8-OH-DPAT inhibits both prandial and waterspray-induced grooming.

The effects of 8-OH-DPAT treatment on rat grooming behaviour, elicited either prandially or in response to spraying with water were investigated. Dose (< or =0.1 mg/kg s.c.) response studies employed momentary time sampling over 30 or 60 min with behaviour being scored in one of 6 or 7 (depending on food availability) mutually exclusive categories (feeding, active, scratching, face-grooming, body grooming, genital-grooming and resting) at 15 s intervals. In non-deprived rats, tested with wet mash available, feeding and activity frequencies were increased, but resting and total grooming were inhibited by 8-OH-DPAT. Face-, body- and genital-grooming occurred at higher levels than scratching, but all categories were reduced with reductions in scratching occurring at a lower dose (0.01 mg/kg). Misting rats with a fine water spray selectively increased body grooming and decreased activity without altering feeding, while 8-OH-DPAT increased feeding and reduced face-, body- and genital-grooming, without affecting already low levels of scratching. In misted rats, tested without food, 8-OH-DPAT reduced face-, body- and genital-grooming and increased resting. These results confirm i) that the water spray technique is a useful method for increasing grooming and ii) that 8-OH-DPAT has a suppressant effect on grooming independent of response competition from enhanced feeding.

Further validation of the Daily Living Tasks Dependent on Vision: identification of domains.

AIM: To examine the Daily Living Tasks Dependent on Vision (DLTV), a visual function questionnaire for domain structure, and redundancy. METHOD: 235 subjects underwent full ophthalmic assessment and completed the DLTV questionnaire by interview. Principal component analysis with varimax rotation and item response theory (IRT) were used to assign the items to domains. The internal consistency of each domain was examined using Cronbach's alpha. Redundancy was assessed by regressing each item in a domain against the remainder of items in that domain. RESULTS: Four domains were identified. Domain 1 was formed by nine items, which after applying IRT were seen to be among the most difficult questions in the instrument. Domain 2 contained eight items, all of which fell in the easier half of the instrument on applying IRT. Domain 3 contained only three items, all of which were among the easier questions and appear to deal with peripheral vision function. Domain 4 consisted of two items dealing with adaptation to light and dark conditions. Cronbach's alpha for each domain was 0.96, 0.93, 0.73, 0.66. Redundancy was found to be present in domain 1, which was therefore reduced by two items, with little effect on internal consistency. CONCLUSIONS: The authors believe using the domains identified in this report will optimise the information provided by patients on their ability to function on visually demanding tasks.

Subjective self-control and behavioural impulsivity coexist in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) has been associated with impulse regulation problems. This study investigated subjective and behavioural impulsivity in women with anorexia nervosa (n=15) and a control group (n=16). METHOD: A self-report measure (the impulsiveness, venturesomeness, and empathy questionnaire; I(7)) and two behavioural measures (a continuous performance task [CPT]; and a novel risk taking measure [Bets 16]) of impulsivity were used along with the Beck Depression Inventory (BDI). RESULTS: The AN group had elevated BDI scores and lower self-reported impulsiveness and venturesomeness scores, but they also displayed impulsive behaviour on the CPT (more errors of commission with faster reaction times). DISCUSSION: The coexistence, in AN, of self-reported self-control and behavioural impulsivity indicates that the relationship between impulsivity and disordered eating in AN is more complex than previously recognised and supports the view that self-awareness in AN is low.

Impulsivity, risk taking and recreational 'ecstasy' (MDMA) use.

The present study investigated characteristics of recreational drug users, especially 'ecstasy' (MDMA) users, in 254 undergraduates. All participants completed a drug history questionnaire (DHQ), the impulsiveness venturesomeness and empathy questionnaire, a novel risk-taking task (Bets16), and 59 also completed the tri-dimensional personality questionnaire (TPQ). DHQ responses allocated participants to five groups: non-drug controls, cannabis users, polydrug (no ecstasy) users, low (<20 occasions) ecstasy users and high (>20 occasions) ecstasy users. Eighteen percent of the sample had used ecstasy and of the ecstasy users, only one had not used other substances. A larger proportion of high ecstasy users had also used amphetamines, cocaine and LSD in comparison to the low ecstasy and non-ecstasy polydrug users. High ecstasy users typically took significantly more ecstasy tablets compared with low ecstasy users. Impulsiveness, venturesomeness and novelty seeking behaviour increased from the non-drug users to high ecstasy users. Ecstasy users (low and high) and polydrug (non-ecstasy) users had higher levels of impulsivity, venturesomeness and novelty seeking behaviour compared with non-drug users. Furthermore, high ecstasy users scored higher on the Bets16 risk-taking measure than non-drug users, cannabis users and low ecstasy users. The findings are discussed in relation to: (i) the possibility that increased impulsivity pre-dated drug use; and (ii) the possible link between impulsivity and the putative serotonergic neurotoxicity of ecstasy.

