Olanzapine Treatment of Adolescent Rats Alters Adult D2 Modulation of Cortical Inputs to the Ventral Striatum

The striatal dopamine system undergoes vast ontogenetic changes during adolescence, making the brain vulnerable to drug treatments that target this class of neurotransmitters. Atypical antipsychotic drugs are often prescribed to children and adolescents for off-label treatment of neuropsychiatric disorders, yet the long-term impact this treatment has on brain development remains largely unknown.

Adolescent male rats were treated with olanzapine or vehicle for 3 weeks (during postnatal day 28-49) using a dosing condition designed to approximate closely D2 receptor occupancies in the human therapeutic range. We assessed D2 receptor modulation of corticostriatal inputs onto medium spiny neurons in the adult ventral striatum using in vitro whole-cell current clamp recordings.

The D2/D3 agonist quinpirole (5 µM) enhanced cortically driven medium spiny neuron synaptic responses in slices taken from adult rats treated with vehicle during adolescence, as in untreated adult rats. However, in slices from mature rats treated with olanzapine during adolescence, quinpirole reduced medium spiny neuron activation. The magnitude of decrease was similar to previous observations in untreated, prepubertal rats. These changes may reflect alterations in local inhibitory circuitry, as the GABA-A antagonist picrotoxin (100 µM) reversed the effects of quinpirole in vehicle-treated slices but had no impact on cortically evoked responses in olanzapine-treated slices.

These data suggest that adolescent atypical antipsychotic drug treatment leads to enduring changes in dopamine modulation of corticostriatal synaptic function.