title: Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging.
abstract: BACKGROUND
  The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS.
  
  
  OBJECTIVE
  Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT(1A) receptors, citalopram was co-administered with a highly selective 5-HT(1A) receptor antagonist WAY100635.
  
  
  RESULTS
  Acute citalopram treatment (10 and 20 mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14 days of chronic daily administration of citalopram (20 mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3 mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures.
  
  
  CONCLUSIONS
  The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.
authors.affiliation: Psychobiology Research Group, Institute of Neuroscience, Newcastle upon Tyne, UK.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sekar
authors.forename: M
authors.initials: M
authors.lastname: Verhoye
authors.forename: J
authors.initials: J
authors.lastname: Van Audekerke
authors.forename: G
authors.initials: G
authors.lastname: Vanhoutte
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lowe
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blamire
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: A
authors.initials: A
authors.lastname: Van der Linden
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shoaib
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D010100:Oxygen / Q000097:blood; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D015283:Citalopram; D010100:Oxygen; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide