可卡因对中枢神经系统敏感性的影响
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摘要
本实验采用行为学、电生理学、形态学等方法,探讨可卡因对机体敏感性的影响以及可卡因对以缰核为代表的中枢神经系统的作用及其机理,同时也阐述了应激促进成瘾性药物作用的部分机制,为进一步了解可卡因等成瘾性药物作用的中枢机制提供新的科学理论依据。
本实验开展了如下的工作:①在恐惧条件反射的实验中,观察到可卡因可增加动物的焦虑行为,提高机体对条件刺激的敏感性。②连续的可卡因对缰核的传出纤维——后屈束有独特的神经毒作用,可导致后屈束产生退行性病变。③整体和离体的电生理实验表明,可卡因可直接和间接地提高外侧缰核痛兴奋神经元的兴奋性,其机制是由于药物作用于缰核神经元细胞膜上延迟整流钾离子通道,使通道电流减小造成的。④急性给予可卡因诱导的缰核c-fos 蛋白表达具有区域特异性,即药物可明显增加外侧缰核的Fos-like神经元数量。⑤糖皮质激素可增加外侧缰核的fos 蛋白表达,增强外侧缰核神经元的电活动。⑥用电生理学方法证明了可卡因引起伏隔核电活动增加的反应中,丘脑室旁核的调节作用。
The project of drug abuse is the focused the point for attention to the contemporary society due to the high addictive property, easy relapse and serious hazard to society. It is shown that drug abuse facilitates the release of dopamine, inhibits the reuptake of DA and increases the extracellular levels of DA in mesolimbic dopaminergic reward system, especially, in the nucleus accumbens and ventral tegmental area. The hebenula is innervated by dopaminergic nerve cell and sends projections to the ventral tegmental area. Moreover, there are DA receptor, opiate receptor and DA transporter in the Hb (especially LHb). It is reported that the Hb played an important role in the actions of addictive drug. The aim of this report is to further investigate the effects and mechanism of cocaine on the sensitivity of central nervous system, especially the Hb by the techniques of electrophysiology, morphology and immunohistochemistry as well as the primary observation of the stimulative action of the glucocorticoid on Hb. The main data are described in the following:
1、Effects of cocaine on the startle responses of the rats
The startle responses were induced by conditioned stimulus (CS), and the blood pressure was measured in fear conditioning. The studies showed that the blood pressure was remarkably increased by the conditioned stimulus after 3 days
training. The fear-related behavior was evaluated by measuring freezing time during CS presentation and the freezing response increased obviously after fear conditioning.
Autonomic responses and freezing behavior changed when cocaine was injected into the rats before training everyday. The arterial blood pressure of the cocaine rats was higher than that of the control rats by CS and the freezing behavior of the cocaine rats decreased. The studies suggest that cocaine can increase the excitability of nervous system as well as the sensitivity to CS.
2、The degeneration of fasciculus retroflexus (FR) from LHb induced by continuous cocaine injected.
Although the total volume of cocaine injected is equal, but the pattern of injection is different, the effect of the cocaine injected is also different. The body weight of rats are lessened and the degeneration of FR is induced only by the situation of sustained lower cocaine level, but the interrupted higher cocaine level does not induce any changes in same respect. This tract appeared to be a `weak link' for binge-like intake of dopaminergic stimulants, and this suggested that degeneration in FR might underlie, in part, the progressive effects which develop with repeated binges.
3、Effects of cocaine on the discharge of Hb neurons
After i.v. of cocaine, spontaneous discharges of pain excitation unit of LHb are increased and excitation response to noxious stimulation are increased; however spontaneous discharges of pain inhibition unit of LHb are reduced and inhibition response to noxious stimulation are reduced. Effect of cocaine is not transparent on pain excitatory neuron and pain inhibitory neuron of MHb. It suggest that LHb is highly sensitive to cocaine.
When iontophoresis of cocaine into LHb, spontaneous discharges and excitation response to noxious stimulation of pain excitation unit of LHb are increased; spontaneous discharges and inhibition response to noxious stimulation of pain inhibition unit of LHb are reduced . When the volume of cocaine iontophoresis into same neuron of LHb is obviously increased, the excitation of neuron was more increased. It suggest that cocaine can directly increase the excitation level of LHb neuron.
4、Effects of cocaine on pain threshold in rats
The pain threshold was measured in response to the subcutaneous injection of cocaine by radiant heat-tail method. Lower cocaine levels reduces the pain threshold and higher cocaine levels increases the pain threshold. The finding about interrelation between pain tolerance and drug abuse suggests that drug dependence and pain perception share common neuroanatomical and neurophysiological substrates.
5、Effect of cocaine on delayed rectifier potassium ion channels in Hb
To ensure whether the effects of cocaine on excitability of neuron are related to the permeability of ion channels in LHb or not, the effects of cocaine on delayed rectifier potassium ion channels in Hb is observed by using whole-cell configuration of patch-clamp technique. It is found that cocaine can inhibit the activities of delayed rectifier potassium ion channels and decrease the current of K+ in Hb. It is probably the part of the mechanisms of the cocaine increasing excitability of neuron in LHb.
