Cahir Marie, Mawhinney Tim, King David J
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, BT9 7BL Belfast, Northern Ireland.
Psychopharmacology (Berl). 2004 Mar;172(2):196-201. doi: 10.1007/s00213-003-1639-z. Epub 2003 Oct 8.
Many antipsychotics exhibit potent anti-alpha(1)-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects.
To assess the relative contribution of alpha(1)-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action.
We examined the effect of chronic haloperidol and clozapine treatment on alpha(1)-adrenoceptor characteristics in several rat brain regions. For comparison, D(2)-like dopamine receptor density in the striatum was also determined.
Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased alpha(1)-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of alpha(1)-adrenoceptor binding in the thalamus (73%), but had no effect on alpha(1)-adrenoceptor levels in any other region examined. alpha(1)-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D(2)-like binding in the striatum.
Central alpha(1)-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic alpha(1)-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or alpha(1)-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical alpha(1)-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.
许多抗精神病药物具有强大的抗α(1)-肾上腺素能受体活性，这被认为与典型和非典型抗精神病药物的作用以及中枢介导的副作用的产生有关。
评估α(1)-肾上腺素能受体对氟哌啶醇和氯氮平作用机制的相对贡献，并确定可能的作用位点。
我们研究了慢性氟哌啶醇和氯氮平治疗对大鼠多个脑区α(1)-肾上腺素能受体特性的影响。为作比较，还测定了纹状体中D(2)-样多巴胺受体密度。
氯氮平给药（25mg/kg/天，腹腔注射，21天）显著增加了额叶皮质（44%）、其余皮质（49%）和丘脑（93%）中α(1)-肾上腺素能受体密度，但与溶剂对照组相比，海马体和脊髓中的结合水平未发生变化。氟哌啶醇治疗（1.5mg/kg/天，腹腔注射，21天）也显著增加了丘脑中α(1)-肾上腺素能受体结合密度（73%），但对所检测的任何其他区域的α(1)-肾上腺素能受体水平均无影响。两种抗精神病药物治疗均未显著改变皮质中α(1)-肾上腺素能受体亲和力。与氯氮平相反，氟哌啶醇显著上调了纹状体中多巴胺D(2)-样结合。
慢性氟哌啶醇和氯氮平治疗后，中枢α(1)-肾上腺素能受体受到不同调节。提示丘脑中的α(1)-肾上腺素能受体可能是这两种药物抗精神病活性和/或α(1)-肾上腺素能受体中枢介导副作用的共同解剖学位点，而氯氮平对皮质α(1)-肾上腺素能受体密度的选择性上调可能部分促成了其优越的非典型特性。
