Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

Abstract

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

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

“…These observed changes are in addition to the alterations to various behavioral attributes (including anxiety and depressive-like behaviors) and the dopamine NT system (including receptors, transporters, and synthesis markers) previously reported with the same treatment model in our laboratory. 35 , 39 Although the observed alterations to the 5-HT NT system in the investigated regions provide some evidence of the potential for early APD treatment to elicit long-term alterations to a NT system functioning, further investigations have the potential to uncover both the scope of changes elicited on the 5-HT NT system and potential alterations to other NT groups. Other NT systems including the adrenergic and muscarinic NT systems are also known to be a part of the pharmacological mechanisms of action of APDs and interplay with other NT systems, 37 , 97 – 99 and thus, antagonist actions during the critical neurodevelopmental time period have the potential to elicit long-lasting changes that may be exhibited clinically.…”

“…Furthermore, the subsequent deficiency in projections of the 5-HT NT has been found to result in the disinhibition and therefore enhancement of the DA signal 36 – 38 and correlated to changes in behaviors, as demonstrated in our previous investigations. 35 , 39 Changes in behaviors including enhanced locomotor activity 36 , 37 and anxiolytic and decreased depressive-like behaviors 8 , 36 , 75 , 81 – 84 have previously been uncovered and correlated to the repeated antagonism of the 5-HT 2 receptor, potentially the negatively correlated alterations to the DA signal.…”

“…Potential influencing factors on the observed gender differences in results have been outlined extensively in previous publications. 35 , 39 Specifically, the well-known differences in the development and expression of 5-HT receptors between genders 89 and with the influence of the sex hormones testosterone and estrogen 26 , 82 , 89 – 91 have the potential to play a role in the observed gender differences. Previously demonstrated gender variations to 5-HT-mediated functions have an obvious potential to influence the observed results, 89 , 92 with the sex hormones testosterone and estrogen found to play a critical role.…”

“…Subsequently, there is the potential that early insult/use of potent APDs at this critical time of neurodevelopment may have the ability to cause long-term alterations to the functionality of the NT systems, including that of 5-HT, in a manner that precedes normal brain functioning. 8 , 27 , 34 , 35 With alterations to the 5-HT NT system previously linked to changes in both behavioral attributes (including locomotor, anxiety, and depressive-like behaviors) and furthermore negatively correlated to dopamine NT functioning, 36 – 38 prescription and use of APDs during the critical neurodevelopmental time period have the potential to lead to long-term deficits in brain functioning. 10 , 35 , 39 …”

“… 45 , 46 While investigations into the distribution/density of various NT receptor subtypes, including 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors, have found various immediate alterations following short-term APD treatment, 44 , 45 , 47 studies investigating the long-term effects of early APD treatment have been found to be limited to the DA NT system. 19 , 35 , 48 …”