European Neuropsychopharmacology (v.16, #7)

Schizophrenia-associated neural growth factors in peripheral blood. A review by Nico J.M. van Beveren; Job-Jeroen van der Spelt; Lieuwe de Haan; Durk Fekkes (469-480).
In this paper we review the findings on neural growth factors in the peripheral blood of schizophrenia patients. The studies we review provide evidence for the fact that in schizophrenia the levels of growth factors in peripheral blood are disturbed. The most robust results (7 studies) are reported for S100B protein, which seems to be elevated in acute psychosis and in patients with predominant negative symptoms. We conclude that there are aberrant levels of growth factors in peripheral blood in schizophrenia patients, probably most notably in patients with negative symptoms. Large-scale longitudinal multivariate studies, investigating the levels of several growth factors at the same time might give insight in etiological processes and identify clinically useful subsets of patients within the heterogeneous schizophrenia sample.
Keywords: Schizophrenia; Peripheral blood; Neurotrophic; Neurotrophin; Neural growth factor;

In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1β, TNF-α, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th1: IFN-γ and Th2 / 3: IL-10) cytokines. All of the antidepressants suppressed IFN-γ production in the 10–50 μM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-γ production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-γ production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-γ production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 μM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-γ producing T-cells (Th1 cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed.
Keywords: Antidepressant; Cytokine; Immunomodulation; Interferon-γ; Monocyte; T-cell;

Long-term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia (TD) characterized by repetitive involuntary movements, involving the mouth, face and tongue. TD generally persists after haloperidol withdrawal indicating long lasting changes in brain function that are no longer related to the presence of the drug. The precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. Haloperidol has been shown to induce the expression of the transcription factor nuclear factor-κB (NFκB). NFκB resembles a heterodimer protein composed of a 50 and a 65 kDa subunits and the role of the NFκB subunits on haloperidol-induced toxicity remains still unknown. The aim of the present study is to investigate the role of the p65 and p50 subunits of NFκB on the toxicity induced by chronic haloperidol administration in an experimental model of TD. Rats were treated for 21 days with: haloperidol (1 mg/kg), clozapine (1 mg/kg) or saline. Apomorphine-induced stereotyped behavior was evaluated. Striatal expression of the dopamine transporter (DAT) and the nigral expression of the NFκB p65 and p50 subunits were measured by Western Blot. Haloperidol, but not clozapine, increased stereotyped behavior associated to a decreased striatal DAT expression (p  < 0.01). Haloperidol did not modify the nigral expression of the p65 subunit whereas clozapine decreased it (p  < 0.01). Both drugs induced a significant decrease in the nigral expression of the NFκB p50 (p  < 0.05 and p  < 0.01, respectively). The decrease in nigral expression of the p50 subunit may increase the vulnerability of the dopaminergic neurons to a possible neurotoxic effect of p65 subunits in the haloperidol-treated rats.
Keywords: Haloperidol; Stereotypies; Neurotoxicity; Clozapine; NFκb;

Association study of two serotonin 1A receptor gene polymorphisms and fluoxetine treatment response in Chinese major depressive disorders by Younger W.-Y. Yu; Shih-Jen Tsai; Ying-Jay Liou; Chen-Jee Hong; Tai-Jui Chen (498-503).
The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors. Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors (SSRIs). Recent studies, including our recent findings, have reported that a functional HTR1A C-1019G polymorphism in the promoter region, as well as a nonsynonymous polymorphism, Gly272Asp, may be associated with SSRI pharmacogenetics. In this study, we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine antidepressant effect in 222 Chinese major depressive patients. We also tested the linkage disequilibrium (LD) measurement between HTR1A Gly272Asp and C-1019G polymorphisms, and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and fluoxetine antidepressant response. The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response. The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response. This association is gender-specific and mostly arises from the effect of HTR1A C-1019G polymorphism: female patients with -1019C/C genotype showed a better response than -1019G carriers. These findings need to be confirmed in other ethnic populations.
Keywords: Serotonin 1A receptor; Polymorphism; Fluoxetine; Pharmacogenetics; Selective serotonin reuptake inhibitor;

