Mathé A A, Hertel P, Nomikos G G, Gruber S, Mathé J M, Svensson T H
Department of Clinical Neuroscience, St. Göran's Hospital, Karolinska Institutet, Stockholm, Sweden.
J Neurosci Res. 1996 Nov 1;46(3):316-23. doi: 10.1002/(SICI)1097-4547(19961101)46:3<316::AID-JNR4>3.0.CO;2-N.
Calcitonin gene-related peptide (CGRP) is the major product of the calcitonin gene in brain and exerts a number of actions in the central nervous system (CNS). In particular the finding that CGRP affects dopamine (DA) release and metabolism has raised the possibility that it may play a role in several neuropsychiatric disorders. Consequently, we have here studied the effects of two psychotomimetic drugs, namely, d-amphetamine (AMPH) and phencyclidine (PCP), on CGRP concentrations in brain microdialysates from freely moving rats. The animals were stereotaxically implanted with vertical concentric probes in the medial prefrontal cortex (mPFC), the ventral striatum (vSTR), or the hippocampus; and the experiments were performed 48 hr after surgery. The dialysis probes were perfused with a modified Ringer's solution at the rate of 5 microliters/min. AMPH 1.5 mg/kg, PCP 2.5 mg/kg, or NaCl 0.9% were injected s.c.; and the perfusates were collected at 60 min intervals before and after the injections and used for CGRP-like immunoreactivity (-LI) determination by radioimmunoassay (RIA). In separate experiment, KCl (100 mM), veratridine (50 microM), or tetrodotoxin (2 microM), were added to the perfusate and infused in the vSTR. Baseline levels of CGRP-LI were detected in dialysates from all three regions. Both AMPH and PCP caused a significant and sustained increase (maximum about 300%) in CGRP-LI concentrations, in particular from the mPFC and vSTR, while saline had no effect. KCl and veratridine also increased CGRP-LI in dialysates during the first posttreatment period, while tetrodotoxin induced a significant but delayed decrease in CGRP-LI levels. Finally, cervical dislocation also elevated CGRP-LI in dialysates from the mPFC and the vSTR. Our findings demonstrate that 1) CGRP-LI can be measured in vivo in microdialysates from mPFC, vSTR, and hippocampus; 2) the release in vSTR is action potential-dependent; and 3) systemic administration of AMPH or PCP results in a long-lasting release of CGRP-LI in the mPFC and vSTR, thus demonstrating a novel action of these drugs in the brain. Since other studies have shown that major antipsychotic drugs appear to reduce CGRP release in brain, our study provides, in principle, support for a role of CGRP in psychotic disorders.
降钙素基因相关肽（CGRP）是大脑中降钙素基因的主要产物，在中枢神经系统（CNS）中发挥多种作用。特别是发现CGRP会影响多巴胺（DA）的释放和代谢，这增加了其可能在几种神经精神疾病中起作用的可能性。因此，我们在此研究了两种拟精神病药物，即右旋苯丙胺（AMPH）和苯环利定（PCP），对自由活动大鼠脑微透析液中CGRP浓度的影响。动物通过立体定位将垂直同心探针植入内侧前额叶皮质（mPFC）、腹侧纹状体（vSTR）或海马体；实验在手术后48小时进行。透析探针以5微升/分钟的速率用改良的林格氏溶液灌注。皮下注射AMPH 1.5毫克/千克、PCP 2.5毫克/千克或0.9%氯化钠；在注射前后每隔60分钟收集灌注液，并用于通过放射免疫分析（RIA）测定CGRP样免疫反应性（-LI）。在单独的实验中，将氯化钾（100毫摩尔）、藜芦碱（50微摩尔）或河豚毒素（2微摩尔）添加到灌注液中并注入vSTR。在所有三个区域的透析液中均检测到CGRP-LI的基线水平。AMPH和PCP均导致CGRP-LI浓度显著且持续升高（最高约300%），特别是来自mPFC和vSTR的浓度，而生理盐水则无影响。氯化钾和藜芦碱在治疗后的第一个时间段内也增加了透析液中的CGRP-LI，而河豚毒素则导致CGRP-LI水平显著但延迟下降。最后，颈椎脱臼也提高了mPFC和vSTR透析液中的CGRP-LI。我们的研究结果表明：1）可以在体内测量mPFC、vSTR和海马体微透析液中的CGRP-LI；2）vSTR中的释放依赖于动作电位；3）全身给予AMPH或PCP会导致mPFC和vSTR中CGRP-LI的长期释放，从而证明了这些药物在大脑中的一种新作用。由于其他研究表明主要的抗精神病药物似乎会减少大脑中CGRP的释放，我们的研究原则上为CGRP在精神疾病中的作用提供了支持。
