Stimulation of 5-HT7 receptor during adolescence determines its persistent upregulation in adult rat forebrain areas

Synapse. 2015 Nov;69(11):533-42. doi: 10.1002/syn.21846. Epub 2015 Sep 14.


Brain serotonin 7 (5-HT7) receptors play an important functional role in learning and memory, in regulation of mood and motivation, and for circadian rhythms. Recently, we have studied the modulatory effects of a developmental exposure (under subchronic regimen) in rats with LP-211, a brain-penetrant and selective 5-HT7 receptor agonist. We aimed at further deciphering long-term sequelae into adulthood. LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during the adolescent phase (postnatal days 43-45 to 47-49). When adult (postnatal days >70), forebrain areas were obtained for ex vivo immunohistochemistry, whose results prompted us to reconsider the brain connectivity maps presented in our previous study (Canese et al., Psycho-Pharmacol 2015;232:75-89.) Significant elevation in levels of 5-HT7 receptors were evidenced due to adolescent LP-211 exposure, in dorsal striatum (which also shows an increase of dopaminergic D2 auto-receptors) and-unexpectedly-in piriform cortex, with no changes in ventral striatum. We observed that functional connectivity from a seed on the right hippocampus was more extended than reported, also including the piriform cortex. As a whole, the cortical loop rearranged by adolescent LP-211 exposure consisted in a hippocampus receiving connections from piriform cortex and dorsal striatum, the latter both directly and through functional control over the 'extended amygdala'. Such results represent a starting point to explore neurophysiology of 5-HT7 receptors. Further investigation is warranted to develop therapies for sleep disorders, for impaired emotional and motivational regulation, for attentive and executive deficit. The 5-HT7 agonist LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during adolescence (postnatal days 43-45 to 47-49) in rats. When adult (postnatal days >70), a significant elevation in levels of 5-HT7 receptors were evidenced in dorsal striatum and-unexpectedly-in piriform cortex.

Keywords: D2 receptor; DAT; SERT; dorsal/ventral striata; emotional; immunohistochemisty; motivational and cognitive modulation; network connectivity; piriform cortex.

MeSH terms

  • Animals
  • Immunohistochemistry
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / growth & development
  • Neural Pathways / metabolism
  • Piperazines / pharmacology*
  • Prosencephalon / drug effects*
  • Prosencephalon / growth & development*
  • Prosencephalon / metabolism
  • Rats, Wistar
  • Receptors, Serotonin / metabolism*
  • Serotonin Receptor Agonists / pharmacology*
  • Up-Regulation


  • N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • serotonin 7 receptor