Modulation of Dopaminergic Neuronal Excitability by Zinc through the Regulation of Calcium-related Channels

Depending on the intracellular buffering of calcium by chelation, zinc has the following two apparent effects on neuronal excitability: enhancement or reduction. Zinc increased tonic activity in the depolarized state when neurons were intracellularly dialyzed with EGTA but attenuated the neuronal activity when BAPTA was used as an intracellular calcium buffer. This suggests that neuronal excitability can be modulated by zinc, depending on the internal calcium buffering capacity. In this study, we elucidated the mechanisms of zinc-mediated alterations in neuronal excitability and determined the effect of calcium-related channels on zinc-mediated alterations in excitability. The zinc-induced augmentation of firing activity was mediated via the inhibition of small-conductance calcium-activated potassium (SK) channels with not only the contribution of voltage-gated L-type calcium channels (VGCCs) and ryanodine receptors (RyRs), but also through the activation of VGCCs via melastatin-like transient receptor potential channels. We suggest that zinc modulates the dopaminergic neuronal activity by regulating not only SK channels as calcium sensors, but also VGCCs or RyRs as calcium sources. Our results suggest that the cytosolic calcium-buffering capacity can tightly regulate zinc-induced neuronal firing patterns and that local calcium-signaling domains can determine the physiological and pathological state of synaptic activity in the dopaminergic system.

Mechanism of dopaminergic neurotransmission on morphine addiction and stress depression / 中国药理学通报

Morphine addiction causes the disturbance in the dopaminergic transmission. The activity of dopaminergic neurons in patients with stress depression is reduced. These studies indicate a strong correlation between morphine addiction and stress depression, which involvement of one or more common neurobiological mechanisms. The dysfunction of dopaminergic neurotransmission from the ventral tegmental area(VTA) to the nucleus accumbens (NAc), prefrontal cortex (mPFC), amygdala (Amy), hippocampus (Hip), and striatum (ST) plays an important role in regulating morphine addiction and stress depression. This article summarizes the mechanism of the dopaminergic transmission regulating morphine addiction and stress depression.

Effect of Corydalis Rhizoma and L-tetrahydropalmatine on dopamine system of hippocampus and striatum in morphine-induced conditioned place preference rats / 中国中药杂志

To investigate the effects of Corydalis Rhizoma and L-tetrahydropalma-tine (L-THP) on the levels of dopamine neurotransmitter (DA), dopamine transporter (DAT) and the second dopamine receptor (D2R) in learning and memory-related brain areas, hippocampus and striatum, the DA, DAT and D2R were detected in conditioned place preference (CPP) rats suffered from morphine. And comparation the degree of similarity and consistency of the pharmacological effects was also studied. The rats were trained in black compartments and white ones (drug-paired compartment) with the increasing doses of morphine for 10 days (hypodermically injected from 10 mg•kg⁻¹ to 100 mg•kg⁻¹). Models of CPP were validated in those psychological dependence rats after 48 h training. The dopamine contents were detected as soon as the materials of hippocampus and striatum are harvested from rats of NS control group and model group. The DAT and D2R levels are measured by Western blot. The high, medium and low dose group of Corydalis Rhizoma are given Corydalis Rhizoma 2, 1, 0.5 g•kg⁻¹ water extraction liquid respectively (which contains L-THP were 0.274, 0.137 and 0.137 mg respectively), and the high, medium and low dose group of L-THP were given L-THP 3.76, 1.88, 0.94 mg•kg⁻¹ lavage treatment respectively, NS treatment group were lavaged normal saline for 6 days and they were killed after test of CPP, again tested DA levels and expression of DAT and D2R similar to the front of materials. The reduction effects of CPP were observed in the groups of both Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) subjected to medicine for 6 days (P<0.01). Compared with the NS treatment group and the model group, the higher values including in the contents of neurotransmitter dopamine were detected of hippocampus and striatum (P<0.01, P<0.05), the DAT and D2R protein expression of Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) increased in hippocampus and striatum (P<0.01). Learning and memory-related brain regions hippocampus and striatum was another neuroanatomical sites of action in the treatment of mental dependence of fumarate and L-THP, its mechanism was related to lowering its elevated DA neurotransmitter levels, and increasing the expression of DAT and D2R. Corydalis Rhizoma could be play 14-times roles in effect of L-THP. The similar effects were observed on the neurotransmitter dopamine, DAT and D2R in learning and memory-related brain areas, hippocampus and striatum of the morphine- dependent rats.

Dependence Potential of Tramadol: Behavioral Pharmacology in Rodents

Tramadol is an opioid analgesic agent that has been the subject of a series of case reports suggesting potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive in Korea. In this study, we examined the dependence potential and abuse liability of tramadol as well as its effect on the dopaminergic and serotonergic systems in rodents. In animal behavioral tests, tramadol did not show any positive effects on the experimental animals in climbing, jumping, and head twitch tests. However, in the conditioned place preference and self-administration tests, the experimental animals showed significant positive responses. Taken together, tramadol affected the neurological systems related to abuse liability and has the potential to lead psychological dependence.

Effects of l-tetrahydropalmatine on conditioned place preference and expression of dopamine in the striatum of morphine dependent rats / 中华行为医学与脑科学杂志

Objective To observe effects of conditioned place preference (CPP) of morphine dependent rats,variation of dopamine neurotransmitter and its receptor 2 of the striatum in rats suffered from 1-tetrabydropalmatine(l-THP).Methods The CPP model was established by morphine injection in rats with a increasing dose for 10 days,with the initial dose of 10 mg · kg-1 and the final dose of 100 mg · kg-1,10 mg · kg-1 was increased each day,thus 100 nmg · kg-1 Was injected by day 10.Treatments with administration of 1-THP(3.76,1.88 and 0.94 mg/kg) were performed respectively for 6 days,and the effects of CPP for psychological dependence in these rats were observed.Striatum samples were taken out and their variable contents of dopamine neurotransmitter and its receptor 2 in striatum were detected by high performance liquid chromatography and immunohistochemisty,respectively.Results Compared with the NS treatment group,the time of animals treated with 1-THP (3.76 and 1.88 mg/kg) staying in drug-paired compartment were reduced (354 ± 58,373 ± 79) (P＜ 0.01) ;the raised of variation contents of dopamine neurotransmitter were reduced in striatum from those rats(5.49 ± 1.95,6.11 ± 1.05),while the expression level of dopamine receptor 2 was increased(0.08 ± 0.02,0.07 ± 0.03) (P ＜ 0.01 or P ＜0.05).Conclusion Reversing dopamine neurotransmitter and its receptor 2 in striatum of morphine dependent rats may be one of the possible mechanisms that 1-THP effectively inhibit the effects of morphine CPP.

Dependence Potential of Quetiapine: Behavioral Pharmacology in Rodents

Quetiapine is an atypical or second-generation antipsychotic agent and has been a subject of a series of case report and suggested to have the potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive. In this study, we examined quetiapine's dependence potential and abuse liability through animal behavioral tests using rodents to study the mechanism of quetiapine. Molecular biology techniques were also used to find out the action mechanisms of the drug. In the animal behavioral tests, quetiapine did not show any positive effect on the experimental animals in the climbing, jumping, and conditioned place preference tests. However, in the head twitch and self-administration tests, the experimental animals showed significant positive responses. In addition, the action mechanism of quetiapine was found being related to dopamine and serotonin release. These results demonstrate that quetiapine affects the neurological systems related to abuse liability and has the potential to lead psychological dependence, as well.