Reduced vision in older adults with age related macular degeneration interferes with ability to care for self and impairs role as carer.

AIM: To study the relation between visual impairment and ability to care for oneself or a dependant in older people with age related macular degeneration (AMD). METHOD: Cross sectional study of older people with visual impairment due to AMD in a specialised retinal service clinic. 199 subjects who underwent visual function assessment (fully corrected distance and near acuity and contrast sensitivity in both eyes), followed by completion of a package of questionnaires dealing with general health status (SF36), visual functioning (Daily Living Tasks Dependent on Vision, DLTV) and ability to care for self or provide care to others. The outcome measure was self reported ability to care for self and others. Three levels of self reported ability to care were identified--inability to care for self (level 1), ability to care for self but not others (level 2), and ability to care for self and others (level 3). RESULTS: People who reported good general health status and visual functioning (that is, had high scores on SF36 and DLTV) were more likely to state that they were able to care for self and others. Similarly people with good vision in the better seeing eye were more likely to report ability to care for self and others. People with a distance visual acuity (DVA) worse than 0.4 logMAR (Snellen 6/15) had less than 50% probability of assigning themselves to care level 3 and those with DVA worse than 1.0 logMAR (Snellen 6/60) had a probability of greater than 50% or for assigning themselves to care level 1. Regression analyses with level of care as the dependent variable and demographic factors, DLTV subscales, and SF36 dimensions as the explanatory variables confirmed that the DLTV subscale 1 was the most important variable in the transition from care level 3 to care level 2. The regression analyses also confirmed that the DLTV subscale 2 was the most important in the transition from care level 3 to care level 1. CONCLUSIONS: Ability to care for self and dependants has a strong relation with self reported visual functioning and quality of life and is adversely influenced by visual impairment. The acuity at which the balance of probability shifts in the direction of diminished ability to care for self or others is lower than the level set by social care agencies for provision of support. These findings have implications for those involved with visual rehabilitation and for studies of the cost effectiveness of interventions in AMD.

Alpha2-adrenoceptor antagonism is neither sufficient nor necessary for the distinctive action of atypical neuroleptics on intracranial self-stimulation in the rat.

Response rates in variable-interval intracranial self-stimulation (ICSS) in rats can provide a continuous record of drug-induced changes in brain function. Use of this procedure has been found to distinguish between typical and atypical neuroleptics, with the latter producing a similarly intense but much briefer depression of responding. This difference has been ascribed to the alpha2-adrenoceptor antagonist properties of atypical neuroleptics, but the evidence is ambiguous. The role of alpha2-adrenoceptors was examined in the present study using ventral tegmental ICSS to track the depressant effects of the typical and atypical neuroleptics, haloperidol (0.075 mg/kg) and olanzapine (0.9 mg/kg), injected alone or in combination with an alpha2-adrenoceptor agonist or antagonist. Neither haloperidol nor olanzapine (despite its atypical features) shows appreciable affinity for the alpha2-adrenoceptor. In the present study, olanzapine was found to depress self-stimulation responding dose-dependently, but with considerable recovery after 4 h. Simultaneous administration of alpha2-adrenoceptor receptor agonists or antagonists (respectively clonidine 0.015 mg/kg or idazoxan 3.0 mg/kg) failed significantly to increase or decrease the action of either haloperidol or olanzapine. These results indicate that alpha2-adrenoceptor antagonism does not necessarily promote recovery from neuroleptic-induced depression, and that 'atypical' features do not necessarily depend on alpha2-adrenoceptor antagonism. Various other explanations remain possible, but the accelerated time course of the atypical agents appears to support more recent explanations, based on their rapid dissociation from the D2 receptor.

Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells.

Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin alpha(v)beta(3), has been associated with the metastatic potential of tumor cells. In this study, we used a novel in vitro assay to examine the role of alpha(v)beta(3) in the transmigration of melanoma cells through a monolayer of human lung microvascular endothelial cells. Confocal microscopy revealed the presence of the integrin alpha(v)beta(3) on melanoma membrane protrusions and pseudopods penetrating the endothelial junction. alpha(v)beta(3) was also enriched in heterotypic contacts between endothelial cells and melanoma cells. Transendothelial migration of melanoma cells was inhibited by either a cyclic Arg-Gly-Asp peptide or the anti-alpha(v)beta(3) monoclonal antibody LM609. Although both platelet endothelial cell adhesion molecule-1 and L1 are known to bind integrin alpha(v)beta(3), only L1 serves as a potential ligand for alpha(v)beta(3) during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and alpha(v)beta(3) antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin alpha(v)beta(3) on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells.

Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment.

L1 is a multidomain transmembrane neural recognition molecule essential for neurohistogenesis. While moieties in the immunoglobulin-like domains of L1 have been implicated in both heterophilic and homophilic binding, the function of the fibronectin (FN)-like repeats remains largely unresolved. Here, we demonstrate that the third FN-like repeat of L1 (FN3) spontaneously homomultimerizes to form trimeric and higher order complexes. Remarkably, these complexes support direct RGD-independent interactions with several integrins, including alpha(v)beta(3) and alpha(5)beta(1). A pep- tide derived from the putative C-C' loop of FN3 (GSQRKHSKRHIHKDHV(852)) also forms trimeric complexes and supports alpha(v)beta(3) and alpha(5)beta(1) binding. Substitution of the dibasic RK(841) and KR(845) sequences within this peptide or the FN3 domain limited multimerization and abrogated integrin binding. Evidence is presented that the multimerization of, and integrin binding to, the FN3 domain is regulated both by conformational constraints imposed by other domains and by plasmin- mediated cleavage within the sequence RK( downward arrow)HSK( downward arrow)RH(846). The integrin alpha(9)beta(1), which also recognizes the FN3 domain, colocalizes with L1 in a manner restricted to sites of cell-cell contact. We propose that distal receptor ligation events at the cell-cell interface may induce a conformational change within the L1 ectodomain that culminates in receptor multimerization and integrin recruitment via interaction with the FN3 domain.

The human neural cell adhesion molecule L1 functions as a costimulatory molecule in T cell activation.

L1 is a neural cell adhesion molecule (CAM) known to be important for normal neurological development. Despite being described as a neural CAM, we have documented L1 expression by antigen-presenting cells of myelomonocytic origin. Here we demonstrate that L1 can function as a costimulatory molecule in T cell activation. A monoclonal antibody that abrogates L1-L1 homophilic binding significantly reduced mixed leukocyte responses initiated by allogeneic L1+ dendritic cells. Autologous T cell activation in response to phytohemagglutinin was also inhibited by blockade of L1. In accordance with these results, transfection of human L1 into a murine myeloma cell line significantly increased the capacity of these cells to stimulate xenogeneic T cell responses. As a costimulatory ligand L1 could represent a novel target for immunotherapeutic intervention and may act as an important intermediary in neuroimmunological processes and disease.

Breastfeeding and postpartum maternal care.

The early postpartum period is a time of transition for families. Breastfeeding, the optimal form of feeding for newborns, doesn't always come naturally. Medical interventions at birth can affect early breastfeeding, and close follow up of breastfeeding couplets is essential. New mothers often deal with challenges such a postpartum depression, thyroid disease, perineal pain, and other sexual concerns. Physicians can support families in this transition period to help optimize it for the mother and her baby.

A potential role for the plasmin(ogen) system in the posttranslational cleavage of the neural cell adhesion molecule L1.

