Biomedical subjects

R Weizman

Publications and source records attributed to R Weizman.

At least 37 records · Page 2Linked to original sources

PubMed1999

The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency.

Using the mouse tail-flick assay, we evaluated the antinociceptive effect and the interaction with the opioid, adrenergic, and serotonergic systems of the two "atypical" neuroleptic agents clozapine and olanzapine. Clozapine induced a potent antinociceptive effect in a dose-dependent manner with ED50 of 8.7 mg/kg. This effect was antagonized by the nonselective opioid antagonist naloxone (p < 0.05), implying an opioid mechanism of action involved in clozapine-induced antinociception. Further evaluation demonstrated the involvement of micro1-, micro2-, kappa1- opioid receptor subtypes and of alpha2-adrenoreceptors in clozapine antinociception but not the serotonin receptors. Olanzapine induced a weak antinociceptive effect. The highest effect found was a 50% antinociception following an injection of 10 mg/kg. As the olanzapine dose increased beyond 10 mg/kg, latencies declined almost back to baseline. Yohimbine (an alpha2-adrenoreceptor antagonist) significantly reduced olanzapine's antinociceptive effect almost completely (to 10%; p < 0.05), while both naloxone and metergoline (a nonselective 5-HT receptor antagonist) reduced it only partially. These results indicate the possible involvement of the alpha2-adrenoreceptors in olanzapine antinociception and to a less extent the involvement of opioid and serotonergic receptors. Although both clozapine and olanzapine are dibenzodiazepines with similar "atypical" antipsychotic properties, it seems that they differ notably not only regarding their hematological side effects, but regarding their interaction with the opioid system as well.

Analgesics↗

PubMed1999

Long-lasting effect of early handling on the peripheral benzodiazepine receptor.

The present study determined the impact of early handling (EH) in rats on behavioral response to environmental stress and on peripheral benzodiazepine receptor (PBR) binding characteristics (Bmax and Kd) in various organs. The behavioral consequences of EH in rats were expressed as increased exploratory activity in an open-field paradigm, when compared with nonhandled control rats. These findings are interpreted in terms of decreased emotionality. The biochemical consequences of EH, in both male and female rats, were expressed as the upregulation of PBR in the adrenal and kidney and the downregulation of gonadal (testis and ovary) PBR. It is possible that the long-lasting adrenal and renal changes in PBR expression in EH rats may enable better regulation of the hypothalamic-pituitary-adrenal axis, renin-angiotensin system, and autonomic nervous system responses to stress in adulthood. The significance of the EH-induced reduction in gonadal PBR for gonadal activity in adulthood is as yet unclear.

Adaptation, Biological↗

PubMed1999

A novel allele in the promoter region of the human serotonin transporter gene.

The human serotonin transporter (hSERT) gene is a promising candidate for mediating the genetic susceptibility for various psychiatric conditions such as mood and obsessive-compulsive disorders. Two polymorphic sites in this gene attracted much interest: a VNTR of 17-bp repeats in intron two, and an insertion/deletion in the 5'-flanking promoter region (5-HTT gene-linked polymorphic region-5-HTTLPR) creating a short (S) and a long (L) allele. The 5-HTTLPR polymorphism is situated in a GC-rich region composed of 20-23 bp repeating units. The S and L alleles have 14 and 16 repeat-elements respectively. Positive associations of the 5-HTTLPR polymorphism with mood disorders, anxiety-related personality traits, autism and late-onset Alzheimer's disease have been published, although some non replications were also reported. Here we report a novel allele (termed LJ) in the 5-HTTLPR site. This allele is longer than the L allele by 43 bp, has 18 repeat units and contains two copies of the insertion/deletion sequence arranged in tandem. The LJ allele was found in individuals of Libyan and Tunisian Jewish origin but not in Moroccan or Ashkenazi Jews.

Base Composition↗

PubMed1999

hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21.

