Early antipsychotic treatment in juvenile rats elicits long-term alterations to the adult serotonin receptors

Abstract

BackgroundAntipsychotic drug (APD) prescription/use in children has increased significantly worldwide, despite limited insight into potential long-term effects of treatment on adult brain functioning. While initial long-term studies have uncovered alterations to behaviors following early APD treatment, further investigations into potential changes to receptor density levels of related neurotransmitter (NT) systems are required.MethodsThe current investigation utilized an animal model for early APD treatment with aripiprazole, olanzapine, and risperidone in male and female juvenile rats to investigate potential long-term changes to the adult serotonin (5-HT) NT system. Levels of 5-HT1A, 5-HT2A, and 5-HT2C receptors were measured in the prefrontal cortex (PFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus via Western Blot and receptor autoradiography.ResultsIn the male cohort, long-term changes to 5-HT2A and 5-HT2C receptors were found mostly across hippocampal and cortical brain regions following early aripiprazole and olanzapine treatment, while early risperidone treatment changed 5-HT1A receptor levels in the NAc and PFC. Lesser effects were uncovered in the female cohort with aripiprazole, olanzapine and risperidone to alter 5-HT1A and 5-HT2A receptors in NAc and hippocampal brain regions, respectively.ConclusionThe results of this study suggest that early treatment of various APDs in juvenile rats may cause gender and brain regional specific changes in 5-HT2A and 5-HT2C receptors in the adult brain.

The effects of amphetamine on working memory and locomotor activity in adult rats administered risperidone early in life

“…Using lower but more frequent doses of risperidone, De Santis et al [34] reported that juvenile administration led to greater activity in males relative to females in adulthood. They have also reported sex-specific alterations in regional dopamine and serotonin receptor density after juvenile risperidone administration [20,35]. While we observed sex differences in behavior that were the opposite of those reported by DeSantis et al [34] it is possible that these differences still emanate from sex-specific modifications in dopamine and serotonin neurotransmission induced by chronic risperidone administration.…”

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

“…Western blot procedures were conducted using standard methods used in our laboratory (Jimenez Naranjo et al, 2019; Millard et al, 2019; Osborne et al, 2019a, 2019b). DVC and MBH tissue was individually homogenised (left and right hemispheres combined) in NP-40 cell lysis buffer containing 0.5 mM β-glycerophosphate, 1 mM phenylmethane sulfonyl fluoride and 1% Protease Inhibitor Cocktail, as previously described (De Santis et al, 2018). Samples were centrifuged (20,000 g for 10 minutes), and supernatant was collected and stored (–80°C).…”

Early antipsychotic exposure affects NMDA and GABAA receptor binding in the brains of juvenile rats

“…The therapeutic effects of antipsychotics are attributed to their antagonism at the dopaminergic D2 and serotonergic 5-HT2 receptors (Ginovart and Kapur, 2012;Meltzer and Massey, 2011). Recent studies reported that early antipsychotic treatment altered dopaminergic and serotonergic neurotransmission (De Santis et al, 2018;De Santis et al, 2016;Lian et al, 2016). There is interaction between dopamine and NMDA neurotransmission in various brain regions in the nigrostriatal and mesostriatal circuits (Gardoni and Bellone, 2015).…”