Blunted neurobiological reactivity and attentional bias to threat underlie stress-related disorders in women survivors of intimate partner violence.

BACKGROUND: Intimate partner violence (IPV) alters women's neurobiological stress response systems. We propose that individual differences early in the attentional processing of threats are associated with these neurobiological mechanisms and contribute to mental illness in this population. METHODS: We assessed attentional bias in relation to threat (AB) in women survivors of IPV (n = 69) and controls (n = 36), and examined overall cortisol secretion using hair cortisol (HC), and stress responsiveness measuring salivary cortisol and α-amylase (sAA) before (T0), and after (T1, T2) an acute psychosocial stress task (Trier Social Stress Test). We used repeated-measures ANCOVAs to explore the associations between Group (IPV, control) and AB with acute stress response, and regression models to examine the associations with mental health symptoms. RESULTS: There were no between-group differences in HC levels. An interaction between Group and AB was found regarding cortisol reactivity (p < 0.05). IPV women with threat avoidance AB showed a blunted cortisol response compared to controls and to IPV participants with threat vigilance AB. The association between sAA reactivity and the interaction between Group, AB, and time approached significance (p = 0.07), with a trend to lower sAA levels particularly in IPV women with threat avoidance AB. Group and cortisol reactivity were associated with symptoms of depression, generalized anxiety, and post-traumatic stress disorder (8-20% explained variance). CONCLUSIONS: Threat avoidance AB is associated with blunted acute cortisol response among women exposed to chronic stress (IPV). Experiencing IPV and acute cortisol response appear to be clearly implicated in long-term mental health problems.

On the efficiency of perovskite solar cells with a back reflector: effect of a hole transport material.

Organometal halide perovskites are promising, high-performance absorbers in solar cells. However, the light-harvesting performance of these devices is still limited by excessive charge carrier recombination. Charge carrier management can be improved, taking into account the transport properties of layers surrounding the absorber. In particular, the choice of an appropriate hole-transport material (HTM) could provide a path towards increasing the device performance of perovskite solar cells (PSCs). The Lambertian reflection on the cell's back-surface reflector could increase the power conversion efficiency (PCE) of PSCs as well. Taking into account these facts, we analyse the absorptance and the PCE of a perovskite thin-film solar cell with the Lambertian reflection on the cell's back-surface reflector for various organic and inorganic HTMs. The analysis is done by means of the Monte-Carlo ray tracing simulations complemented by the transfer-matrix method to account for the interference phenomenon in the local generation rate G of carriers in a thin-film multilayer system. This function is employed further in the transport equations to calculate the current-voltage characteristics of the cell. We show that wide band gap HTMs, that possess negligible absorption, increase the photocurrent in the perovskite, passing reflected photons from the back reflector. In contrast, at the same perovskite thickness the PSC gains less photocurrent with narrow band gap HTMs, where an excessive non-radiative recombination takes place. Our analysis demonstrates that the optimal thickness of the solar cell with the typical absorber CH3NH3PbI3 is ∼300 nm, providing the maximal efficiency ∼18.8% for the wide band gap HTM (CuSCN) at the moderate absorber purity (the diffusion length D ∼ 1 µm).

Sex differences in fear memory consolidation via Tac2 signaling in mice.

Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3ß/ß-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory.

Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

BACKGROUND: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. METHODS: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. RESULTS: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. CONCLUSIONS: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status.

Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists.

Effects of topiramate on ethanol-cocaine interactions and DNA methyltransferase gene expression in the rat prefrontal cortex.