We demonstrate a significant association between longer CAG repeats in the hKCa3/KCNN3 calcium-activated potassium channel gene and schizophrenia in Israeli Ashkenazi Jews. We genotyped alleles from 84 Israeli Jewish patients with schizophrenia and from 102 matched controls. The overall allele frequency distribution is significantly different in patients vs controls (P = 0.00017, Wilcoxon Rank Sum test), with patients showing greater lengths of the CAG repeat. Northern blots reveal substantial levels of approximately 9 kb and approximately 13 kb hKCa3/KCNN3transcripts in brain, striated muscle, spleen and lymph nodes. Within the brain, hKCa3/KCNN3transcripts are most abundantly expressed in the substantia nigra, lesser amounts are detected in the basal ganglia, amygdala, hippocampus and subthalamic nuclei, while little is seen in the cerebral cortex, cerebellum and thalamus. In situ hybridization reveals abundant hKCa3/KCNN3 message localized within the substantia nigra and ventral tegmental area, and along the distributions of dopaminergic neurons from these regions into the nigrostriatal and mesolimbic pathways. FISH analysis shows that hKCa3/KCNN3 is located on chromosome 1q21.

Base Sequence↗

PubMed1999

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways.

Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.

Alleles↗

PubMed1999

Image vividness as a psychophysiological regulator in Posttraumatic Stress Disorder.

This study examined the relationship between image vividness and psychophysiological responses to trauma-related stimuli in participants with Posttraumatic Stress Disorder (PTSD). An auditory stimulus related to a shared trauma was presented to participants with and without PTSD and physiological parameters (heart rate and blood pressure) were measured concurrently. A negative correlation was noted in the PTSD group between image vividness and the level of physiological response. When the PTSD group was divided into high and low vividness, the physiological response was higher than that of the non-PTSD controls only when image vividness was low. The results are discussed in the context of Lang' s theoretical model, emphasizing the role of image vividness in the mediation and regulation of psychophysiology.

Acoustic Stimulation↗

PubMed1999

Image control and symptom expression in posttraumatic stress disorder.

Despite the devastating impact of affective dysregulation in posttraumatic stress disorder (PTSD), there has been little research on how trauma relates to affect regulation. This study examines the relationship between the cognitive capacity to control mental images and symptoms of individuals with (N = 23) and without (N = 23) PTSD after exposure to SCUD missile attacks during the Gulf War. The capacity to control mental images, symptoms of posttrauma, anxiety, and anger were assessed. PTSD subjects with a high image control reported a higher capacity to control anger, lower levels of anger state and expression, and lower levels of intrusive symptoms compared with PTSD subjects with low image control. In individuals without PTSD, results show that the better the image control, the lower the control of anger and the higher the expression of anger. Image control seems to play different functions in the emotional regulation of normal subjects (facilitatory) and PTSD patients (protective).

Affect↗

PubMed1998

Effects of peripheral-type benzodiazepine receptor antisense knockout on MA-10 Leydig cell proliferation and steroidogenesis.

The peripheral-type benzodiazepine receptor (PBR) is not only widely expressed throughout the body, but it is also genetically conserved from bacteria to humans. Many functions have been attributed to it, but its primary role remains a puzzle. In the current study, we stably transfected cultures of MA-10 Leydig cells with either control or 18-kDa PBR antisense knockout plasmids. The antisense knockout vector was driven by the human enkephalin promoter, which contains two cAMP response elements, such that cAMP treatment of transfected cells could superinduce 18-kDa PBR antisense RNA transcription and, hence, down-regulate endogenous 18-kDa PBR mRNA levels. Control and knockout MA-10 cell lines were then compared at the level of receptor binding, thymidine incorporation, and steroid biosynthesis. Eighteen-kilodalton PBR knockout reduced the maximal binding capacity of tritium-labeled PBR ligands, and the affinity of receptors to the ligands remained unaltered. Additionally, 24-h accumulation of progesterone was lower in the knockout cells. Exposure of the two cell types to 8-bromo-cAMP resulted in a robust increase in steroid production. However, a complex pattern of steroid accumulation was observed, in which further progestin metabolism was indicated. The later decline in accumulated progesterone as well as the synthesis of androstenedione were different in the two cell types. At the level of cell proliferation, reduction of 18-kDa PBR mRNA showed no effect. Thus, we conclude that the 18-kDa PBR may have a more important role in steroidogenesis than in proliferation in this Leydig cell line.

Algestone↗

PubMed1998

The function of image control in the psychophysiology of posttraumatic stress disorder.

