Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders

• Published in: Psychopharmacology 2014-03, Vol.231 (6), p.1191-1200
• Main Authors: Khatri, Nidhi, Simpson, Kimberly L., Lin, Rick C. S., Paul, Ian A.
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animal behavior; Animals; Animals, Newborn; Autism; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - growth & development; Brain - metabolism; Citalopram - pharmacology; Exploratory Behavior - drug effects; Female; Freezing Reaction, Cataleptic - drug effects; Health aspects; Locomotion - drug effects; Male; Neurology; Neurosciences; Original Investigation; Oxadiazoles - pharmacology; Pharmacology/Toxicology; Phenols; Physiological aspects; Piperazines - pharmacology; Psychiatry; Psychopharmacology; Pyridines - pharmacology; Quinoxalines - pharmacology; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT1B - metabolism; Rodents; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; Social aspects; Social Behavior
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3242-2

Rationale Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in autistic spectrum disorders (ASDs). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear. Objective We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT 1A and/or 5-HT 1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure. Methods Male and female rat pups were treated from postnatal days 8 to 21. In Experiment 1, pups received citalopram (20 mg/kg/day), saline, (±)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT; 0.5 mg/kg/day) or 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2- a ]-quinoxaline dimaleate (CGS-12066B; 10 mg/kg/day). In Experiment 2, a separate cohort of pups received citalopram (20 mg/kg/day), or saline which was combined with either N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -2-pyridinylcyclo-hexanecarboxamide maleate (WAY-100635; 0.6 mg/kg/day) or N -[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1′-biphenyl-4-carboxamide (GR-127935; 6 mg/kg/day) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development. Results Direct and indirect neonatal stimulation of 5-HT 1A or 5-HT 1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD. Conclusion Increased stimulation of 5-HT 1A and 5-HT 1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.