BACKGROUND AND PURPOSE: Recent and ongoing clinical studies have indicated that topiramate (Topamax®) could be effective in treating ethanol or cocaine abuse. However, the effects of topiramate on the co-administration of ethanol and cocaine remain largely unknown. EXPERIMENTAL APPROACH: We studied the effects of topiramate, in Wistar rats, on operant ethanol self-administration with the co-administration of cocaine (i.p.). The psychomotor effects of topiramate were examined before ethanol self-administration and cocaine exposure. Blood samples were collected to analyse ethanol and cocaine metabolism (blood ethanol levels and benzoylecgonine). Quantitative real-time PCR was used to characterize the gene expression in the prefrontal cortex. KEY RESULTS: Topiramate prevented the cocaine-induced increased response to ethanol in a dose-dependent manner without causing any motor impairment by itself. This effect was observed when topiramate was administered before ethanol access, but not when topiramate was administered before the cocaine injection. Topiramate did not block cocaine-induced psychomotor stimulation. Topiramate reduced blood ethanol levels but did not affect cocaine metabolism. Ethanol increased the gene expression of DNA methyltransferases (Dnmt1 and Dnmt3a), the corepressor Dnmt1-associated protein 1 (Dmap1), and the RNA methyltransferase Trdmt1. These effects were prevented by topiramate or cocaine. Gene expression of histone deacetylase-2 and glutamate receptor kainate-1 were only increased by cocaine treatment. Topiramate and cocaine co-administration caused an up-regulation of dopamine (Drd1, Th) and opioid (Oprm1) receptor genes. Topiramate showed a tendency to alter episodic-like memory. CONCLUSIONS AND IMPLICATIONS: Topiramate is an effective inhibitor of the cocaine-induced increase in operant ethanol self-administration.

Pilot-scale road subbase made with granular material formulated with MSWI bottom ash and stabilized APC fly ash: environmental impact assessment.

A granular material (GM) to be used as road sub-base was formulated using 80% of weathered bottom ash (WBA) and 20% of mortar. The mortar was prepared separately and consisted in 50% APC and 50% of Portland cement. A pilot-scale study was carried on by constructing three roads in order to environmentally evaluate the performance of GM in a real scenario. By comparing the field results with those of the column experiments, the overestimations observed at laboratory scale can be explained by the potential mechanisms in which water enters into the road body and the pH of the media. An exception was observed in the case of Cu, whose concentration release at the test road was higher. The long-time of exposure at atmospheric conditions might have favoured oxidation of organic matter and therefore the leaching of this element. The results obtained showed that immobilization of all heavy metals and metalloids from APC is achieved by the pozzolanic effect of the cement mortar. This is, to the knowledge of the authors, the only pilot scale study that is considering reutilization of APC as a safe way to disposal.

Maternal deprivation and adolescent cannabinoid exposure impact hippocampal astrocytes, CB1 receptors and brain-derived neurotrophic factor in a sexually dimorphic fashion.

We have recently reported that early maternal deprivation (MD) for 24 h [postnatal day (PND) 9-10] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (CP) [0.4 mg/kg, PND 28-42] in Wistar rats induced, in adulthood, diverse sex-dependent long-term behavioral and physiological modifications. Here we show the results obtained from investigating the immunohistochemical analysis of CB1 cannabinoid receptors, glial fibrillary acidic protein (GFAP) positive (+) cells and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the same animals. MD induced, in males, a significant increase in the number of GFAP+ cells in CA1 and CA3 areas and in the polymorphic layer of the dentate gyrus (DG), an effect that was attenuated by CP in the two latter regions. Adolescent cannabinoid exposure induced, in control non-deprived males, a significant increase in the number of GFAP+ cells in the polymorphic layer of the DG. MD induced a decrease in CB1 expression in both sexes, and this effect was reversed in males by the cannabinoid treatment. In turn, the drug "per se" induced, in males, a general decrease in CB1 immunoreactivity, and the opposite effect was observed in females. Cannabinoid exposure tended to reduce BDNF expression in CA1 and CA3 of females, whereas MD counteracted this trend and induced an increase of BDNF in females. As a whole, the present results show sex-dependent long-term effects of both MD and juvenile cannabinoid exposure as well as functional interactions between the two treatments.

The brain pattern of c-fos induction by two doses of amphetamine suggests different brain processing pathways and minor contribution of behavioural traits.

Previous studies have shown that amphetamine (AMPH) markedly activates dopaminergic projection areas, together with some important limbic nuclei. However, a global picture of the brain areas activated is lacking and the contribution of the dose of the drug and individual differences to this global brain activation is not known. In the present experiment, we studied in adult male rats the c-fos expression induced by two doses of AMPH (1.5 and 5 mg/kg sc) in a wide range of brain areas, and investigated the possible contribution of novelty-induced activity and anxiety traits. AMPH administration increased Fos+ neurons in an important number of telencephalic, diencephalic and brainstem areas. Interestingly, the ventral tegmental area (VTA) and the dorsal raphe nucleus were activated by the drug, but c-fos expression was restricted to non-dopaminergic and non-serotoninergic neurons, those activated in the VTA being predominantly GABAergic. The use of the factorial analysis, which grouped the areas in function of the correlation between the number of Fos+ neurons observed in each area, revealed three main factors, probably reflecting activation of various relatively independent brain circuits: the first included medial prefrontal cortex regions, most dorsal and ventral striatal subregions and VTA; the second, raphe nuclei; and the third, the different subdivisions of the paraventricular nucleus of the hypothalamus. Other areas such as the central amygdala did not group around any factor. The finding that an important number of activated areas grouped around specific factors is suggestive of activation of partially independent brain circuits. Surprisingly, a minor contribution of novelty-induced activity and anxiety traits on brain activation induced by AMPH was found. It is possible that normal variability in these traits is poorly related to the effects of AMPH or that c-fos expression is not a good tool to reveal such differences.

