Early changes in neuropeptide mRNA expression in the striatum following reserpine treatment

Chronic dopamine depletion produces neurochemical changes within the striatum as well as enhanced behavioral and metabolic responses to dopamine agonists. Changes in striatal neuropeptides have been consistently described, including increased expression of preproenkephalin mRNA and decreased expression of preprotachykinin and prodynorphin mRNA. Acute dopamine depletion following treatment with reserpine also produces enhanced behavioral and metabolic responses to agonist treatment which develop rapidly. In the present study, we used in situ hybridization histochemistry to investigate whether acute neurochemical changes occur following reserpine treatment. We evaluated neuropeptide mRNA expression in the striatum and nucleus accumbens at several time points from 6 to 120 h following single doses of reserpine and AMPT. The aim of these studies was to determine if changes in neuropeptide mRNA expression occur following acute dopamine depletion and whether such changes are specific to the striatum. Changes in striatal neuropeptide mRNA expression developed rapidly. Preproenkephalin mRNA expression by striatopallidal neurons was unchanged at 48 h, but increased by 44% at 120 h. Preprotachykinin mRNA expression in striatonigral neurons was increased at 6 h and then fell, with a maximal decrease of 45% at 48 h and partial recovery by 120 h. Prodynorphin mRNA expression was unchanged. Expression of preproenkephalin and preprotachykinin mRNA was also examined in subregions of the striatum and the nucleus accumbens. Expression of preproenkephalin mRNA was uniform in the striatum and higher in the core than the shell of the nucleus accumbens. Preprotachykinin mRNA expression in the striatum was higher in the lateral quadrants and was higher in the shell than in the core of the nucleus accumbens. The changes in neuropeptide mRNA following treatment with reserpine were only found in the striatum. These data provide further evidence for early alterations in neuronal function in the striatum following acute dopamine depletion and suggest that neuropeptide expression by striatonigral neurons may be more rapidly regulated in response to changes in dopamine levels.     

强啡肽致脊髓损伤中非阿片样受体机制的研究

目的：探讨强啡肽（dynorphin,Dyn）致脊髓损伤的作用中是否有兴奋性氨基酸的N－甲基－D－门冬氨酸（NMDA）受体通过非阿片途径进行介导,为临床治疗脊髓继发性损伤提供新的思路。方法：通过大鼠蛛网膜下腔置管注药模型,观察不同剂量的非竞争性NMDA受体拮抗剂MK－801对DynA(1-13）致脊髓损伤作用中神经功能和组织病理改变的影响。结果：预先鞘内注射MK－801能明显缓解DynA(1-13)对神经功能和组织病理的损害作用,且呈一定的量效关系。结论：强啡肽致脊髓损伤的非阿片途径中至少有一定部分是通过NMDA受体介导的。     

Mephedrone alters basal ganglia and limbic dynorphin systems

Mephedrone (4‐methymethcathinone) is a synthetic cathinone designer drug that disrupts central nervous system (CNS) dopamine (DA) signaling. Numerous central neuropeptide systems reciprocally interact with dopaminergic neurons to provide regulatory counterbalance, and are altered by aberrant DA activity associated with stimulant exposure. Endogenous opioid neuropeptides are highly concentrated within dopaminergic CNS regions and facilitate many rewarding and aversive properties associated with drug use. Dynorphin, an opioid neuropeptide and kappa receptor agonist, causes dysphoria and aversion to drug consumption through signaling within the basal ganglia and limbic systems, which is affected by stimulants. This study evaluated how mephedrone alters basal ganglia and limbic system dynorphin content, and the role of DA signaling in these changes. Repeated mephedrone administrations (4 × 25 mg/kg/injection, 2‐h intervals) selectively increased dynorphin content throughout the dorsal striatum and globus pallidus, decreased dynorphin content within the frontal cortex, and did not alter dynorphin content within most limbic system structures. Pretreatment with D₁‐like (SCH‐23380) or D₂‐like (eticlopride) antagonists blocked mephedrone‐induced changes in dynorphin content in most regions examined, indicating altered dynorphin activity is a consequence of excessive DA signaling. Synapse 68:634–640, 2014 . © 2014 Wiley Periodicals, Inc.     

Kappa opioid receptor binding in major depression: A pilot study

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [¹¹C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [¹¹C]GR103545 total volume of distribution (V_T) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole‐brain voxel‐wise analyses were also performed. [¹¹C]GR103545 V_T did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [¹¹C]GR103545 V_T was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend‐level inverse correlation was observed between [¹¹C]GR103545 V_T and cortisol area‐under‐the curve with respect to ground during the mTSST (p = 0.081). No whole‐brain voxel‐wise contrasts were significant. Regional [¹¹C]GR103545 V_T, a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co‐occurring mood and substance use disorders, as well as depression with psychotic features.     

鞘内注射强啡肽A(1-17)对不同功能运动神经元群树突的影响

目的:探讨强啡肽A对大鼠趾长伸肌(EDL,快肌)、比目鱼肌(SOL,慢肌)两种不同功能运动神经元(Mn)群树突的影响。方法:采用脊髓蛛网膜下隙给予强啡肽A,以霍乱毒素B亚单位结合辣根过氧化酶(CB-HRP)逆行标记EDL-Mn、SOL-Mn群,Mesulam-TMB法显示两运动神经元群被标记的树突。结果:与相应对照组比,强啡肽A致一过性后肢瘫大鼠用药后1h,位于腰4~5脊髓节段腹角的EDL-Mn、SOL-Mn群树突的分布范围减小,尤以EDL-Mn群为甚;EDL-Mn平均树突长度比对照缩短59.5%,而SOL-Mn平均树突长度比对照缩短35.6%。永久性后肢瘫大鼠用药后3h,EDL-Mn群仅见胞体和近端树突;与之相比,SOL-Mn群仍保留有较长的树突和较广的分布范围。结论:强啡肽A致一过性后肢瘫大鼠两群运动神经元树突明显受累,且以EDL-Mn群为甚,其差别可能与两群运动神经元所接受强啡肽A信息传入不同有关。     

Molecular examination of the endogenous opioid system in rhesus macaque monkeys with self-injurious behavior

Self-injurious behavior (SIB) can lead to serious injury and occurs in approximately 1%–4% of the adult population, with higher incidences in adolescent and institutionalized populations, as well as in children with developmental disorders such as Autism. SIB also spontaneously occurs in a low percentage of captive monkeys. Rhesus macaque (Macaca mulatta) monkeys are evolutionarily and physiologically similar to humans, share 93% genetic sequence similarity to humans, and have long been used as testing subjects for vaccine and clinical trials. Previous studies hypothesized that altered endogenous opioid expression occurs in the brains of individuals and animals that self-injure. We examined the regional mRNA expression of opioid signaling genes in sixteen rhesus macaques that exhibited SIB and eight sex- and age- matched controls. The brain regions examined are linked to reward reinforcement and stress adaptation including the hypothalamus, orbital frontal cortex, nucleus accumbens, hippocampus, caudate, and the amygdala. We found decreased μ-opioid receptor (OPRM1) in the amygdala of monkeys with SIB, and reduced prodynorphin (PDYN) in the hypothalamus. Our data suggest dysfunction in the regulation of opioid peptide precursors and calls for further investigation of the endogenous opioid system in SIB.