Olanzapine Treatment of Adolescent Rats Causes Enduring Specific Memory Impairments and Alters Cortical Development and Function

Abstract

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28–49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABAA receptors with open Cl− channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.

Early antipsychotic treatment in childhood/adolescent period has long-term effects on depressive-like, anxiety-like and locomotor behaviours in adult rats

“…Milstein and colleagues (Milstein et al 2013) investigated the effects of early Olanzapine treatment on locomotor activity in adulthood, with no changes to numerous parameters of the open-field test observed. Similarly, the present study found increases in the activity levels of Olanzapine-treated animals in the FS test but not in the Open-Field/Holeboard test, potentially due to the increased stress levels induced by the FS testing procedure.…”

“…Although current clinical research into the use of APDs in the adolescent population over both a short term period of between 1-2 months, and longer-term period of up to 6 months has found some benefits in the treatment of some mental illness symptomology (Stigler et al 2004; Kumra et al 2008;Zuddas et al 2011), there is limited data on the potential for longterm alterations to adult behaviours (Milstein et al 2013;Shu et al 2014;Varela et al 2014).…”

“…Although the effects of childhood/adolescent APD use on adult behaviours is unknown in a clinical setting, current animal studies have shown that early drug treatment for a period of up to 4 weeks can result in various significant alterations in the dopaminergic and serotonergic pathways in the brain long-term (Maciag et al 2006;Moran-Gates et al 2006;Vinish et al 2012;Milstein et al 2013;Varela et al 2014), including permanent changes in the distribution of NT receptors and dendritic architecture (Maciag et al 2006;Moran-Gates et al 2006;Milstein et al 2013), with minimal evidence of the direct effects on behaviour. Alterations to the production, transport and binding of DA and 5-HT in the cortical and striatal brain regions have already been directly linked to changes in behavioural attributes, including locomotor activity levels along with depressive-like and anxiety-like behaviours.…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…Still, it remains plausible that ultra-structural changes such as alterations in the dendritic spines can occur (Frost et al 2010;Milstein et al 2013).…”

“…A few preclinical studies over the past five years have also started to examine long-term neurobiological consequences of adolescent treatment with atypical APDs (De Santis et al 2016;Milstein et al 2013;Qiao et al 2013;Vinish et al 2013). For example, adolescent treatment with olanzapine has been shown to induce long-term deficits in behaviour in adulthood, such as alterations in working memory, fear conditioning, reward behaviour (to amphetamine) and anxiety/depression-related behaviour, as well as changes in neurotransmission in the NAc, and dendritic spine pruning in other major brain regions (Brooks et al 2016;De Santis et al 2016;Milstein et al 2013;Xu et al 2015).…”