The physiological response to trauma-related stimuli of up to one third of participants with posttraumatic stress disorder (PTSD) cannot be discriminated from that of controls. Psychophysiological measures (heart rate and blood pressure) of 22 PTSD and 23 control civilian participants, all exposed to missile attacks during the Gulf War, were recorded while listening to five scripts. The physiological response of PTSD subjects with high image control (IC) was lower than that of PTSD participants with low IC and similar to that of non-PTSD subjects. The physiological response poorly discriminated high IC PTSD participants from controls, but was successful in discriminating low IC PTSD subjects from controls with 91% specificity and 92% sensitivity. Image control is proposed as a function influencing physiological response in PTSD.

Adult↗

PubMed1997

Peripheral-type benzodiazepine receptor ligands and serum steroid hormones.

The peripheral-type benzodiazepine receptors (PBR) are involved in various cellular functions, including steroidogenesis. The impact of these receptor ligands has been demonstrated mainly in steroidogenic cells. The aim of the present study was to assess in intact female rats the effect of chronic (21 days) administration of the PBR ligands PK 11195 (15 mg/kg) and Ro 5-4864 (5 mg/kg), the mixed ligand diazepam (5 mg/kg), and the central benzodiazepine receptor ligand clonazepam (1 mg/kg) on PBR binding characteristics in steroidogenic (ovary and adrenal) and non-steroidogenic (uterus and kidney) organs, as well as on serum hormonal steroids (estradiol, progesterone, and corticosterone). Selective and mixed PBR ligands up-regulated PBR density in the two steroidogenic organs, while Ro 5-4864 also induced elevation of the receptor density in the non-steroidogenic organs. In contrast to Ro 5-4864, PK 11195 treatment down-regulated renal PBR. Clonazepam elevated adrenal PBR. On the serum hormonal level, Ro 5-4864 suppressed estradiol secretion. The other ligands did not affect hormonal steroid levels. It appears that in female rats, at least at these doses and dosing schedules, there is no correlation between the impact of chronic in vivo exposure to these agents on PBR density and ovarian and adrenal hormone levels.

Adrenal Glands↗

PubMed1997

Effect of the pregnane-related GABA-active steroid alphaxalone on mice performance in the staircase test.

We evaluated the modulatory effect of the GABA-active neurosteroid alphaxalone on the staircase test behavior of mice. Results were compared with the benzodiazepine alprazolam, the GABA(A) agonist muscimol and the peripheral steroids corticosterone and progesterone. Alphaxalone and alprazolam reduced rearing activity in a dose-dependent manner, at doses that did not suppress climbing. The rearing-suppression effect of alprazolam, but not of alphaxalone, was blocked by the benzodiazepine antagonist flumazenil. No such dissociation between the effect on rearing and climbing was obtained with muscimol, and both activities were suppressed, in a flumazenil-insensitive pattern, at high doses. Corticosterone and progesterone did not affect the behavior of the mice. The lack of sensitivity of both phenobarbital and alphaxalone to flumazenil indicates that neither agents act via the benzodiazepine recognition site at the GABA(A) receptor complex.

Alprazolam↗

PubMed1997

Augmentation of opioid induced antinociception by the atypical antipsychotic drug risperidone in mice.

Risperidone is a novel atypical neuroleptic with a favorable profile of side effects due to its unique pharmacological activity: it exhibits both potent dopamine D2 and 5-HT2 receptor blocking activity, as well as high affinity for alpha1 and alpha2 adrenergic receptors and histamine H1 receptor. We found that risperidone has a potent antinociceptive effect in the tailflick assay with an ED50 of 26.4 mg/kg. This effect of risperidone was antagonized by naloxone (P < 0.05). This sensitivity to naloxone indicates that at least some of the analgesic effects of risperidone are mediated by an opioid mechanism of action. beta-FNA (mu1 mu2-antagonist), naloxonazine (mu1-antagonist) and norbinaltorphamine (nor-BNI; kappa1-analgesia) reversed risperidone antinociceptive effect (P < 0.05). Naltrindole (delta-antagonist) only partially reversed risperidone antinociceptive effect. We found that the sensitivity of risperidone antinociceptive effect to selective antagonists implies involvement of mu1-, mu2- and kappa1-opioid and to a lesser extent delta-opioid mechanisms. These results suggest a possible role for risperidone both in the management of pain and in the management of opiate withdrawal and detoxification.

