Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study

Abstract

LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44-48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e., hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations.

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

“…Consistent with this, adult challenge with LP-211 did not lead to a differential activation of the nucleus accumbens: this accumbal stimulation by LP-211 was indeed independent on whether adult rats were adolescent-LP-211 preexposed or not (Altabella et al, 2014). On the other side, the septum was the only brain area, across the whole forebrain, actually showing (upon adult drug challenge) a differential change due to the developmental exposure: the septum did not respond to a LP-211 challenge in naive rats but displayed a strong activation due to adolescent pre-exposure to the same drug (Altabella et al, 2014). As a matter of fact, lower levels of SERT in the nucleus accumbens were indicative of a stable rearrangement: such modifications (most probably) involved neuroreceptor systems other than the 5-HT7 one.…”

“…However, changes in the levels of expression of the receptor itself, which was target of the pharmacological treatment, remained elusive. The only study in which we identified a persistent change in 5‐HT7 receptor (5‐HT7‐R) levels was pointing to the septum (see Altabella et al, ). Such a region, however, was outside of those areas found to display a permanent change in network connectivity (Canese et al, ).…”

“…Our recent findings confirm that exposure to LP‐211, a brain‐penetrant and selective agonist (Hedlund et al ; Leopoldo et al, ), may generate persistent changes in adult behavior (De Filippis et al, ; Ruocco et al, ), and rearrangement in forebrain morphology (Ruocco et al, ). As a consequence, through magnetic resonance, modifications in response of forebrain areas following acute drug challenge (Altabella et al, ) as well as in connectivity within these brain networks (Canese et al, ) were found in adult rats exposed to adolescent LP‐211. One implication of our results was that adult, adolescent‐LP‐211 exposed rats might display a profile of enhanced cognition and dampened emotions/motivation.…”

“…There, as a long‐term consequence of developmental exposure to LP‐211, we found in adult rats a reduced expression of SERT in ventral and of D2 receptors in dorsal striata, respectively. The lower level of SERT in the nucleus accumbens, however, was not accompanied by any detectable change of the 5‐HT7‐R expression (Altabella et al, ). Consistent with this, adult challenge with LP‐211 did not lead to a differential activation of the nucleus accumbens: this accumbal stimulation by LP‐211 was indeed independent on whether adult rats were adolescent‐LP‐211 pre‐exposed or not (Altabella et al, ).…”

“…The lower level of SERT in the nucleus accumbens, however, was not accompanied by any detectable change of the 5‐HT7‐R expression (Altabella et al, ). Consistent with this, adult challenge with LP‐211 did not lead to a differential activation of the nucleus accumbens: this accumbal stimulation by LP‐211 was indeed independent on whether adult rats were adolescent‐LP‐211 pre‐exposed or not (Altabella et al, ). On the other side, the septum was the only brain area, across the whole forebrain, actually showing (upon adult drug challenge) a differential change due to the developmental exposure: the septum did not respond to a LP‐211 challenge in naive rats but displayed a strong activation due to adolescent pre‐exposure to the same drug (Altabella et al, ).…”