Anxiety and ethanol consumption in victorious and defeated mice; effect of κ-opioid receptor activation by Natalia Kudryavtseva; Mirjam A.F.M. Gerrits; Damira F. Avgustinovich; Michael V. Tenditnik; Jan M. Van Ree (504-511).
Alcohol consumption and addiction have been related to anxiety and the anxiolytic effect of ethanol. It has been shown in mice that losers with repeated experience of social defeats are more anxious than winners with repeated experience of victories. Mice with a different social status were tested for their oral ethanol consumption using a free two bottle choice paradigm and for their social approach behaviour after ethanol consumption using the partition test, in which anxiety is an important component. In addition, the sensitivity of the animals for the κ-opioid receptor agonist U-50,488H (2.5 mg/kg, s.c.) was assessed using the partition test, in which this drug has been shown to induce anxiolytic-like effects. Further, the effect of daily treatment with U-50,488H for 8 days on ethanol consumption was tested in animals that had consumed ethanol and were subjected during these 8 days to a period of 5 days of interruption of ethanol supply and subsequently to a period of 3 days of renewed access to ethanol.Losers consumed more ethanol than winners. Consumption of ethanol was accompanied by a decrease of anxiety level, as evidenced by an increased approach behaviour in the partition test. U-50,488H stimulated ethanol consumption after a period of 5 days of interruption of ethanol supply and drug treatment in the losers, but not in the winners. U-50,488H increased approach behaviour in the losers not consuming ethanol and decreased this behaviour in the winners, especially in those that had consumed ethanol. It is postulated that U-50,488H acts as a partial agonist in this respect. The increased anxiety may be related to the enhanced ethanol consumption in the losers, which may be of relevance for the etiology of alcohol addiction.
Keywords: κ-opioids; Ethanol; Mice; Anxiety; U-50, 488H; Winners; Losers; Social status;

Lack of effect of acute dopamine precursor depletion in nicotine-dependent smokers by Kevin F. Casey; Chawki Benkelfat; Simon N. Young; Marco Leyton (512-520).
Nicotine increases dopamine (DA) release but its role in nicotine dependence remains unclear.To assess the role of DA in nicotine craving and self-administration using acute phenylalanine/tyrosine depletion (APTD).Fifteen nicotine-dependent men ingested, a minimum of 3 days apart, a nutritionally balanced amino acid (AA) mixture (BAL), a mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, and APTD followed by the immediate DA precursor, l-DOPA. Beginning 3 h after ingestion of the AA mixture, subjects smoked 4 cigarettes. Craving, mood, and other aspects of subjective state were assessed with self-report scales. Smoking puff topography was measured with a computerized flowmeter.APTD did not change smoking puff topography, cigarette craving, or subjective effects of smoking.The findings suggest that in nicotine-dependent smokers craving for cigarettes, subjective effects of nicotine, and the self-administration of freely available cigarettes are largely unrelated to acute changes in DA neurotransmission.
Keywords: Smoking; Addiction; Motivation; Reward; Nicotine; Dopamine;

Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists by Lucia Carboni; Miriam Vighini; Chiara Piubelli; Laura Castelletti; Alberto Milli; Enrico Domenici (521-537).
Chronic administration of antidepressants is required for their efficacy, suggesting the involvement of long-term modifications. As the impact of antidepressant treatment on the brain molecular machinery is not completely understood, we performed a proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine, with an NK1 receptor antagonist, GR205171, and a CRF receptor 1 antagonist, DMP696. After 2D electrophoresis, protein expression levels were compared with both univariate and multivariate statistical analyses and identified by mass spectrometry. All treatments modified levels of actin isoforms, whereas both fluoxetine and GR205171 reduced synapsin II. Fluoxetine treatment increased ERK2 and NP25 and decreased vacuolar ATP synthase. After GR205171 treatment, protein disulphide isomerase A was reduced; dynamin 1 and aldose reductase increased. DMP696 modulated DRP2, pyruvate kinase, LDH and ATP synthase. Although each compound induced a specific pattern of protein modulation, data suggest that antidepressants share the ability of modulating neural plasticity.
Keywords: 2D electrophoresis; Antidepressive agents; Proteomics; Neurokinin1 receptor; Corticotropin-releasing hormone; Serotonin uptake inhibitors;

Melatonin affects the immobility time of rats in the forced swim test: The role of serotonin neurotransmission by Vincenzo Micale; Anna Arezzi; Liborio Rampello; Filippo Drago (538-545).
The efficacy of melatonin or its derivatives in depressive patients has been recently considered for clinical application. However, the evidence for its effect on experimental models of depression is not consolidated. Here, the effects of melatonin on the model of forced swim test (FST) paradigm were studied in male rats of the Wistar strain after acute intraperitoneal (i.p.) administration of 0.1, 0.5 or 1 mg/kg of the hormone. Melatonin at doses of 0.5 and 1 mg/kg, but not of 0.1 mg/kg, decreased the immobility of rats in the FST paradigm suggesting a possible antidepressant-like activity. The dose of 0.5 mg/kg appeared to be as potent as clomipramine 50 mg/kg in reducing the immobility time of rats in the FST paradigm. The effect of melatonin on immobility time of rats in the FST paradigm was abolished by the simultaneous injection of the non-selective melatonin antagonist, luzindole (0.25 mg/kg, subcutaneously). Similarly, administration of small quantities of serotonin (5-HT, 5 ng/1 μl) or of the 5-HT2A/5-HT2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (2 ng/1 μl) injected into the amygdale totally suppressed the reduction of immobility time in the FST paradigm induced by melatonin 0.5 mg/kg. These results may suggest that effects of melatonin on the behavioral reaction of rats in the FST paradigm are due to an interaction of the hormone with central 5-HT neurotransmission.
Keywords: Melatonin; Forced swim test; Antidepressant activity; 5-HT; Luzindole;