Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist

Rossella Canese, Francesca Zoratto, Luisa Altabella, Paola Porcari, Laura Mercurio, Francesco De Pasquale, Erica Butti, Gianvito Martino, Enza Lacivita, Marcello Leopoldo, Giovanni Laviola, Walter Adriani

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: The serotonin 7 receptor (5-HT7-R) is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation. Objectives: We investigated long-term consequences of subchronic treatment, during adolescence (43-45 to 47-49 days old) in rats, with a novel 5-HT7-R agonist (LP-211, 0 or 0.250 mg/kg/day). Methods: We evaluated behavioural changes as well as forebrain structural/functional modifications by in vivo magnetic resonance (MR) in a 4.7 T system, followed by ex vivo histology. Results: Adult rats pre-treated during adolescence showed reduced anxiety-related behaviour, in terms of reduced avoidance in the light/dark test and a less fragmented pattern of exploration in the novel object recognition test. Diffusion tensor imaging (DTI) revealed decreased mean diffusivity (MD) in the amygdala, increased fractional anisotropy (FA) in the hippocampus (Hip) and reduced axial (D∥) together with increased radial (D⊥) diffusivity in the nucleus accumbens (NAcc). An increased neural dendritic arborization was confirmed in the NAcc by ex vivo histology. Seed-based functional MR imaging (fMRI) identified increased strength of connectivity within and between " limbic " and " cortical" loops, with affected cross-correlations between amygdala, NAcc and Hip. The latter displayed enhanced connections through the dorsal striatum (dStr) to dorsolateral prefrontal cortex (dl-PFC) and cerebellum. Functional connection also increased between amygdala and limbic elements such as NAcc, orbito-frontal cortex (OFC) and hypothalamus. MR spectroscopy (1H-MRS) indicated that adolescent LP-211 exposure increased glutamate and total creatine in the adult Hip. Conclusions: Persistent MR-detectable modifications indicate a rearrangement within forebrain networks, accounting for long-lasting behavioural changes as a function of developmental 5-HT7-R stimulation.

Original languageEnglish
Pages (from-to)75-89
Number of pages15
JournalPsychopharmacology
Volume232
Issue number1
DOIs
Publication statusPublished - 2015

Keywords

  • Amygdala
  • Anxiety
  • Cortical loop
  • DTI
  • Functional connectivity
  • Hippocampus
  • Limbic loop
  • Magnetic resonance spectroscopy
  • Nucleus accumbens
  • Serotonin 7 receptor

ASJC Scopus subject areas

  • Pharmacology

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