??-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 {"type":"entrez-protein","attrs":{"text":"SKF83566","term_id":"1157390490","term_text":"SKF83566"}}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.     

S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.     

Severe congenital absence of skin in a preterm infant

A severe case of aplasia cutis congenita in a preterm infant is described. Although major problems with thermoregulation and fluid balance were anticipated, these parameters were relatively easy to control once the patient was stabilized. Meticulous skin care and rapid formation of a membranous-like fibrous tissue layer covering the denuded areas probably played an important role in minimizing excessive fluid and heat loss. The prognosis in aplasia cutis congenita is determined by the underlying associated anomalies, the severity of skin lesions and, in our case, the maturity of the infant who died from complications of prematurity.     

Distribution of the 5-hydroxytryptamine2C receptor protein in adult rat brain and spinal cord determined using a receptor-directed antibody: Effect of 5,7-dihydroxytryptamine

A synthetic peptide, corresponding to the N-terminal decapeptide (+Y¹¹C¹²) of the rat 5-hydroxytryptamine_2C(5-HT_2C) receptor protein was used to produce a sheep polyclonal antiserum. Western blot analysis showed that the resultant antibody G241 recognised two membrane proteins, one (55 kDa) approximating the molecular mass of the 5-HT_2C receptor (52 kDa) and a second (63 kDa), which may be a glycosylated form of the receptor protein. HEK 293 cells transfected with human 5-HT_2CcDNA displayed intense cell surface immunoreactivity with the 5-HT_2Cantiserum, which was completely prevented by incubating the antibody with the synthetic 5-HT_2C peptide (10 μM), whilst neither non-immune serum nor untransfected cells displayed any immunoreactivity. A radioimmunoassay was developed to quantify the regional distribution of 5-HT_2C-like immunoreactivity (LI) in the adult rat brain. The choroid plexus contained five-fold higher levels of 5-HT_2C-LI than any brain region but high levels were found in the frontal cortex, septum, hypothalamus, and striatum, intermediate levels in the thalamus and midbrain, and lower levels in brainstem, cerebellum, and spinal cord. In rat cortical membranes, the B_max value from [³H]-mesulergine binding was ten-fold lower than 5-HT_2C-LI levels determined by radioimmunoassay, which may reflect measurement of internalised receptor protein by radioimmunoassay which is not detected with conventional 5-HT_2Cligands. Ten days after depletion of 5-HT with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), there was a significant increase in 5-HT_2C-LI in the choroid plexus and the ventral cervical spinal cord, suggesting that receptors therein are located post-synaptic to destroyed serotonergic nerve terminals. In contrast, the significant reduction in 5-HT_2C-LI observed in the midbrain, brainstem, and dorsal thoracic spinal cord following 5,7-DHT implies that 5-HT_2Creceptors may be located on 5-HT nerve terminals in these regions. Synapse 27:45–56, 1997. © 1997 Wiley-Liss, Inc.     

Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT₆ receptors

There is increasing awareness of the importance that early environmental factors have on brain development and their role in the neurobiology of neurodevelopmental disorders including schizophrenia. The isolation reared rat attempts to model adverse effects that human social isolation (absence of social contact) can have on normal brain development. The isolation reared rat also models aspects of schizophrenia including the development of persistent learning and memory deficits. This short review concentrates on the effects of isolation rearing on cognition, including deficits in novel object discrimination, and the neural mechanisms that may underlie this impairment. There is evidence that a key effect of social isolation may be loss of neuronal plasticity combined with change in the functional state of various cortical and hippocampal neurotransmitters, including glutamate and serotonin. Reduced glutamate function may underlie the deficits in novel object discrimination, which can be reversed by administration of a 5-HT₆ receptor antagonist. This suggests that the 5-HT₆ antagonists may act by reducing 5-HT₆ receptor mediated activation of GABA, resulting in glutamate disinhibition. Thus drugs acting at 5-HT₆ receptors may offer a novel approach to treat neurodevelopmental cognitive symptoms, including those seen in schizophrenia.This article is part of a Special Issue entitled ‘Serotonin’.     

Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects

Neonatal maternal separation (MS) has been used to model long-term changes in neurochemistry and behaviour associated with exposure to early-life stress. This study characterises changes in behavioural and neuroendocrine parameters following MS. On postnatal days (PND) 3-15, male and female Long-Evans rats underwent 3 h daily MS. Non-handled (NH) control offspring remained with the dams. Starting at PND 90, behaviour was assessed at weekly intervals in the elevated plus-maze, elevated T-maze, and locomotor activity boxes, and body weight monitored throughout. At the end of the study, adrenals were weighed and blood collected for analysis of plasma corticosterone and adrenocorticotropic hormone (ACTH) under basal conditions and following restraint stress. As adults, MS weighed more than NH animals. Activity on the open arms of the plus-maze was similar between MS and NH animals. In the T-maze, MS males had shorter emergence latencies than their NH counterparts. Spontaneous ambulation in a novel environment was significantly higher in MS than in NH animals, and males exhibited overall lower activity than females. Basal plasma corticosterone was lower in MS than in NH females, but no rearing condition difference was observed following restraint stress. Females had higher corticosterone and ACTH levels than males, whereas adrenal glands of MS animals weighed less than those of NH controls. The MS paradigm caused long-term gender dependent effects on behaviour and HPA axis status. The consistent gender differences confirm and expand existing results showing altered anxiety and stress reactivity in male and female rats.     

Iron supplement in pregnancy and development of gestational diabetes—a randomised placebo-controlled trial

Objective  To test the hypothesis that iron supplement from early pregnancy would increase the risk of gestational diabetes mellitus (GDM).
Design  Randomised placebo-controlled trial.
Setting  A university teaching hospital in Hong Kong.
Population  One thousand one hundred sixty-four women with singleton pregnancy at less than 16 weeks of gestation with haemoglobin (Hb) level between 8 and 14 g/dl and no pre-existing diabetes or haemoglobinopathies.
Methods  Women were randomly allocated to receive 60 mg of iron supplement daily ( n = 565) or placebo ( n = 599). Oral glucose tolerance tests (OGTTs) were performed at 28 and 36 weeks. Women were followed up until delivery.
Outcome measures  The primary outcome was development of GDM at 28 weeks. The secondary outcomes were 2-hour post-OGTT glucose levels, development of GDM at 36 weeks and delivery and infant outcomes.
Results  There was no significant difference in the incidence of GDM in the iron supplement and placebo groups at 28 weeks (OR: 1.04, 95% confidence interval [CI]: 0.7–1.53 at 90% power) or 36 weeks. Maternal Hb and ferritin levels were higher in the iron supplement group at delivery ( P < 0.001 and P = 0.003, respectively). Elective caesarean section rate was lower in the iron supplement group (OR: 0.58, 95% CI: 0.37–0.89). Infant birthweight was heavier ( P = 0.001), and there were fewer small-for-gestational-age babies in the iron supplement group (OR: 0.46, 95% CI: 0.24–0.85).
Conclusion  Iron supplement from early pregnancy does not increase the risk of GDM. It may have benefits in terms of pregnancy outcomes.     

Social deprivation and the causes of stillbirth and infant mortality.

AIMS: To investigate the relation between social deprivation and causes of stillbirth and infant mortality. METHODS: Stillbirths and infant deaths in 6347 enumeration districts in Wales were linked with the Townsend score of social deprivation. In 1993-98 there were 211 072 live births, 1147 stillbirths, and 1223 infant deaths. Poisson regression analysis was used to estimate the magnitude of effect for associations between the Townsend score and categories of death by age and the causes of death. The relative risk of death between most and least deprived enumeration districts was derived. RESULTS: Relative risk of combined stillbirth and infant death was 1.53 (95% CI 1.35 to 1.74) in the most deprived compared with the least deprived enumeration districts. The early neonatal mortality rate was not significantly associated with deprivation. Sudden infant death syndrome showed a 307% (95% CI 197% to 456%) increase in mortality across the range of deprivation. Deaths caused by specific conditions and infection were also associated with deprivation, but there was no evidence of a significant association with deaths caused by placental abruption, intrapartum asphyxia, and prematurity. CONCLUSIONS: Collaborative public health action at national and local level to target resources in deprived communities and reduce these inequalities in child health is required. Early neonatal mortality rates and deaths from intrapartum asphyxia and prematurity are not significantly associated with deprivation and may be more appropriate quality of clinical care indicators than stillbirth, perinatal, and neonatal mortality rates.     

Living with Marfan syndrome I. Perceptions of the condition

We present data from an exploratory study of 174 adults with Marfan syndrome regarding their cognitive perceptions of the condition as postulated by the self-regulatory model (Leventhal H, Benyamini Y, Brownlee S et al. In: Petrie KI, Weinman JA, eds. Perceptions of Health and Illness: Current Research and Applications. Amsterdam, The Netherlands: Harwood Academic, 1997: 19-45; Leventhal H, Nerenz DR, Steele DJ. In: Baum A, Taylor SE, Singer JE, eds. Handbook of Psychology and Health. Hillsdale, NJ: Lawrence Erlbaum Associates, 1984: 219-252). The vast majority of the respondents had adequate general knowledge about Marfan syndrome. Eighty-three percent of the respondents perceived Marfan syndrome as having had significant adverse consequences on their lives. Having striae, pain (sore joints), and depression were each independently correlated with this view. Fifty-eight percent of the respondents indicated that they felt they had low to moderate control over their condition, demonstrating variability. History of aortic dissection, pain (sore joints), and depressive symptoms were each negatively correlated with the view that Marfan syndrome is a curable/controllable condition. Moreover, approximately 28% view the condition as a lethal condition, whereas 67% view it as a serious condition. Forty-four percent of the cohort were found to have significant symptomatology of depression independent of beta- and Ca2+-channel blockade use. Respondents cited both advantages and disadvantages of being affected. Genetic counseling that addresses patients' perceptions of Marfan syndrome, and its associated pain, fatigue, and depressive symptoms, may enhance patient adaptation to the condition.