Lhuillier Loic, Mombereau Cedric, Cryan John F, Kaupmann Klemens
Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Neuropsychopharmacology. 2007 Feb;32(2):388-98. doi: 10.1038/sj.npp.1301102. Epub 2006 May 17.
Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug-induced neuroadaptive changes. Recent attention has been given to compounds activating GABA(B) receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA(B) receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA(B) receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA(B) receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor deltaFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited deltaFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA(B) receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.
接触可卡因会引发选择性行为和分子适应性变化。在啮齿动物中，急性可卡因会导致运动活动增加，而长期药物接触则会导致行为运动敏化，这被认为是药物诱导的神经适应性变化的结果。最近，激活GABA(B)受体的化合物作为潜在的抗成瘾疗法受到了关注。特别是，变构正性GABA(B)受体调节剂的原理在这方面非常有前景，因为正性调节剂缺乏如巴氯芬等完全GABA(B)受体激动剂的镇静和肌肉松弛特性。在此，我们研究了全身性应用GABA(B)受体正性调节剂GS39783（N,N'-二环戊基-2-甲基硫烷基-5-硝基嘧啶-4,6-二胺）对急性和慢性给予可卡因的动物的影响。GS39783和巴氯芬均剂量依赖性地减弱了急性可卡因诱导的运动亢进。此外，这两种化合物还有效阻断了可卡因诱导的纹状体复合体中Fos的诱导。在慢性研究中，GS39783适度减弱了可卡因诱导的运动敏化。慢性可卡因会诱导转录因子deltaFosB的积累，并上调cAMP反应元件结合蛋白（CREB）和32 kDa的多巴胺和cAMP调节磷蛋白（DARPP-32）。GS39783阻断了伏隔核和背侧纹状体中DARPP-32和CREB的诱导/激活，并部分抑制了背侧纹状体中deltaFosB的积累。总之，我们的数据表明，GS39783减弱了啮齿动物接触可卡因的急性行为效应，此外还防止了多巴胺能信号通路中选择性长期适应性变化的诱导。因此，有必要进一步研究将GABA(B)受体正性调节作为治疗可卡因依赖以及可能其他滥用药物的新型治疗策略。