L1 is a neural recognition molecule that promotes neural developmental and regenerative processes. Posttranslational cleavage of L1 is believed to be important for regulating its function in vivo, but little is known of the proteolytic systems responsible. In this study we present evidence that plasmin can regulate both L1 expression and function. The addition of plasmin to cell lines results in a dose-dependent loss of surface L1 expression, with the simultaneous appearance of soluble L1 species. The addition of plasminogen to primary neurons and melanoma cells also resulted in the generation of plasmin and the concomitant release of L1. One product of plasmin-mediated cleavage is an amino-terminal fragment of approximately 140 kDa that has been previously described as a natural posttranslational cleavage product in vivo. This fragment was confirmed to result from cleavage at two sites in the middle of the third fibronectin-like domain of L1. Cleavage at a further site, proximal to the transmembrane domain of L1, was also observed at higher plasmin concentrations. Plasmin was further confirmed to abrogate homophilic L1 interactions required for cellular aggregation. Based on these findings we propose that plasmin is likely to be an important regulator of L1-mediated processes including those documented in the nervous system.

Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival.

Growth and dissemination of malignant melanoma has a profound impact on our population, and little is known concerning the mechanisms controlling this disease in humans. Evidence is provided that integrin alpha(v)beta3 plays a critical role in M21 melanoma tumor survival within human skin by a mechanism independent of its known role in angiogenesis. Antagonists of alpha(v)beta3 blocked melanoma growth by inducing tumor apoptosis. Moreover, M21 melanoma cell interactions with denatured collagen, a known ligand for alpha(v)beta3, caused a 5-fold increase in the relative Bcl-2:Bax ratio, an event thought to promote cell survival. Importantly, denatured collagen colocalized with alpha(v)beta3-expressing melanoma cells in human tumor biopsies, suggesting that alpha(v)beta3 interaction with denatured collagen may play a critical role in melanoma tumor survival in vivo.

Neurotransmitter system interactions revealed by drug-induced changes in motivated behavior.

The present article reviews studies conducted either in collaboration with Jac Herberg, or in parallel with those studies that used consummatory behavior and responding for intracranial self-stimulation (ICSS) to investigate interactions between neurotransmitter systems. The studies reviewed include investigations of the role of dopamine in 8-OH-DPAT-induced feeding; the role of 5-HT3 receptors in the stimulant and depressant effects of nicotine on responding for ICSS; the interaction of D2 and 5-HT2 antagonists in sucrose consumption, and the differential contributions of alpha2-adrenoceptor and 5-HT2 antagonism to the rapid recovery of ICSS responding from depression produced by atypical neuroleptics. Further studies of the role of alpha2-adrenoceptor antagonism in the pattern of response decrements produced by neuroleptics on schedule-controlled responding for food confirm that the behavioral effects of monoamine interactions vary, depending on the specific receptor subtypes targeted and the behavioral paradigm employed. Consequently, the clinical relevance of findings will crucially depend on the choice of appropriate behavioral measures.

Rapid recovery of self-stimulation responding from depression by clozapine is prevented by the alpha 2-adrenoceptor agonist, clonidine.

Typical and atypical antipsychotic agents were tested on rats responding for variable-interval electrical stimulation of the ventral tegmental area (VTA). The typical neuroleptics, chlorpromazine and haloperidol, led to prolonged depression of responding lasting at least 4 h, whereas response rates after similarly effective doses of the atypical agents, clozapine and risperidone, recovered to control levels in the same period. The role of alpha 2-adrenoceptors in producing these differences was investigated by administering clozapine together with an alpha 2-adrenoceptor agonist, clonidine, and chlorpromazine together with an alpha 2-adrenoceptor antagonist, idazoxan. The addition of clonidine extended the response-depressant activity of clozapine, resulting in prolonged depression comparable to that produced by chlorpromazine or haloperidol. Conversely, the addition of idazoxan to chlorpromazine shortened the duration of chlorpromazine's suppressant action to a level comparable to that of clozapine or risperidone. These results suggest that the brevity of clozapine's effects on operant behaviour (a feature which may be related to its reduced liability to extrapyramidal side-effects) may be a consequence of its alpha 2-adrenoceptor antagonist properties.

L1 makes immunological progress by expanding its relations.

