title: Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors' Behavioral and Neurochemical Effects.
abstract: BACKGROUND
  The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine.
  
  
  METHODS
  Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC(-/-)) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme.
  
  
  RESULTS
  In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC(-/-) mice, as administration of 8-bromoadenosine 3', 5'-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes.
  
  
  CONCLUSIONS
  Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Munari
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Provensi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Passani
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Benetti
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: Corradetti
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, Firenze, Italy (Drs Munari, Provensi, Passani, Galeotti, Benetti, Corradetti, and Blandina); Dipartimento di Medicina Clinica e Sperimentale, Universitá di Foggia, Viale Luigi Pinto, 1 - 71100, Foggia Italy (Dr Cassano); Centro de Memória-Instituto do Cérebro-Pontificia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil (Dr Benetti).Present address (L.M.): Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.Present address (F.B.): Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, Porto Alegre, RS 90050-17, Brazil. patrizio.blandina@unifi.it.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Blandina
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D061218:Depressive Disorder, Treatment-Resistant / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008762:Methylhistidines / Q000378:metabolism; D008784:Methysergide / Q000494:pharmacology; D018345:Mice, Knockout; D017374:Paroxetine / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D000928:Antidepressive Agents; D015283:Citalopram; D017362:Cyclic AMP Response Element-Binding Protein; D006632:Histamine; D006640:Histidine Decarboxylase; D008762:Methylhistidines; D008784:Methysergide; D017374:Paroxetine; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C028309:alpha-fluoromethylhistidine
keywords: CREB; Histidine decarboxylase; citalopram; in vivo microdialysis; reboxetin; tail suspension test