Acetylcholinesterase Inhibitors Are Neither Necessary nor Desirable for Microdialysis Studies of Brain Acetylcholine

Acetylcholine (ACh) is important in normal brain function as well as mental illness. Specifically, ACh is of interest in cognitive dysfunction in Alzheimer’s disease and schizophrenia (1), and possibly also negative and positive symptoms in schizophrenia (2). In vivo measurement of brain ACh is also important to animal studies of drugs, e.g. antipsychotic drugs (APDs) to treat Alzheimer’s disease and schizophrenia (3,4,5). Because of the low sensit iv i ty of conventional ACh measurements, most investigators have used acetylcholinesterase (AChE) inhibitors to increase basal extracellular ACh concentrations to readily detectable levels. However, there is growing evidence that the use of AChE inhibitors may interfere with the study of drug effects on ACh release. Thus, AChE inhibitors may alter muscarinic/nicotinic ACh receptor-mediated transmission because of the huge increases in extracellular ACh levels they produce. It is obviously not possible to study any additional effect of AChE inhibitors themselves on extracellular ACh, which may be of interest in some experimental disease models or drug-interaction studies. Thus, we have found that the effect of some drugs on ACh release differs in the presence and absence of neostigmine, a widely used AChE inhibitor. For example, clozapine (20 mg/kg), the prototypical atypical APD, has been reported to acutely increase ACh release in rat medial prefrontal cortex (mPFC), nucleus accumbens (NAC) and striatum (STR) in the presence of 0.3 μM neostigmine in the perfusion medium (31), whereas we have found that clozapine (20 mg/kg), in the absence of neostigmine, increases ACh release only in the mPFC, and not in the other two regions (4). Similarly, in the absence of AChE inhibitors (4), we could not replicate the report that haloperidol (1 mg/kg), a typical APD, increases striatal ACh release in the presence of 0.01 μM neostigmine (6). These results provide a strong rationale for ACh microdialysis studies without the use of AChE inhibitors. This review further discusses the importance of AChE inhibitor-free microdialysis for ACh. The review of Tsai (7) should also be consulted. Acetylcholinesterase Inhibitors Are Neither Necessary nor Desirable for Microdialysis Studies of Brain Acetylcholine