DOPAMINERGIC REGULATION OF STRIATAL ACETYLCHOLINE-RELEASE - THE CRITICAL ROLE OF ACETYLCHOLINESTERASE INHIBITION

This study examined the effects of different levels of acetylcholinest erase (AChE) inhibition on dopaminergic regulation of striatal acetylc holine (ACh) release as estimated by in vivo brain microdialysis. Syst emic administration of d-amphetamine (2 or 10 mg/kg) increased the str iatal output of ACh when the AChE inhibitor neostigmine (0.1 mu M) was present in the perfusion fluid. In contrast, when the same experiment s were conducted at 0.01 mu M neostigmine, d-amphetamine failed to aff ect (2 mg/kg) or significantly decreased (10 mg/kg) striatal ACh outpu t, The inhibitory action of the D-2 receptor agonist quinpirole (0.2 m g/kg) was significantly greater at 0.01 mu M than at 0.1 mu M neostigm ine. Similarly, there was a nonsignificant trend for the D? antagonist raclopride (1 mg/kg)to stimulate ACh release to a greater extent at t he low neostigmine concentration. In contrast, the stimulant effects o f systemic administration of the D-1 agonist A-77636 (1.46 mg/kg) on s triatal ACh release were the same at the two neostigmine concentration s. These results demonstrate that the concentration of an AChE inhibit or in the perfusion solution can quantitatively and even qualitatively influence the manner in which dopaminergic agents regulate ACh overfl ow in the striatum. On comparing the present results with earlier repo rts concerning the effects of d-amphetamine on tissue concentrations o f ACh, it is tentatively concluded that a low neostigmine concentratio n is the more physiologically relevant condition. Under such condition s, at moderate doses d-amphetamine does not appear to alter striatal A Ch release, with this likely being due to the opposing actions of D-1 and D-2 receptors. Nevertheless, until the endogenous interstitial con centrations of striatal ACh can be measured by other methods, the phys iological relevance of ACh microdialysis studies in the striatum will remain uncertain.