to examine the effects of interventions on each outcome, with group as the between-subjects variable and time as the within-subjects variable. The primary analysis was the group-by-time interaction. RESULTS: The 2-by-3 mixed-model ANOVA revealed a significant group-by-time interaction for changes in pressure pain thresholds over masseter (P<.01) and temporalis (P =.003) muscle latent TrPs and also for active mouth opening (P<.001) in favor of the manipulative and soft tissue groups. Between-group effect sizes were small. CONCLUSIONS: The application of an atlanto-occipital thrust manipulation or soft tissue technique targeted to the suboccipital muscles led to an immediate increase in pressure pain thresholds over latent TrPs in the masseter and temporalis muscles and an increase in maximum active mouth opening. Nevertheless, the effects of both interventions were small and future studies are required to elucidate the clinical relevance of these changes. LEVEL OF EVIDENCE : Therapy, level 1b. J Orthop Sports Phys Ther 2010;40(5):310-317. doi:10.2519/jospt.2010.3257. KEYWORDSDS: cervical manipulation, muscle trigger points, neck, TMJ, upper cervical.

Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression

BACKGROUND ; AIMS: Integrin alphavbeta6 is highly expressed on certain activated epithelia, where it mediates attachment to fibronectin and serves as coreceptor for the activation of latent transforming growth factor (TGF)-beta1. Because its role in liver fibrosis is unknown, we studied alphavbeta6 function in vitro and explored the antifibrotic potential of the specific alphavbeta6 antagonist EMD527040. METHODS: Experimental liver fibrosis was studied in rats after bile duct ligation (BDL) and in Mdr2(abcb4)(-/-) mice. Different doses of EMD527040 were given to rats from week 2 to 6 after BDL and to Mdr2(-/-) mice from week 4 to 8. Liver collagen was quantified, and expression of alphavbeta6 and fibrosis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. alphavbeta6-expressing cells, bile duct proliferation, and apoptosis were assessed histologically. The effect of EMD527040 on cholangiocyte adhesion, proliferation, apoptosis, and TGF-beta1 activation was studied in vitro. RESULTS: alphavbeta6 was highly expressed on proliferating bile duct epithelia in fibrosis, with 100-fold increased transcript levels in advanced fibrosis. EMD527040 attenuated bile ductular proliferation and peribiliary collagen deposition by 40%-50%, induced down-regulation of fibrogenic and up-regulation of fibrolytic genes, and improved liver architecture and function. In vitro alphavbeta6 inhibition reduced activated cholangiocyte proliferation, their adhesion to fibronectin, and endogenous activation of TGF-beta1 by 50% but did not affect bile duct apoptosis. CONCLUSIONS: Integrin alphavbeta6 is strongly up-regulated in proliferating bile duct epithelia and drives fibrogenesis via adhesion to fibronectin and auto/paracrine TGF-beta1 activation. Pharmacologic inhibition of alphavbeta6 potently inhibits the progression of primary and secondary biliary fibrosis.

Novel screening tools for latent tuberculosis: time to leave an old friend?

PURPOSE OF REVIEW: Therapeutic inhibition of tumour necrosis factor-alpha strongly increases the risk of reactivation in latent tuberculosis infection. Recent blood tests based on antigen-specific T cell response and measuring production of interferon-gamma, so called interferon-gamma release assays (IGRAs), are promising novel tools to identify infected patients. The performance of diagnostic testing for latent tuberculosis infection in patients with rheumatic diseases will be discussed. RECENT FINDINGS: In patients with rheumatoid arthritis, IGRAs are more sensitive and more specific than traditional tuberculin skin testing. They are unaffected by Bacillus-Calmette-Guérin vaccination and most nontuberculous mycobacteria. Most comparative studies show a better performance of the IGRAs than tuberculin skin testing in terms of a higher specificity. The rate of indeterminate results may be affected by glucocorticoids and the underlying disease but appears independent of disease-modifying antirheumatic drugs. Despite using identical Mycobacterium tuberculosis antigens, the two commercially available tests show differences in clinical performance. SUMMARY: The current information about the performance of the tuberculin skin testing and the IGRAs in the detection of latent tuberculosis infection in patients with rheumatic diseases strongly suggest a clinically relevant advantage of the IGRAs. Their use will help to reduce overuse and underuse of preventive treatment in tumour necrosis factor inhibition.

Prospective memory, executive functions, and metacognition are already differentiated in young elementary school children: Evidence from latent factor modelling

This study investigated the empirical differentiation of prospective memory, executive functions, and metacognition and their structural relationships in 119 elementary school children (M = 95 months, SD = 4.8 months). These cognitive abilities share many characteristics on the theoretical level and are all highly relevant in many everyday contexts when intentions must be executed. Nevertheless, their empirical relationships have not been examined on the latent level, although an empirical approach would contribute to our knowledge concerning the differentiation of cognitive abilities during childhood. We administered a computerized event-based prospective memory task, three executive function tasks (updating, inhibition, shifting), and a metacognitive control task in the context of spelling. Confirmatory factor analysis revealed that the three cognitive abilities are already empirically differentiable in young elementary school children. At the same time, prospective memory and executive functions were found to be strongly related, and there was also a close link between prospective memory and metacognitive control. Furthermore, executive functions and metacognitive control were marginally significantly related. The findings are discussed within a framework of developmental differentiation and conceptual similarities and differences.