Dopaminergic dysregulation in nucleus accumbens has been implicated in the origin of schizophrenia. Accumbal cholinergic interneurons exert powerful modulatory control of local dopamine function, through nicotinic receptors located on dopamine terminals. Fast-scan cyclic voltammetry in rat brain slices in vitro was used to measure dopamine release evoked by high-frequency electrical stimulation, mimicking phasic dopamine activity. We investigated whether cholinergic regulation of stimulated dopamine release was disrupted by pretreatment with phencyclidine, a non-competitive NMDA receptor antagonist, which provides a well validated animal model of schizophrenia. Dihydro-β-erythroidine, an antagonist at β2-subuit containing nicotinic receptors, caused a concentration-dependent enhancement of stimulated dopamine release, indicating cholinergic inhibitory control over dopamine release. The agonist, nicotine, also caused concentration-dependent increases in release, consistent with rapid desensitisation of the receptors previously described. In slices taken from animals pretreated with phencyclidine, the augmentation of electrically-stimulated dopamine release elicited by both drugs was attenuated, particularly when each drug was applied at high concentration. In addition, the concentration-dependence of each drug effect was lost. Taken together these findings indicate that pretreatment with phencyclidine causes changes in acetylcholine systems modulating dopamine release in accumbens. Since phencyclidine treatment was terminated at least a week before the slices were taken, the effects are due to long-term changes in function resulting from the treatment, rather than from transient changes due to the presence of the drug at test. Such enduring dysregulation of cholinergic control of phasic dopamine release could account for deficits in behaviours mediated by accumbal dopamine seen in schizophrenia, and may provide a route for novel therapeutic strategies to treat the disease.

伏隔核中的多巴胺能失调与精神分裂症的起源有关。Accumbal 胆碱能中间神经元通过位于多巴胺末端的烟碱受体对局部多巴胺功能施加强大的调节控制。体外大鼠脑切片的快速扫描循环伏安法用于测量由高频电刺激引起的多巴胺释放，模拟阶段性多巴胺活动。我们调查了刺激多巴胺释放的胆碱能调节是否被苯环利定预处理破坏，苯环利定是一种非竞争性 NMDA 受体拮抗剂，它提供了一种经过充分验证的精神分裂症动物模型。Dihydro-β-erythroidine 是一种含有烟碱样受体的 β2-subuit 的拮抗剂，可引起刺激多巴胺释放的浓度依赖性增强，表明对多巴胺释放的胆碱能抑制控制。激动剂尼古丁也引起释放的浓度依赖性增加，与先前描述的受体的快速脱敏一致。在取自用苯环利定预处理的动物切片中，两种药物引起的电刺激多巴胺释放的增加被减弱，特别是当每种药物以高浓度使用时。此外，每种药物作用的浓度依赖性也消失了。综上所述，这些发现表明，苯环利定预处理会导致乙酰胆碱系统发生变化，从而调节伏隔核中的多巴胺释放。由于苯环利定治疗在切片前至少一周终止，因此影响是由于治疗引起的长期功能变化，而不是由于测试中药物的存在造成的短暂变化。这种对阶段性多巴胺释放的胆碱能控制的持久失调可以解释精神分裂症中由累积多巴胺介导的行为缺陷，