Dose-dependent opposite effects of nortriptyline on affective-like behavior in adolescent rats: Comparison with adult rats

• Published in: European journal of pharmacology 2021-11, Vol.910, p.174465-174465, Article 174465
• Main Authors: Bis-Humbert, Cristian, García-Cabrerizo, Rubén, García-Fuster, M. Julia
• Format: Article
• Language: English
• Subjects: Adolescence; Adolescent; Adult; Affective Symptoms - chemically induced; Affective Symptoms - pathology; Affective Symptoms - physiopathology; Age Factors; Animals; Antidepressant; Antidepressive Agents - administration & dosage; BDNF; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Neurogenesis; Neurogenesis - drug effects; Neurogenesis - physiology; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Nortriptyline; Nortriptyline - administration & dosage; Rats; Rats, Sprague-Dawley
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174465

Antidepressant drugs elicit different behavioral and neurochemical responses with age. In fact, the use of antidepressants during adolescence is associated with an increased risk of suicidal thinking, being the best pharmacological treatment during this critical period a matter of constant debate in terms of its risk-benefit outcome. In this regard, the present study compared the effects of nortriptyline (3–10 mg/kg, 7 days) on regulating different aspects of affective-like behavior by screening adolescent and adult Sprague-Dawley rats through several consecutive tests (forced-swim, open field, sucrose preference). Brains were later collected to evaluate hippocampal neurogenesis and mBDNF protein content as potential molecular correlates of the observed behavioral responses. The main results in adolescent rats showed that nortriptyline induced dose-dependent opposite effects: while 3 mg/kg decreased immobility and increased mBDNF (indicative of an antidepressant-like response), 10 mg/kg decreased exploratory time in the open field and mBDNF (suggestive of an anxiogenic-like response). These effects were not associated with changes in neurogenesis regulation. In adult rats, nortriptyline failed to modulate affective-like behavior or the neuroplasticity markers evaluated at the doses tested. In conclusion, clear behavioral and neurochemical differences were observed between adolescent and adult rats in response to nortriptyline treatment. Interestingly, while nortriptyline displayed an antidepressant-like potential at the lowest dose examined in adolescence, a higher dose shifted these results towards a negative outcome, thus reinforcing the need to extreme caution when considering this treatment for our younger population. •Dose-dependent opposite behavioral effects of nortriptyline in adolescent rats.•Antidepressant-vs. anxiogenic-like responses in a dose-dependent manner.•Hippocampal BDNF regulation in a dose-dependent manner.•These behavioral effects in adolescence were independent of neurogenesis regulation.•No effects were observed by nortriptyline with the doses tested in adult rats.