6、Cocaine-inducted expression of the Fos protein in hebenula
The c-fos is a kind of immediate-early gene and has been used widely as a
本实验开展了如下的工作:①在恐惧条件反射的实验中,观察到可卡因可增加动物的焦虑行为,提高机体对条件刺激的敏感性。②连续的可卡因对缰核的传出纤维——后屈束有独特的神经毒作用,可导致后屈束产生退行性病变。③整体和离体的电生理实验表明,可卡因可直接和间接地提高外侧缰核痛兴奋神经元的兴奋性,其机制是由于药物作用于缰核神经元细胞膜上延迟整流钾离子通道,使通道电流减小造成的。④急性给予可卡因诱导的缰核c-fos 蛋白表达具有区域特异性,即药物可明显增加外侧缰核的Fos-like神经元数量。⑤糖皮质激素可增加外侧缰核的fos 蛋白表达,增强外侧缰核神经元的电活动。⑥用电生理学方法证明了可卡因引起伏隔核电活动增加的反应中,丘脑室旁核的调节作用。
The project of drug abuse is the focused the point for attention to the contemporary society due to the high addictive property, easy relapse and serious hazard to society. It is shown that drug abuse facilitates the release of dopamine, inhibits the reuptake of DA and increases the extracellular levels of DA in mesolimbic dopaminergic reward system, especially, in the nucleus accumbens and ventral tegmental area. The hebenula is innervated by dopaminergic nerve cell and sends projections to the ventral tegmental area. Moreover, there are DA receptor, opiate receptor and DA transporter in the Hb (especially LHb). It is reported that the Hb played an important role in the actions of addictive drug. The aim of this report is to further investigate the effects and mechanism of cocaine on the sensitivity of central nervous system, especially the Hb by the techniques of electrophysiology, morphology and immunohistochemistry as well as the primary observation of the stimulative action of the glucocorticoid on Hb. The main data are described in the following:
1、Effects of cocaine on the startle responses of the rats
The startle responses were induced by conditioned stimulus (CS), and the blood pressure was measured in fear conditioning. The studies showed that the blood pressure was remarkably increased by the conditioned stimulus after 3 days
training. The fear-related behavior was evaluated by measuring freezing time during CS presentation and the freezing response increased obviously after fear conditioning.
Autonomic responses and freezing behavior changed when cocaine was injected into the rats before training everyday. The arterial blood pressure of the cocaine rats was higher than that of the control rats by CS and the freezing behavior of the cocaine rats decreased. The studies suggest that cocaine can increase the excitability of nervous system as well as the sensitivity to CS.
2、The degeneration of fasciculus retroflexus (FR) from LHb induced by continuous cocaine injected.
Although the total volume of cocaine injected is equal, but the pattern of injection is different, the effect of the cocaine injected is also different. The body weight of rats are lessened and the degeneration of FR is induced only by the situation of sustained lower cocaine level, but the interrupted higher cocaine level does not induce any changes in same respect. This tract appeared to be a `weak link' for binge-like intake of dopaminergic stimulants, and this suggested that degeneration in FR might underlie, in part, the progressive effects which develop with repeated binges.
3、Effects of cocaine on the discharge of Hb neurons
After i.v. of cocaine, spontaneous discharges of pain excitation unit of LHb are increased and excitation response to noxious stimulation are increased; however spontaneous discharges of pain inhibition unit of LHb are reduced and inhibition response to noxious stimulation are reduced. Effect of cocaine is not transparent on pain excitatory neuron and pain inhibitory neuron of MHb. It suggest that LHb is highly sensitive to cocaine.
When iontophoresis of cocaine into LHb, spontaneous discharges and excitation response to noxious stimulation of pain excitation unit of LHb are increased; spontaneous discharges and inhibition response to noxious stimulation of pain inhibition unit of LHb are reduced . When the volume of cocaine iontophoresis into same neuron of LHb is obviously increased, the excitation of neuron was more increased. It suggest that cocaine can directly increase the excitation level of LHb neuron.
4、Effects of cocaine on pain threshold in rats
The pain threshold was measured in response to the subcutaneous injection of cocaine by radiant heat-tail method. Lower cocaine levels reduces the pain threshold and higher cocaine levels increases the pain threshold. The finding about interrelation between pain tolerance and drug abuse suggests that drug dependence and pain perception share common neuroanatomical and neurophysiological substrates.
5、Effect of cocaine on delayed rectifier potassium ion channels in Hb
To ensure whether the effects of cocaine on excitability of neuron are related to the permeability of ion channels in LHb or not, the effects of cocaine on delayed rectifier potassium ion channels in Hb is observed by using whole-cell configuration of patch-clamp technique. It is found that cocaine can inhibit the activities of delayed rectifier potassium ion channels and decrease the current of K+ in Hb. It is probably the part of the mechanisms of the cocaine increasing excitability of neuron in LHb.
6、Cocaine-inducted expression of the Fos protein in hebenula
The c-fos is a kind of immediate-early gene and has been used widely as a
引文
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