Abstract
AIMS: Pharmacological-challenge magnetic resonance imaging (phMRI) is powerful new tool enabling researchers to map the central effects of neuroactive drugs in vivo. To employ this technique pre-clinically, head movements and the stress of restraint are usually reduced by maintaining animals under general anaesthesia. However, interactions between the drug of interest and the anaesthetic employed may potentially confound data interpretation. NMDA receptor (NMDAR) antagonists used widely to mimic schizophrenia have recently been shown to interact with the anaesthetic halothane. It may be the case that neural and cerebrovascular responses to NMDAR antagonists are dependent on the types of anaesthetic used. METHODOLOGY: We compared the phMRI response to NMDAR antagonist ketamine in rats maintained under α-chloralose to those under isoflurane anaesthesia. A randomized placebo/vehicle controlled design was used in each of the anaesthetic groups. RESULTS: Changes in the anaesthetic agent resulted in two very different profiles of activity. In the case of α-chloralose, positive activations in cortical and sub-cortical structures reflected a response which was similar to patterns seen in healthy human volunteers and metabolic maps of conscious rats. However, the use of isoflurane completely reversed such effects, causing widespread deactivations in the cortex and hippocampus. CONCLUSION: This study provides initial evidence for a drug-anesthetic interaction between ketamine and isoflurane that is very different from responses to α-chloralose-ketamine.
Highlights
The neuronal activity induced by acute drug challenges retains close spatial and temporal relationships with the central hemodynamic response that can be measured by pharmacological-challenge magnetic resonance imaging (Leslie et al, 2000)
Plots of the signal changes show a similar time-dependent effect to ketamine in all the regions inspected (e.g medial prefrontal and posterior hippocampus), with a rapid increase or decrease in BOLD typically reaching the maxima or minima 5-6 minutes after ketamine administration
We describe the use of pharmacological-challenge magnetic resonance imaging (phMRI) to investigate the effects of an intravenous and a volatile anaesthetic on the ketamine-induced BOLD response
Summary
The neuronal activity induced by acute drug challenges retains close spatial and temporal relationships with the central hemodynamic response that can be measured by pharmacological-challenge magnetic resonance imaging (phMRI) (Leslie et al, 2000) In recent years, this method has been applied to study the central effects of drugs on neurotransmitter pathways both in human and animal models. For most pre-clinical experiments it is usually necessary to maintain animals under general anaesthesia to minimize head movements and stress induced by restraint Under these conditions, phMRI responses to the drug of interest can vary considerably compared to the awake state (Luo et al, 2007; Skoubis et al, 2006; Zhang et al, 2000), as anaesthetics will likely alter the properties of neuronal activity and neurovascular coupling, due to their action on different receptors (Alkire et al, 2008). For many anaesthetics, the target receptors or neurotransmitters remain unknown, making it difficult to predict the influence these agents have on underlying neural circuits following pharmacological stimulation (Steward et al, 2005)
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