Dopaminergic Regulation of Striatal Acetylcholine Release: The Critical Role of Acetylcholinesterase Inhibition

Abstract

This study examined the effects of different levels of acetylcholinesterase (AChE) inhibition on dopaminergic regulation of striatal acetylcholine (ACh) release as estimated by in vivo brain microdialysis. Systemic administration of d‐amphetamine (2 or 10 mg/kg) increased the striatal output of ACh when the AChE inhibitor neostigmine (0.1 µM) was present in the perfusion fluid. In contrast, when the same experiments were conducted at 0.01 µM neostigmine, d‐amphetamine failed to affect (2 mg/kg) or significantly decreased (10 mg/kg) striatal ACh output. The inhibitory action of the D2 receptor agonist quinpirole (0.2 mg/kg) was significantly greater at 0.01 µM than at 0.1 µM neostigmine. Similarly, there was a nonsignificant trend for the D2 antagonist raclopride (1 mg/kg) to stimulate ACh release to a greater extent at the low neostigmine concentration. In contrast, the stimulant effects of systemic administration of the D1 agonist A‐77636 (1.46 mg/kg) on striatal ACh release were the same at the two neostigmine concentrations. These results demonstrate that the concentration of an AChE inhibitor in the perfusion solution can quantitatively and even qualitatively influence the manner in which dopaminergic agents regulate ACh overflow in the striatum. On comparing the present results with earlier reports concerning the effects of d‐amphetamine on tissue concentrations of ACh, it is tentatively concluded that a low neostigmine concentration is the more physiologically relevant condition. Under such conditions, at moderate doses d‐amphetamine does not appear to alter striatal ACh release, with this likely being due to the opposing actions of D1 and D2 receptors. Nevertheless, until the endogenous interstitial concentrations of striatal ACh can be measured by other methods, the physiological relevance of ACh microdialysis studies in the striatum will remain uncertain.

Selective Antagonism at Dopamine D3 Receptors Enhances Monoaminergic and Cholinergic Neurotransmission in the Rat Anterior Cingulate Cortex

“…Thus, recalculation of these data as percent changes from basal release shows that apparent changes in the release of either ACh or DA are, in fact, independent from neostigmine concentrations in the perfusion fluid (see for example Di Chiara et al, 1996;Acquas and Di Chiara, 1999). These conclusions are also consistent with those of Acquas and Fibiger (1998), which showed that DA regulation of striatal ACh release is independent from neostigmine concentrations when data are expressed as percent values of basal release. That said, in order to avoid these methodological issues and potential confounding variables, there is a growing body of evidence supporting the rationale for the use of new sensitive analytical methods for the detection of ACh and choline without the use of acetylcholinesterase inhibitors in the perfusion medium (see for example Hows et al, 2002;Ichikawa et al, 2000Ichikawa et al, , 2002.…”

Tolerance to the procholinergic action of the D1 receptor full agonist dihydrexidine

“…Previous microdialysis studies have clearly shown that the stimulatory effect of D1 receptor agonists on ACh efflux in the striatum is independent of the concentration of the cholinesterase inhibitor neostigmine, which is commonly added to the perfusion solution to elevate basal ACh efflux (DeBoer and Abercrombie 1996; Acquas and Fibiger 1998). On the other hand, the concentration of neostigmine does affect the tonic regulation of ACh outflow in the striatum through D1 receptors (DeBoer and Abercrombie 1996; Acquas and Di Chiara 1999).…”

Development of a liquid chromatography/tandem mass spectrometry method for the quantitation of acetylcholine and related neurotransmitters in brain microdialysis samples

“…One fundamental problem with these methods is that the inclusion of AChE inhibitors leads to changes in the physiology of the system being investigated. For example, De Boer et al [28] and Acquas and Fibiger [29] reported that perfusion fluid containing neostigmine quantitatively and qualitatively influenced the manner in which dopaminergic agents regulated ACh overflow in the striatum. Furthermore, AChE inhibitors contained in the perfusion fluid could mask, or indeed exaggerate, small drug-related changes in ACh levels as well as alter transmission of other systems within the perfused area [30][31][32][33][34].…”