The cell-adhesion molecule L1 was originally described in the nervous system. It has recently been detected in CD4+ T lymphocytes, peripheral B lymphocytes, and granulocytes in the human immune system and in similar leucocyte types in the murine immune system. L1 mediates neural recognition by Ca+2, Mg+2-independent homophilic binding. In the human and murine immune systems, L1 binds to the "classical" vitronectin receptor, alphaVbeta3, and fibronectin receptor, alpha5beta1, respectively, and abstains from homophilic binding. Homophilic L1 binding probably involves antiparallel alignment of several interactive domains. Integrin binding is mediated by a short segment of immunoglobulinlike domain 6, which includes two RGD repeats in rodent L1 and one RGD motif in human L1. L1 is modulated in activated leucocytes in vitro in parallel to L-selectin, and diverse cell types release intact L1 in vivo and in vitro. Released L1 can bind to laminin and adheres to the extracellular matrix of sciatic nerve, M21 melanoma, and possibly spleen and other tissues. It can support integrin-dependent cell migration and preliminary data implicate it in tumor development and transnodal lymphocyte migration.

The Arg-Gly-Asp motif in the cell adhesion molecule L1 promotes neurite outgrowth via interaction with the alphavbeta3 integrin.

The cell adhesion molecule L1 is a potent inducer of neurite outgrowth and it has been implicated in X-linked hydrocephalus and related neurological disorders. To investigate the mechanisms of neurite outgrowth stimulated by L1, attempts were made to identify the neuritogenic sites in L1. Fusion proteins containing different segments of the extracellular region of L1 were prepared and different neuronal cells were assayed on substrate-coated fusion proteins. Interestingly, both immunoglobulin (Ig)-like domains 2 and 6 (Ig2, Ig6) promoted neurite outgrowth from dorsal root ganglion cells, whereas neural retinal cells responded only to Ig2. L1 Ig2 contains a previously identified homophilic binding site, whereas L1 Ig6 contains an Arg-Gly-Asp (RGD) sequence. The neuritogenic activity of Ig6 was abrogated by mutations in the RGD site. The addition of RGD-containing peptides also inhibited the promotion of neurite outgrowth from dorsal root ganglion cells by glutathione S-transferase-Ig6, implicating the involvement of an integrin. The monoclonal antibody LM609 against alphavbeta3 integrin, but not an anti-beta1 antibody, inhibited the neuritogenic effects of Ig6. These data thus provide the first evidence that the RGD motif in L1 Ig6 is capable of promoting neurite outgrowth via interaction with the alphavbeta3 integrin on neuronal cells.

The nitric oxide synthesis inhibitor L-NAME produces anxiogenic-like effects in the rat elevated plus-maze test, but not in the social interaction test.

The effects of the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME) were investigated in two animal models of anxiety: the elevated plus-maze and the social interaction test. In the elevated plus-maze, L-NAME (12.5-50 mg/kg) had an anxiogenic-like profile as indicated by dose-dependent reductions in the time spent on the open arms, open arm entries, the percentage of open arm entries and head dips, but there was no significant effect on the number of stretch attend postures. In contrast, L-NAME (12.5-50 mg/kg) failed to modify time spent in social interaction but did reduce a measure of vertical activity. The differential effects of L-NAME in the two anxiety paradigms are discussed.

Social interaction: responses to chlordiazepoxide and the loss of isolation-reared effects with paired-housing.

This study investigated the action of chlordiazepoxide (CDP), on the social interaction (SI) of adult rats maintained in one of three housing conditions: (i) group-reared, (ii) isolated from weaning or (iii) paired during adulthood after initial isolation at weaning (pair-housed former isolates; PHFIs). Group-reared rats and PHFIs rats were housed in pairs starting 21 days prior to the first experiment. For these two groups, CDP (2.5 and 5.0 mg/kg) increased SI in unfamiliar, but not familiar (cagemate) pairings. In rats isolated throughout, SI was markedly increased and this was unaffected by CDP. Isolated rats also exhibited increased motor activity (MA) during SI tests, and the MA of both isolates and PHFIs was reduced by CDP. Finally, levels of aggression were very low except in isolates, where a relatively modest increase in aggression was reversed by either pairing or CDP. To summarise, isolation-induced increases in SI and aggression were reversed by pairing, but pairing only attenuated isolation-induced increases in MA. Although CDP reduced the elevated aggression and MA of isolated rats, it had no effect on their elevated SI scores. These data question the permanence of anxiety-related, isolation-induced behavioural changes and stand in contrast to the irreversible anxiogenic profile reported for isolation-reared rats in the elevated X-test.