Eitan Gur

Evidence for an association between the dopamine D3 receptor gene DRD3 and schizophrenia

Association of the dopamine D3 receptor gene (DRD3) and schizophrenia was examined in unrelated Israeli and Italian schizophrenic patients and ethnically matched normal control subjects. In the combined sample, there was a significant excess of DRD3 allele 2 among the schizophrenic patients (chi2 = 4.70, d.f. 1, p = 0.03). Comparison of genotype frequencies revealed an excess of the 2-2 genotype in the combined schizophrenic sample (chi2 = 8.30, d.f. 1, p = 0.01) and in the non-Ashkenazi Israeli schizophrenics alone (chi2 = 5.70, d.f. 2, p = 0.05). DRD3 2-2 genotype conferred a significantly increased risk of schizophrenia (chi2 = 8.21, d.f. 1, p = 0.004; OR = 2.87, CI 95% = 1.36-5.76) in the combined sample and in the non-Ashkenazi Israeli schizophrenics (chi2 = 7.22, d.f. 1, p = 0.04; OR = 7.22, CI 95% = 1.04-24.83). In the combined and Italian samples, allele 2 was associated with early age of onset as was the 2-2 genotype in the combined sample and non-Ashkenazi group. The 2-2 genotype was associated with poor response to neuroleptics, particularly in the non-Ashkenazi, Israeli schizophrenics. The possibility that DRD3 or a locus in linkage disequilibrium with it may play a role in the transmission of schizophrenia, is considered in relation to previous positive and negative reports.

The Amygdala Regulates the Pituitary-Adrenocortical Response and Release of Hypothalamic Serotonin following Electrical Stimulation of the Dorsal Raphe Nucleus in the Rat

The amygdala is known to modulate the function of the hypothalamo-pituitary-adrenocortical (HPA) axis, but the mechanism of this effect is still not clear. In the present study we examined the specific role of the serotonin (5-HT) system in mediating the effect of the amygdala on the activity of the HPA axis. Bilateral lesions of the amygdala in rats reduced the adrenocorticotropin (ACTH) and corticosterone responses to electrical stimulation of the dorsal raphe nucleus, where the cell bodies of serotonergic neurons are located. Amygdala lesions had no effect on the ACTH and corticosterone responses to administration of a 5-HT1A receptor agonist directly into the paraventricular nucleus (PVN) of the hypothalamus, indicating that there was no impairment in the activity of postsynaptic 5-HT1A receptors in the hypothalamus. In vivo microdialysis showed that amygdala lesions markedly attenuated the effect of electrical stimulation of the dorsal raphe to increase extracellular secretion of 5-HT in the PVN. This is the first demonstration that the amygdala has a facilitatory effect on the function of dorsal raphe 5-HT neurons which project to the PVN, and suggests a mechanism by which the amygdala may modulate the function of the HPA axis.

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.

Managing Childhood Overweight: Behavior, Family, Pharmacology, and Bariatric Surgery Interventions

IntroductIon A dramatic rise in overweight has been recently shown to occur among male and female adolescents in many countries, reaching epidemic proportions in Western industrialized countries (1). This increase in childhood obesity places a significant burden on physical, psychological, and social health and calls for an urgent implementation of diverse treatment strategies. It is currently accepted, and probably even required, for professionals to relate to childhood overweight, which signifies a physiological construct, rather than to childhood obesity, which bears considerable derogatory connotation (1). Accordingly, the US Centers for Disease Control and Prevention defines overweight among individuals 2–19 years old as the 95th percentile or greater of BMI-for-age (BMI = weight/height2), and risk for overweight as the 85th to 95th percentile of BMI-for-age (2). In this review we will use the term overweight, unless the use of obesity is required. Treating overweight children is of extreme importance, not only because it affects their physical and psychological well-being and development, but because a considerable proportion of overweight children are at risk to become obese adults (3). Thus, although the indications for medical interventions in overweight children are still not well defined, it is suggested, in accordance with this risk-related definition, that treatment is required in almost all overweight children, and in at risk for overweight children with related medical complications (1). All the authors of the present review article took part in an international multiprofessional consensus meeting dedicated to the issue of pediatric obesity held at the Dead Sea in Israel, in March 2004. The result of this meeting was a comprehensive consensus document where the evidence was summarized, and recommendations developed (1). The present review incorporates the findings of this consensus meeting with respect to currently available treatment options in pediatric obesity with an updated comprehensive systematic literature search of the Cochrane, PUBMED, PSYCHLIT, PSYCHINFO, and ERIC databases. Originally, we aimed to carry out a literature search for the decade before the consensus meeting (1994–2003), but subsequently added comprehensive updated information, including data published between 2004 and 2007. This time period has envisioned the most dramatic increase in the rates of pediatric obesity ever to occur (1). This suggests the presence of a very different treatment environment than before (3), calling for a critical appraisal of currently adequate treatments, promotion of new strategies, and enhancing the conditions for improving treatment outcome. The review is based on a total of 80 articles published between the years 1994 and 2007. The following interventions will be discussed: dieting and nondieting weight reduction programs (15 articles), change in lifestyle (18 articles), behavioral treatment (12 articles), family interventions (18 articles), pharmacotherapy (18 articles), surgical interventions (9 articles), and multidisciplinary in-patient interventions (7 articles) (quite a few articles relate to more than one treatment strategy). The study relates mostly to the findings of randomized control trials (RCTs), or controlled trials, unless otherwise specified.

