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Biomedical subjects

B Lerer

Publications and source records attributed to B Lerer.

At least 55 records · Page 3Linked to original sources
PubMed2000

Subchronic fluoxetine administration to rats: effects on 5-HT autoreceptor activity as measured by in vivo microdialysis.

Subchronic administration of fluoxetine to rats has been shown to induce subsensitivity of presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors, and also postsynaptic 5-HT(1A) receptors in the hypothalamus. We investigated the effects of administration of fluoxetine (10 mg/kg i.p.) to rats for 6 days on presynaptic 5-HT(1A) receptor activity in the hypothalamus, postsynaptic 5-HT(1A) receptor activity in the hippocampus, and presynaptic 5-HT(1B) autoreceptor activity in both areas, using in vivo microdialysis. The effect of the 5-HT(1B/1D) antagonist (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5- methyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-carboxamide (GR 127935) (5 mg/kg s.c.) to elevate 5-hydroxytryptamine (5-HT) levels was reduced in hippocampus but not hypothalamus of fluoxetine-treated rats. Fluoxetine did not alter either presynaptic 5-HT(1A) autoreceptor activity, as measured by the effect of injection of 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.2 mg/kg or 50 microg/kg s.c.) on 5-HT levels in the hypothalamus, or postsynaptic 5-HT(1A) receptor activity, as measured by the effect of 8-OH-DPAT (0.2 mg/kg s.c.) on cyclic AMP accumulation, in the hippocampus.

Animals↗
PubMed2000

Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings.

The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5' regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism (chi2TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95.

Brain Chemistry↗
PubMed2000

A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6.

Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.

Chromosome Mapping↗
PubMed2000

Balancing speed of response to ECT in major depression and adverse cognitive effects: role of treatment schedule.

Schedule of administration (number of ECT per week and total number of treatments in the course) is one of a number of factors that may significantly influence the degree of cognitive impairment induced by ECT. We examined the effect of twice (ECT x 2) versus three times weekly (ECT x 3) bilateral ECT on cognitive function, particularly memory, in patients with major depression. Two studies were conducted, both double blind and controlled by the administration of simulated ECT (anesthesia and muscle relaxant only with no electrical stimulation). The results of these studies showed that the antidepressant effect of the two schedules, when assessed at the end of the ECT course, was equal. Speed of response was significantly greater with ECT x 3 but this schedule induced more severe memory impairment, even when the number of ECT in the series was not significantly different between the two groups. These findings are in general accordance with other studies that were similar in design although not as rigorously controlled. They support the conclusion that ECT x 2 is the more appropriate schedule for regular clinical practice unless speed of response is an overriding concern. In an era when patients administered ECT tend to be older and are more likely to manifest cognitive impairment for other reasons, choice of schedule is of particular relevance along with other factors such as electrode placement and stimulus intensity that influence ECT-induced cognitive impairment.

Adult↗
PubMed2000

An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.

We assessed whether the efficacy of plant-source derived phosphatydilserine (one of the phospholipids which play an important functional role in membrane-related processes in the brain) for treatment of age related cognitive decline is consistent with previous (placebo controlled) positive findings with bovine derivative of PS (BC-PS). Eighteen healthy elderly volunteers meeting Age Associated Memory Impairment inclusion and exclusion criteria were treated for 12 weeks with plant-source derived phosphatydilserine (PS) (100 mg x 3/day p.o.) and evaluated at base line, after 6 weeks of treatment and at the end of the trial. Fifteen concluded the study. All but two outcome measures elicited a significant drug over time effect. Post-hoc paired t-tests showed that the significant effect was attributable to an improvement from base line to week 6 and that effect was maintained at week 12. These results are encouraging. However, they await double-blind controlled verification in a large sample before suggesting that this may be a viable approach to the treatment of age-related cognitive decline, without exposing the patients to possible hazards involved in the treatment with bovine derivative of PS (BC-PS).

Aged↗
PubMed1999

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

Adult↗
PubMed1999

Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo.

Venlafaxine is a dual serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake inhibitor which has been claimed to have an onset of antidepressant action which is faster than for other comparable drugs. The effects of venlafaxine on brain 5-HT levels in vivo have not yet been examined. Acute administration of venlafaxine to rats by i.p. injection resulted in dose-dependent increases in cortical and hippocampal 5-HT levels, as measured by in vivo microdialysis, over the range 5-20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.) for 4 weeks did not change basal 5-HT levels in either brain area. The effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg s.c.) to reduce 5-HT levels was unaffected by chronic venlafaxine at this dose, indicating that there was no change in sensitivity of presynaptic 5-HT1A autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Clinical doses of fluoxetine and cerebral blood flow in healthy volunteers.

RATIONALE: Of the specific serotonin reuptake inhibitors (SSRIs), fluoxetine is perhaps the most widely used. Anecdotal reports, mostly in the non-medical press, have suggested that it may positively affect psychological functioning and enhance quality of life in the absence of overt psychiatric disorder. Such wide-spread use in not supported by scientific data. OBJECTIVE: This prospective single blind study examined the effects of long term administration of clinical doses of fluoxetine on cerebral blood flow (CBF) in healthy volunteers. METHODS: Fifteen healthy subjects were examined by Tc99m HMPAO SPECT after 2 weeks of placebo administration and then after 6 weeks of fluoxetine, administered at 20 mg per day. Blood for fluoxetine and norfluoxetine plasma levels was drawn to ensure compliance. Tc99m HMPAO uptake was analyzed by the region of interest approach, normalized to the cerebellum, and by statistical parametric mapping (SPM). RESULTS: No statistically significant differences between the two conditions were detected by both techniques. Correlation analysis between fluoxetine and norfluoxetine plasma levels and rCBF yielded no statistically significant values. CONCLUSION: Our findings suggest a differential effect of fluoxetine on CBF under the following conditions: (i) mental health versus psychiatric illness; (ii) acute versus long term administration. Our findings further emphasize the importance of longitudinal studies in elucidating the physiology of the normal brain as well as the pathophysiology of psychiatric disorders.

Adult↗
PubMed1999

Low doses of ipsapirone increase growth hormone but not oxytocin secretion in normal male and female subjects.

OBJECTIVE: The present study investigated whether administration of a 5-HT1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects. METHODS: Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design. RESULTS: Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups. CONCLUSIONS: The effects of gender and age on the degree of stimulation of GH secretion by 5-HT1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects.

Adult↗
PubMed1999

5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.

Adrenocorticotropic Hormone↗
PubMed1999

Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia.

The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.

Adolescent↗
PubMed1999

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Female↗
PubMed1999

Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia.

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.

Adult↗
PubMed1999

A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus.

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of </=2 cM, in the largest multigenerational BP pedigree series reported to date. A two-point heterogeneity (alpha=0.5) LOD score of 3.35 (P<.000156) was found at the D21S1260 locus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neighboring markers was consistent with these results (PL-HetLOD = 3.25). In the design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective approach to genotyping this large sample set. Linkage analyses were performed with an "affecteds-only" method. As such, our results are based solely on genetic information from affected individuals, without assumptions about the disease-locus genotypes of the unaffecteds. Furthermore, for ease of comparison, this study was performed with the same approach as a 10-cM genome scan for BP loci, the results of which will be reported elsewhere.

Bipolar Disorder↗