Karler R, Bedingfield J B, Thai D K, Calder L D
Department of Pharmacology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Brain Res. 1997 May 23;757(2):228-35. doi: 10.1016/s0006-8993(97)00221-7.
Pharmacological studies have shown that a variety of neuroeffectors are involved in behavioral sensitization to amphetamine-induced stereotypy. In the present work, the effect of some of these drugs on sensitization was studied after intracortical administration in order to determine the role of the cortex in mediating their systemic effects. The dopamine antagonists sulpiride and spiperone were both ineffective against the acute response to amphetamine; nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, and THIP, a GABA(A) agonist, blocked the acute response and the induction of sensitization to amphetamine. On the other hand, mecamylamine, the nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the cortex is not a locus of its activity. Anisomycin, an inhibitor of protein synthesis, and diltiazem, a calcium-channel blocker, were both ineffective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expression of sensitization; therefore, the ability of the other drugs to block expression must reside within another locus. Bicuculline injected intracortically in non-convulsant doses produced a stereotypy indistinguishable from that induced by amphetamine; and the effect was readily antagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to block the bicuculline-induced stereotypy; we conclude, therefore, that the stereotypic effect of bicuculline is not mediated by dopamine. These results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory system. The data also suggest that cortical dopamine, as well as the NMDA and GABA(A) systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved in sensitization exert their effects at different brain loci.
药理学研究表明，多种神经效应器参与了对苯丙胺诱导的刻板行为的行为敏化。在本研究中，为了确定皮质在介导这些药物全身效应中的作用，研究了其中一些药物经皮质内给药后对敏化的影响。多巴胺拮抗剂舒必利和螺哌隆对苯丙胺的急性反应均无效；然而，两者都能阻断敏化的诱导，这表明中脑皮质多巴胺通路不参与急性反应，但对敏化的诱导是必需的。NMDA受体拮抗剂CPP和GABA(A)激动剂THIP均能阻断对苯丙胺的急性反应和敏化的诱导。另一方面，烟碱型胆碱能拮抗剂美加明未能影响急性反应或敏化的诱导，这表明皮质不是其作用位点。蛋白质合成抑制剂茴香霉素和钙通道阻滞剂地尔硫䓬对急性反应均无效，但均能阻断诱导。除CPP和THIP外，所有药物对敏化的表达均无效；因此，其他药物阻断表达的能力一定存在于另一个位点。以非惊厥剂量皮质内注射荷包牡丹碱产生的刻板行为与苯丙胺诱导的刻板行为无法区分；全身或皮质内给予CPP很容易拮抗这种效应。相比之下，无论通过哪种给药途径，舒必利都不能阻断荷包牡丹碱诱导的刻板行为；因此，我们得出结论，荷包牡丹碱的刻板效应不是由多巴胺介导的。这些结果表明，苯丙胺诱导的刻板行为在皮质中是通过去除对兴奋系统的抑制性控制来介导的。数据还表明，皮质多巴胺以及NMDA和GABA(A)系统在对苯丙胺的敏化中很重要。总体而言，数据表明参与敏化的不同神经效应器在不同的脑位点发挥作用。
