Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using 3H-MK801 (NMDA-R antagonist), 3H-CNQX (AMPA-R antagonist) and 3H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D2/D3 receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D1/D5) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter 3H-CNQX or 3H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated 3H-MK801 binding in the hippocampal formation with significant increases in the CA1 and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced 3H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased 3H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen.

The role of anesthetics in animal research models is crucial, yet often ignored, and is almost never the primary focus of examination. Here, we investigated the impact of anesthetic regimens on different parameters of hemodynamics (blood pressure (BP) and heart rate (HR)), metabolism (glucose, insulin, and free fatty acids (FFA)), and inflammation (IL-6 and TNF-α) in two frequently used mouse strains (C57BL/6 and FVB). All animals were at a similar surgical plane of anesthesia, mechanically ventilated, and monitored for 60 min. The following anesthetic regimens were studied: (1) fentanyl-ketamine-midazolam (FKM), (2) fentanyl-midazolam-haldol (FMH), (3) pentobarbital (P), (4) fentanyl-fluanisone-midazolam (FFM), (5) fentanyl-midazolam-acepromazine (FMA), (6) ketamine-medetomidine-atropine (KMA), (7) isoflurane (ISO), and (8) propofol-fentanyl-midazolam (PFM). Metabolic and inflammatory parameters were compared with those obtained from non-anesthetized animals. Hemodynamics: BP >80 mm Hg were only obtained with KMA, whereas hypotension (BP <60 mm Hg) was observed with FKM and P. HR >500 beats/min was observed with ISO and PFM, whereas HR <400 beats/min was induced with KMA, FMH (BL/6), P (BL/6), and FKM (FVB). Metabolism: Glucose and insulin were most disturbed by KMA and ISO and mildly disturbed by FMA, whereas FFM, PFM, and P did not have any effect. FFA increased largely by FMA, with ISO and FKM having no effects. Inflammation: Cytokines were increased least with ISO/FFM/FMA, whereas FKM and KMA induced the largest increases in cytokines. When aiming at achieving surgical anesthesia without large disturbances in hemodynamic, metabolic, and inflammatory profiles, FFM, ISO, or PFM may be the most neutral anesthetic regimens in mice.

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