De Rover Mischa, Lodder Johannes C, Schoffelmeer Anton N M, Brussaard Arjen B
Department of Experimental Neurophysiology, Centre for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Synapse. 2005 Jan;55(1):17-25. doi: 10.1002/syn.20087.
Repeated exposure to drugs of abuse causes persistent behavioral sensitization and associated adaptations of striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Microdialysis and neurochemical studies suggest that intermittent morphine treatment may lead to a long-term increase in both ACh and dopaminergic neurotransmission in the nucleus accumbens (NAc). This implies that both cholinergic modulation of GABA synapses and their sensitivity to dopaminergic transmission might be changed, ultimately leading to a modified NAc output. Here we investigate to what extent cholinergic modulation and sensitivity to amphetamine, causing endogenous dopamine efflux, of GABAergic transmission in the nucleus accumbens are affected 3 weeks after a period of daily morphine injections in adult rats. To this end, we recorded medium spiny neurons using whole cell voltage clamp and monitored the frequency and amplitude of spontaneous GABAergic synaptic currents. We observed that the effect of nicotine on the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was suppressed in rats pretreated with morphine, whereas the effects of mecamylamine and tetrodotoxin (TTX) were increased. These results indicate that the probability of GABA release was increased and that this effect resulted from an upregulation of the endogenous activation of presynaptic nicotinic receptors. In addition, we observed an increased sensitivity to in vitro application of amphetamine. This suggests that the long-term increase in dopaminergic transmission caused by the morphine treatment affects GABA synapses in the NAc. Hence, there may be two parallel synaptic mechanisms by which drugs of abuse may affect processing and integration of NAc inputs.
反复接触滥用药物会导致持续的行为敏化以及纹状体神经传递的相关适应性变化，这被认为在药物成瘾的某些方面起着重要作用。微透析和神经化学研究表明，间歇性吗啡治疗可能导致伏隔核（NAc）中乙酰胆碱（ACh）和多巴胺能神经传递的长期增加。这意味着GABA突触的胆碱能调制及其对多巴胺能传递的敏感性可能都会发生变化，最终导致伏隔核输出的改变。在此，我们研究成年大鼠在每日注射吗啡一段时间后3周，伏隔核中GABA能传递的胆碱能调制以及对引起内源性多巴胺外流的苯丙胺的敏感性受到何种程度的影响。为此，我们使用全细胞电压钳记录中型多棘神经元，并监测自发GABA能突触电流的频率和幅度。我们观察到，在吗啡预处理的大鼠中，尼古丁对自发抑制性突触后电流（sIPSCs）频率的影响受到抑制，而美加明和河豚毒素（TTX）的影响则增强。这些结果表明，GABA释放的概率增加，并且这种效应是由突触前烟碱受体的内源性激活上调所致。此外，我们观察到对体外应用苯丙胺的敏感性增加。这表明吗啡治疗引起的多巴胺能传递的长期增加会影响伏隔核中的GABA突触。因此，滥用药物可能通过两种平行的突触机制影响伏隔核输入的处理和整合。
