Raynor K, Lucki I, Reisine T
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia.
J Pharmacol Exp Ther. 1993 Apr;265(1):67-73.
Multiple somatostatin (SRIF) receptor subtypes, which mediate distinct biological actions of SRIF, are expressed in the rat central nervous system. In the present study, we examined the effects of local injections of SRIF and the SRIF analogs MK 678 and CGP 23996 into the anterior nucleus accumbens on locomotor activity. The binding of [125I]Tyr11-SRIF to membranes from rat nucleus accumbens was potently and monophasically inhibited by SRIF. MK 678 inhibited only 58% of specific [125I]Tyr11-SRIF binding, indicating that the nucleus accumbens expresses both SRIF1 (MK 678-sensitive) and SRIF2 (MK 678-insensitive) receptors. The inhibition of [125I]Tyr11-SRIF binding by CGP 23996 was best fit by a two-site model, and analysis indicated an approximately 100-fold selectivity of this peptide for SRIF receptor subtypes. Intra-accumbens injections of SRIF (3.2-100 ng/side) produced significant increases in locomotor activity with a maximal 212% increase relative to saline control. This effect was mediated by SRIF1 receptors, as MK 678 (1-320 ng/side) produced a dose-dependent significant increase in locomotor activity with a maximal 228% increase relative to saline control, comparable to that attained with 3 to 10 micrograms of d-amphetamine. In contrast, CGP 23996 did not affect locomotor activity at doses of 3.2 to 1000 ng/side. The retroenantiomer hexapeptide analog L363-572, which is 70-fold less potent than MK 678 to inhibit radioligand binding to SRIF1 receptors, did not affect locomotor activity at doses up to 100 ng/side. These results indicate that SRIF1 receptors mediate the locomotor-activating effects of SRIF in the nucleus accumbens of the rat.
多种介导生长抑素（SRIF）不同生物学作用的生长抑素受体亚型在大鼠中枢神经系统中表达。在本研究中，我们检测了向伏隔核前部局部注射SRIF以及SRIF类似物MK 678和CGP 23996对运动活性的影响。[125I]酪氨酸11 - SRIF与大鼠伏隔核膜的结合受到SRIF的强烈单相抑制。MK 678仅抑制58%的特异性[125I]酪氨酸11 - SRIF结合，表明伏隔核同时表达SRIF1（对MK 678敏感）和SRIF2（对MK 678不敏感）受体。CGP 23996对[125I]酪氨酸11 - SRIF结合的抑制作用最适合用双位点模型来描述，分析表明该肽对SRIF受体亚型具有约10倍的选择性。向伏隔核内注射SRIF（3.2 - 100 ng/侧）可使运动活性显著增加，相对于生理盐水对照组最大增加212%。这种作用是由SRIF1受体介导的，因为MK 678（1 - 320 ng/侧）可使运动活性产生剂量依赖性显著增加，相对于生理盐水对照组最大增加228%，与3至10微克右旋苯丙胺所达到的增加幅度相当。相比之下，CGP 23996在3.2至1000 ng/侧的剂量下不影响运动活性。反向对映体六肽类似物L363 - 572抑制放射性配体与SRIF1受体结合的效力比MK 678低70倍，在高达100 ng/侧的剂量下不影响运动活性。这些结果表明，SRIF1受体介导了SRIF在大鼠伏隔核中的运动激活作用。