Marked dissociation between hypothalamic-pituitary-adrenal activation and long-term behavioral effects in rats exposed to immobilization or cat odor.

Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, there are controversial results regarding the effects of urine/feces odors. In the present work, we studied in two experiments the relationship between the degree of stress experienced by the animals during exposure to IMO, urine odors or fur odors (as assessed by hypothalamic-pituitary-adrenal activation and plasma glucose) and the short- and long-term behavioral consequences. In the first experiment, rats were individually exposed for 15 min to a novel environment (white large cages) containing either clean cat litter (controls) or litter soiled by cats (urine odors). Half of the rats in each condition were left to freely explore the environment whereas the others were subjected to immobilization (IMO) within the cages. Although ACTH, corticosterone and glucose responses to IMO were much stronger than those to the white cages with clean litter or urine odors (which did not differ from each other), no effect of treatments on anxiety-like behavior in the elevated plus-maze (EPM) were found one week later. However, previous IMO exposure did cause sensitization of the ACTH response to the EPM. In the second experiment, the response to white large cages containing either no odor (controls), litter soiled by cats (urine odor) or a cloth impregnated with cat odor (fur odor) was compared. Urine and fur odors elicited similar ACTH and corticosterone responses that were higher than those of controls, but plasma glucose levels were slightly higher in rats exposed to fur odor. When compared to controls, activity was only diminished in the novel cages containing fur odor. Similarly, fur odor-exposed rats, but not those exposed to urine odor, showed signs of enhanced anxiety in the EPM seven days later, although the ACTH response to the EPM was similar in the three groups. The present data demonstrate: (a) a marked dissociation between the degree of ACTH, corticosterone and glucose responses to stressors and their long-term anxiety-like effects; (b) that the type of cat odor is critical in determining the short-term and long-term physiological and behavioral consequences of exposure; and (c) that plasma ACTH released during brief exposure to the EPM does not appear to reflect anxiety-like behavior.

Previous exposure to immobilisation and repeated exposure to a novel environment demonstrate a marked dissociation between behavioral and pituitary-adrenal responses.

Activation of the hypothalamus-pituitary-adrenal (HPA) axis is presumably related to the degree of novelty and considered to reflect emotional reactivity. Exposure to novel environments can allow us to simultaneously evaluate both behavior and HPA activation and therefore it is an appropriate design to directly study the relationship between both responses. In the present experiment, we studied how previous exposure to a severe stressor (2 h of immobilisation, IMO, 5 days before testing) and repeated exposure to the same novel environment (a holeboard, HB) altered behavioral and HPA response to the HB. Previous exposure to IMO did not alter any behavior during the first exposure to the HB (5 min), but elicited a greater ACTH response as compared to stress-naive rats. However, corticosterone response did not differ between groups, probably because maximum corticosterone levels are never reached before 15-20 min. Repeated exposure of IMO and stress-naive rats to the HB every other day resulted in progressively lower levels of activity/exploration in both groups, whereas the ACTH and corticosterone responses were basically maintained intact over the days. The present results demonstrate a double dissociation between behavior and HPA activation in the HB. First, a single exposure to IMO elicited a long-lasting sensitisation of the HPA axis that apparently was not a direct consequence of fear/anxiety elicited by the novel environment. Second, progressive familiarisation of the animals with a novel environment resulting in apparently lower levels of motivation to explore did not appear to reduce the stressful properties of the situation as evaluated by ACTH release.

Litter size affects emotionality in adult male rats.

