Article

Antipsychotic and antidepressant co-treatment: Effects on transcripts of inducible postsynaptic density genes possibly implicated in behavioural disorders

Laboratory of Molecular Psychiatry and Pharmacotherapeutics, Department of Neuroscience, Section of Psychiatry, University School of Medicine "Federico II", Edificio 18, Via Sergio Pansini 5, 80131 Naples, Italy.
Brain research bulletin (Impact Factor: 2.97). 02/2009; 79(2):123-9. DOI: 10.1016/j.brainresbull.2009.01.006
Source: PubMed

ABSTRACT Selective serotonin reuptake inhibitors (SSRIs) and antipsychotics co-administration is a widely used strategy to treat both psychotic depression and depressive symptoms in schizophrenia. Nonetheless, the molecular mechanisms involved in the therapeutic benefits of antidepressant-antipsychotic combination are still elusive. It has been suggested that co-administration of SSRIs and antipsychotics may result in molecular changes different from their individual effects. In the present study, we evaluated the acute effects of two SSRIs, citalopram and escitalopram, alone or in combination with haloperidol, on the expression of Homer1a together with its splice variant ania-3, and p11, two genes linked respectively to dopaminergic and serotonergic neurotransmission and involved in synaptic plasticity. Homer1a and ania-3 were induced in the striatum by haloperidol, alone and in combination with SSRIs, but not by SSRIs only. Haloperidol+citalopram co-administration induced a stronger Homer1a expression than haloperidol alone in the ventrolateral caudate-putamen. No signal was detected for p11 in striatum, while there were no significant differences among treatments in cortical subregions. Homer1a was significantly down-regulated in the parietal cortex by all treatments. These results demonstrated that haloperidol+citalopram combination exerts synergistic effects on Homer expression, suggesting that citalopram may influence the impact by haloperidol on the dopaminergic neurotransmission. Moreover, present findings confirm that Homer1a and ania-3 are strongly induced in striatum by haloperidol, while they are not influenced by citalopram or escitalopram in this region. Oppositely, in the cortex the two transcripts are modulated by both haloperidol and SSRIs, suggesting a possible role of both dopamine and serotonin in their cortical regulation.

Download full-text

Full-text

Available from: Carmine Tomasetti, Aug 05, 2015
0 Followers
 · 
127 Views
  • Source
    • "This panel comprised BDNF, Arc, VGLUT1 as well as the immediate early gene Homer1a and the post-synaptic density scaffolding protein Shank1B. Like BDNF, Arc and VGLUT1, the modulation of Homer1a by antidepressants (Dell'aversano et al. 2009) and the depressivelike phenotype induced by the genetic deletion of Homer (Jaubert et al. 2007), points to a key role of this gene in the pathophysiology of depression. Moreover, Shank1B expression was decreased in an animal model of depression (Serres et al. 2010), although no studies have investigated its modulation by antidepressant treatment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evidence of early changes in neural plasticity may aid the prediction of rapid-onset antidepressant drugs. Here we compared the dual α₂-adrenoceptor antagonist/5-HT-noradrenaline reuptake inhibitor (SNRI), S35966, to the SNRI, venlafaxine, with regards to their effect on rat brain expression of a panel of neural plasticity-related genes: Arc, BDNF, and VGLUT1, as well as Homer1a and Shank1B (not studied previously). Abundance of mRNA was determined by in-situ hybridization in cortical and hippocampal regions 2 h and 16 h following drug administration for 14, 7 and 1 d. After 14 d, both S35966 and venlafaxine increased mRNA of all genes, including Homer1a and Shank1B, and effects were similarly time- and region-dependent. After 7 d, S35966 elevated Arc, Shank1B and BDNF mRNA, whereas venlafaxine increased Shank1B mRNA only. Finally, after 1 d (acute administration), S35966 increased Arc and Homer1a mRNA whereas venlafaxine had no effect on any gene examined. In summary, a 14-d course of treatment with S35966 or venlafaxine induced similar region- and time-dependent increases in expression of neural plasticity-related genes including Shank1B and Homer1a. Some genes responded earlier to S35966, suggesting that drugs with combined α₂-adrenoceptor antagonist/SNRI properties may elicit more rapid changes in markers of neural plasticity than a SNRI alone.
    The International Journal of Neuropsychopharmacology 05/2011; 15(5):617-29. DOI:10.1017/S1461145711000733 · 5.26 Impact Factor
  • Source
    • "Results showed that, in the acute paradigm, the combined treatment with haloperidol plus valproate induced striatal Homer1a expression at a lesser extent as compared to that induced by haloperidol alone. In fact, as already described in our previous studies (Ambesi-Impiombato et al., 2007; de Bartolomeis et al., 2002; Dell'Aversano et al., 2009; Polese et al., 2002; Tomasetti et al., 2007), in caudate-putamen Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Indeed, haloperidol plus valproate association also robustly induced the gene, but demonstrated a significant reduction in the extent of the increase of Homer1a signal as compared to haloperidol alone. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30 mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15 mg/kg), which has been demonstrated to display antidepressant action in bipolar depression.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2010; 35(1):184-97. DOI:10.1016/j.pnpbp.2010.10.025 · 4.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.
    Pharmaceuticals 09/2010; 3(10). DOI:10.3390/ph3103040
Show more