Animals↗

PubMed1997

Impact of pregnancy and lactation on GABA(A) receptor and central-type and peripheral-type benzodiazepine receptors.

The effect of pregnancy and lactation on GABA(A) receptor and central- and peripheral-type benzodiazepine receptors (CBR and PBR, respectively) was studied in female Sprague-Dawley rats. Pregnancy was associated with increased CBR density (on day 19) in the hippocampus and with decreased [3H]Ro 15-1788-specific binding in the hypothalamus during pregnancy and lactation. A similar decrease in [3H]PK 11195-specific binding was observed in the hypothalamus and pituitary. An increase in PBR density in the ovary and uterus was observed during pregnancy, while adrenal PBR density was down-regulated during pregnancy and lactation. It seems that the hormonal changes occurring during pregnancy and lactation play a role in the regulation of CBR and PBR in discrete tissues.

Animals↗

PubMed1997

Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia.

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially kappa 3, in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose-response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for kappa 3 and mu receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated kappa 1 mechanisms of action. We did not detect any involvement of the delta receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with kappa 3 receptors and to a lesser extent with kappa 1 as well as its activity as partial mu receptor agonist.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

Flunarizine analgesia is mediated by mu-opioid receptors.

We evaluated the opioid antinociceptive mechanism of the calcium channel blocker flunarizine. Flunarizine produced a dose-dependent analgesia in the hot plate test which was antagonized by general (naloxone) and mu [beta-fualtrexamine (beta-FNA)]-opioid antagonists, indicating a role for mu receptors in flunarizine analgesia. Naltrindole (delta1 antagonist) did not affect flunarizine analgesia. A fixed subthreshold dose of flunarizine augmented mu (morphine) analgesia and blocked delta1 [enkephalin, [D-Pen2,5] (DPDPE)] analgesia. Apparently, flunarizine has mu agonistic activity and delta1 antagonist or mixed agonistic-antagonistic activity.

Animals↗

PubMed1997

Peripheral-type benzodiazepine receptor ligands modulate human natural killer cell activity.

Following our earlier work, we evaluated the in vitro effect of ligands active at the peripheral-type benzodiazepine receptors on human natural killer cell activity. Peripheral blood mononuclear cells were incubated with benzodiazepine receptor ligands. After 4 h we observed a nonspecific inhibition of natural killer cell activity induced by both peripheral (Ro5-4864 and PK 11195) and central (clonazepam) benzodiazepine receptor ligands; after 24 h, the suppressive activity was specific to peripheral and mixed (diazepam) ligands, and the central-type ligand had no effect. This significant, specific suppression of NK cell activity was completely reversed by the addition of human recombinant interleukin-2 or human leukocyte interferon. Our research provides additional information on the immunomodulatory effects of peripheral-type benzodiazepine ligands. Further studies are needed to clarify the underlying mechanism of natural killer cell inhibition and to determine the clinical implications of these findings.

Humans↗

PubMed1997

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

Adolescent↗

PubMed1997

Role of peripheral-type benzodiazepine receptors in steroidogenesis.

Peripheral-type benzodiazepine (BZ) receptors (PBRs) have been identified in various peripheral tissues as well as in glial cells in in the brain. PBRs are located mainly on the outer mitochondrial membrane and bind with high affinity the BZ Ro 5-4864 (4'-cholorodiazepam) and the non-BZ PK 11195 (an isoquinoline carboxamide derivative), but bind with very low affinity the BZ clonazepam. PBRs have been cloned from various species. PBRs are multimeric receptors composed of the 18-kDa binding site for isoquinolines, the 32-kDa voltage-dependent anion channel, and the 30-kDa adenine nucleotide carrier (which binds BZs). The expression of PBRs is especially high in steroidogenic organs. Steroid administration affects PBR density, whereas depletion of hormones by hypophysectomy in female rats, or castration (surgical or chemical) in male rats, decreases PBR density in endocrine organs, which can be elevated to normal values after administration of the appropriate hormone. PBRs are probably involved in several functions, including cell proliferation, respiration, and steroidogenesis. It has been suggested that PBRs are involved in the translocation of cholesterol from the outer to the inner membrane of the mitochondria and have an effect on the biosynthesis of steroids.

Animals↗