Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats

Abstract.

Rationale: The effects of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists model aspects of schizophrenic symptomatology. Because effects on both cortical cholinergic transmission and attentional processes have been hypothesized to represent components of the properties of psychotogenic drugs, the present study investigated the effects of ketamine on the activity of cortical cholinergic inputs and attentional performance. Objective: To determine the effects of acute and repeated ketamine administration on cortical acetylcholine release and performance of rats in an operant task designed to assess sustained attention performance. Methods: Experiment 1 assessed the effects of ketamine (2.0–20.0 mg/kg, i.p.) on medial prefrontal acetylcholine release using in vivo microdialysis. In experiment 2, animals were pretreated with 2.0 mg/kg or 25.0 mg/kg ketamine for 7 days. Cortical acetylcholine release was assessed in these rats following the subsequent administration of a 'challenge' dose of 2.0 mg/kg on days 1, 8, and 15 following completion of the pretreatment regimen. Experiment 3 assessed the effects of acute ketamine administration (2.0, 4.0, and 8.0 mg/kg, i.p.) on sustained attention performance. In experiment 4, animals trained in the sustained attention task were pretreated with 25.0 mg/kg ketamine or vehicle for 7 days. In these animals, the performance effects of 2.0 mg/kg ketamine administered 1, 8, or 15 days after completion of the pretreatment regimen were assessed. Results: The acute administration of ketamine dose dependently increased cortical acetylcholine release by up to 250% above baseline and for over 40 min following the highest dose of ketamine. Pretreatment with 2.0 mg or 25.0 mg/kg did not robustly alter the effects of subsequent ketamine administration on cortical acetylcholine release. In animals performing the sustained attention task, administration of the highest dose of ketamine resulted in high levels of errors of omission, while the administration of the two smaller doses did not affect performance. Pretreatment with 25.0 mg/kg disrupted the attentional performance during the pretreatment period, but it did not affect the baseline performance thereafter. Furthermore, ketamine pretreatment did not systematically alter the performance effects of subsequent ketamine administration. Conclusions: The robust stimulation of cortical acetylcholine release represents a potent component of the pharmacological effects of ketamine. The effects of acute ketamine on attentional performance were limited to high rates of omissions. Repeated ketamine administration 'sensitized' neither cortical acetylcholine release nor attentional performance. These effects of repeated ketamine differ substantially from those of another major psychotogenic drug, amphetamine, and thus support the view that ketamine and amphetamine model fundamentally different aspects of schizophrenia.