Li Zhu, Ichikawa Junji, Meltzer Herbert Y
Division of Psychopharmacology, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Psychopharmacology (Berl). 2003 May;167(3):315-23. doi: 10.1007/s00213-003-1418-x. Epub 2003 Mar 28.
Atypical, but not typical, antipsychotic drugs (APDs), produce preferential increases in dopamine (DA) and acetylcholine (ACh) release in rat medial prefrontal cortex (mPFC) compared to the nucleus accumbens (NAC). The increase in DA release has been attributed, in part, to their greater serotonin (5-HT)(2A) relative to D(2) receptor occupancy, while the basis for the increase in ACh has not yet been determined. Loxapine, a dibenzoxazepine congener of clozapine, is generally considered to be a typical APD because it produces significant extrapyramidal symptoms (EPS) in humans, at generally recommended clinical doses (60-100 mg/day), and catalepsy in rodents, although several studies have found it to be effective at lower doses which do not produce significant EPS. Moreover, loxapine, like its congener clozapine, has higher affinity for serotonin (5-HT)(2A) than dopamine D(2) receptors, in vitro, suggesting the possibility it could be an atypical APD with clozapine-like potential.
The purpose of this study was to compare the effects of loxapine on DA and ACh release in the mPFC and NAC with those of ziprasidone, a novel atypical APD, and thioridazine, which is generally classified as a typical APD.
Loxapine, 0.03-10 mg/kg, increased prefrontal dopamine release with the magnitude of this increase exceeding that in the NAC, at all doses, other than the 10 mg/kg dose. The effect of loxapine (0.3 mg/kg) on DA release in the prefrontal cortex was attenuated by WAY 100635 (0.2 mg/kg), a 5-HT(1A) antagonist, as is the case for other atypical APDs. Ziprasidone (0.1-3 mg/kg) also preferentially increased DA release in the mPFC compared to NAC. Thioridazine (5 and 20 mg/kg) did not increase DA release in either the mPFC or NAC. Loxapine (3 mg/kg) and ziprasidone (1 and 3 mg/kg), but not thioridazine (10 and 20 mg/kg), significantly increased cortical ACh release.
Loxapine has effects on cortical and NAC DA and ACh release which are comparable to those of known atypical APDs. Ziprasidone and thioridazine have effects on cortical DA and ACh characteristic of atypical and typical APDs, respectively. It is concluded that further clinical studies of the atypical APD properties of loxapine are indicated.
与伏隔核（NAC）相比，非典型而非典型抗精神病药物（APD）能使大鼠内侧前额叶皮质（mPFC）中的多巴胺（DA）和乙酰胆碱（ACh）释放优先增加。DA释放的增加部分归因于它们相对于D₂受体占有率而言更高的5-羟色胺（5-HT）₂A受体占有率，而ACh增加的基础尚未确定。洛沙平是氯氮平的二苯并恶嗪同类物，通常被认为是典型的APD，因为在一般推荐的临床剂量（60 - 100毫克/天）下，它会在人类中产生显著的锥体外系症状（EPS），在啮齿动物中产生僵住症，尽管有几项研究发现它在不产生显著EPS的较低剂量下也有效。此外，洛沙平与其同类物氯氮平一样，在体外对5-羟色胺（5-HT）₂A受体的亲和力高于多巴胺D₂受体，这表明它有可能是具有氯氮平样潜力的非典型APD。
本研究的目的是比较洛沙平与新型非典型APD齐拉西酮以及通常被归类为典型APD的硫利达嗪对mPFC和NAC中DA和ACh释放的影响。
0.03 - 10毫克/千克的洛沙平增加了前额叶多巴胺释放，除10毫克/千克剂量外，在所有剂量下这种增加的幅度都超过了NAC中的增加幅度。与其他非典型APD情况相同，5-HT₁A拮抗剂WAY 100635（0.2毫克/千克）减弱了洛沙平（0.3毫克/千克）对前额叶皮质中DA释放的作用。与NAC相比，齐拉西酮（0.1 - 3毫克/千克）也优先增加了mPFC中的DA释放。硫利达嗪（5和20毫克/千克）在mPFC或NAC中均未增加DA释放。洛沙平（3毫克/千克）和齐拉西酮（1和3毫克/千克），但不是硫利达嗪（10和20毫克/千克），显著增加了皮质ACh释放。
洛沙平对皮质和NAC中DA和ACh释放的影响与已知的非典型APD相当。齐拉西酮和硫利达嗪分别对皮质DA和ACh具有非典型和典型APD的特征性影响。得出结论，有必要对洛沙平的非典型APD特性进行进一步的临床研究。