Chronic clomipramine alters presynaptic 5-HT1B and postsynaptic 5-HT1A receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors in the hypothalamus, and on postsynaptic 5-HT(1A) receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT(1A) autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2mg/kg or 50 microg/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT(1B) receptors, as measured by the effect of an injection of the 5-HT(1B/1D) antagonist GR 127935 (5mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5-HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT(1A) receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 microg/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors, but that these effects are highly region-specific.

Chlorpromazine prophylaxis of steroid-induced psychosis

We report a case of successful prophylactic treatment for psychiatric side effects of megadose glucocorticoid therapy by the administration of chlorpromazine. We review currently used prophylactic treatment strategies and discuss the rationale for adding neuroleptic treatment as an alternative to these strategies.

Effects of triiodothyronine and fluoxetine on 5-HT1A and 5-HT1B autoreceptor activity in rat brain: regional differences.

The thyroid hormone triiodothyronine (T3) augments and accelerates the effects of antidepressant drugs. Although the majority of studies showing this have used tricyclics, a few studies have shown similar effects with the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. In this study we investigated the effects of fluoxetine (5 mg/kg), T3 (20 microg/kg) and the combination of these drugs, each administered daily for 7 days, on serotonergic function in the rat brain, using in vivo microdialysis. Fluoxetine alone induced a trend towards desensitization of 5-HT1A autoreceptors as shown by a reduction in the effect of 8-OH-DPAT to lower 5-HT levels in frontal cortex, and desensitized 5-HT1B autoreceptors in frontal cortex. The combination of fluoxetine and T3 induced desensitization of 5-HT1B autoreceptors in hypothalamus. Since there is evidence linking hypothalamic function and depression, we suggest that this effect may partly account for the therapeutic efficacy of the combination of an SSRI and T3.

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT1A and 5-HT1B receptor activity in rat hippocampus and hypothalamus

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.

Chronic electroconvulsive shock and 5-HT autoreceptor activity in rat brain: an in vivo microdialysis study

SummaryIn vivo microdialysis was used to determine the effects of chronic electroconvulsive shock (ECS), given daily for 10 days, on basal 5-HT levels in rat frontal cortex and hippocampus and on the effect of systemic administration of the 5-HT-la receptor agonist, 8-OH-DPAT (0.2 mg/kg), to reduce 5-HT levels in these areas by activation of somatodendritic autoreceptors. Neither basal 5-HT levels nor the effects of 8-OH-DPAT on 5-HT levels were altered after chronic ECS. The effect of systemic administration of the 5-HT1A and 5-HT1B antagonist, (±)-pindolol (10mg/kg), to increase 5-HT levels in hippocampus, was also not affected by chronic ECS.

Functional effects of corticosterone on 5-HT1A and 5-HT1B receptor activity in rat brain: in vivo microdialysis studies

Glucocorticoid hormones are known to be elevated in depression, and to interact with serotonin 5-HT(1A) receptors at both the presynaptic and postsynaptic levels. Since one of the presumed mechanisms of action of antidepressant drugs is induction of changes in sensitivity of 5-HT(1A) and also 5-HT(1B) receptors, the effects of repeated administration of corticosterone (50 mg/kg s.c. b.i.d. for 10 days) on activities of these receptors were determined using in vivo microdialysis in freely moving rats. Presynaptic 5-HT(1A) receptor activity, as measured by the effect of a challenge dose (0.2 mg/kg s.c.) of the 5-HT(1A) agonist 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) to reduce 5-HT levels in the hypothalamus, was not affected by corticosterone administration. Presynaptic 5-HT(1B) receptor activity, as measured by the effect of the 5-HT(1B) receptor 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 increase 5-HT levels, was increased in hypothalamus but not hippocampus of corticosterone-treated rats. Postsynaptic 5-HT(1A) receptor activity, as measured by the effect of 8-OH-DPAT to increase cyclic AMP levels in the hippocampus, was not affected by corticosterone administration. The decrease in presynaptic 5-HT(1B) receptor activity after chronic administration of antidepressant drugs complements the increases in 5-HT(1B) receptor number observed in animal models of depression.