The role of natural variations in pre-weaning litter size in rodent adult emotionality and the importance of maternal care as a possible mediating factor have been frequently neglected. To address these issues, maternal behaviour of Sprague-Dawley dams differing in natural number of pups was studied for the first seven postnatal days. Later, adult behaviour of representative male offspring was studied in the elevated plus-maze, the circular corridor, the dark-light box and the forced swimming test. Three groups of offspring were selected in function of the number of littermates: L<10 group (less than 10 pups per dam), L10-15 (between 10 and 15 pups per dam) and L>15 group (more than 15 pups per dam). L<10 litters showed a reduced habituation of activity across time in a circular corridor and as compared to L>15 litters, L<10 litters showed a lower activity during the first 5 min of exposure to the circular corridor. L<10 litters had also higher signs of anxiety in the elevated plus-maze, in comparison to the other two groups. In addition, L<10 litters showed in the forced swimming test reduced struggling and more mild swimming behavior than the other two groups. These abnormalities in L<10 litters are not explained by maternal behavior since they received individually more maternal care than L>15, as assessed by total licking-grooming observed during the whole observation period divided by number of pups. Although previous data from several laboratories have demonstrated that low maternal care is associated with heightened emotionality at adulthood, the present results suggest an important contribution of spontaneous litter size to adult emotional behavior that cannot be explained by concomitant changes in maternal care.

Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas.

PURPOSE: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. METHODS: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. RESULTS: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. CONCLUSIONS: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.

Influence of reactivity to novelty and anxiety on hypothalamic-pituitary-adrenal and prolactin responses to two different novel environments in adult male rats.

Since stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is involved in some stress-related pathologies, much attention has been paid in laboratory animals to the study of the relationship between endocrine, particularly HPA, responsiveness to stressors and other individual characteristics, such as reactivity to novelty and fear/anxiety. In the present study, adult male rats were classified as high or low reactive to novelty (HR versus LR), as a function of the horizontal activity displayed during 30 min in a circular corridor, and as high or low anxiety (HA versus LA) as a function of the time spent in the open arms of the elevated plus-maze. Then, the behavioural and hormonal response to two distinct novel environments (the hole-board and the light-dark) was assessed in the same subjects, using a counterbalanced design. Plasma prolactin, ACTH and corticosterone responses to the hole-board were higher than to the light-dark, a good correlation between the two tests being found for each hormone. Whereas the hormonal response to the novel environments was not affected by anxiety, HR rats showed a consistently higher HPA response than LR rats when the criteria to classify the animals were the activity during the first 15 min in the circular corridor, but not when the activity during the second 15 min was considered. Neither trait affected prolactin response. The present results demonstrate a good within-individual consistency of the endocrine response to novel environments and support the hypothesis of a higher HPA response to stressors for HR versus LR rats. In contrast, no contribution of fear/anxiety to endocrine responsiveness was observed.

[Pulmonary embolism and myxoma of right atrial]. / Tromboembolismo pulmonar secundario a mixoma gigante de aurícula derecha.

We describe the case of a patient diagnosed of pulmonary embolism, in whom transthoracic echocardiography demonstrated a large mass. It was completely removed and histologic examination showed a very calcification myxoma. This case is of interest because localization and extension of myxoma, the atypical histologic appearance, and in fact the diagnosis and treatment prevented new pulmonary embolism that could be lethal.

Perseverance of exploration in novel environments predicts morphine place conditioning in rats.

Reactivity to novelty has been related to operant drug self-administration but does not seem involved in the conditioned place preference (CPP). To further assess this issue our aims were to investigate: (1) the importance of the initial versus delayed activity in the novel environment to predict the CPP induced by morphine; (2) the separate contribution of trait anxiety in morphine CPP. Male Sprague-Dawley rats were exposed to a circular corridor for 30 min to assess reactivity to novelty and to the elevated plus-maze and the light-dark tests as measures of anxiety and morphine CPP was then studied (three pairings with 5 mg/kg s.c. morphine and three with saline). Delayed activity in the corridor (16-30 min) correlated positively with CPP score, whereas the initial activity (0-15 min) did not. High-responders (HR), those more active during the second half of the corridor, developed morphine CPP in contrast to low-responders (LR). Also, HR and LR did not differ in anxiety nor any plus-maze or light-dark test measure correlated with CPP behaviour. Enhanced vulnerability to develop morphine CPP is predicted by a higher delayed activity in a novel environment, regardless of anxiety.