Simultaneous, in vivo monitoring of 10 neurotransmitters in rat prelimbic cortex (PrL) reveals that systemic and local administration of the atypical antipsychotic olanzapine (olz) differentially altered only serotonin (5HT) levels

Abstract

Prefrontal cortex function is disrupted in patients with schizophrenia (J Neurosci 32:3022, 2012). 5HT receptors are known to be of key importance in the mechanism of action of atypical antipsychotics (Curr Opin Pharmacol 11:59, 2011). This study is testing the hypothesis that systemic and direct PrL administration of olz alters neurotransmitter levels in the PrL. Adult, male Sprague‐Dawley rats were anesthetized with isoflurane and received olz by IV injection (n=4, 1 mg/kg) or directly into the PrL by reverse dialysis (n=4, 100 μM). Histological analysis confirmed that transmitter measures were obtained from the PrL. IV olz significantly (P<0.05) altered only levels of dopamine (+108%), 5HT (‐39%), and adenosine (‐25%). Mean plasma level of olz during dialysis sampling of the PrL was in the therapeutic range (194 ng/mL; JPET 305:625, 2003). Direct delivery of olz to the PrL significantly altered levels of dopamine (+146%), 5HT (+31%), adenosine (‐39%), glycine (‐38%), and aspartate (‐50%). Whereas both routes of olz delivery increased dopamine, IV olz decreased 5HT but direct PrL delivery of olz increased 5HT. This differential response of 5HT suggests that IV olz decreases 5HT in the PrL by activating 5HT1A autoreceptors on brainstem 5HT neurons. Support: NIH grants MH45361 (HAB), D007268 (OSM), EB003320 (RTK), Dept Anesthesiology