α1与β肾上腺素受体间的交互作用

α１与β肾上腺素受体间的交互作用张幼怡韩启德（北京医科大学第三医院血管医学研究所，北京１０００８３）Ａｂｓｔｒａｃｔα１－ａｎｄβ－ＡｄｒｅｎｏｃｅｐｔｏｒｓｃｒｏｓｓｔａｌｋｅａｃｈｏｔｈｅｒａｔｌｅｖｅｌｓｏｆｍＲＮＡ，ｐｒｏｔｉｅｎ，ａｓｗｅｌ...     

Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats

Rationale Many behavioral effects of delta-9-tetrahydrocannabinol (THC), including its discriminative-stimulus effects, are modulated by endogenous opioid systems.Objective To investigate opioid receptor subtypes involved in the discriminative effects of THC.Methods Rats trained to discriminate 3 mg/kg i.p. of THC from vehicle using a two-lever operant drug-discrimination procedure, were tested with compounds that bind preferentially or selectively to either mu-, delta- or kappa-opioid receptors.Results The preferential mu-opioid receptor agonist heroin (0.3–1.0 mg/kg, i.p.), the selective delta-opioid receptor agonist SNC-80 (1–10 mg/kg, i.p.) and the selective kappa-opioid receptor agonist U50488 (1–10 mg/kg, i.p.) did not produce generalization to the discriminative effects of THC when given alone. However, heroin, but not SNC-80 or U50488, significantly shifted the dose–response curve for THC discrimination to the left. Also, the preferential mu-opioid receptor antagonist naltrexone (0.1–1 mg/kg, i.p.), the selective delta-opioid receptor antagonist, naltrindole (1–10 mg/kg, i.p.) and the kappa-opioid receptor antagonist nor-binaltorphimine (n-BNI, 5 mg/kg, s.c.), did not significantly reduce the discriminative effects of the training dose of THC. However, naltrexone, but not naltrindole or n-BNI, significantly shifted the dose–response curve for THC discrimination to the right. Finally, naltrexone, but not naltrindole or n-BNI, blocked the leftward shift in the dose–response curve for THC discrimination produced by heroin.Conclusions mu- but not delta- or kappa-opioid receptors are involved in the discriminative effects of THC. Given the role that mu-opioid receptors play in THCs rewarding effects, the present findings suggest that discriminative-stimulus effects and rewarding effects of THC involve similar neural mechanisms.     

Gene frequencies of transferrin (TfC) subtypes in Western Germany (Düsseldorf region)

Summary Transferrin (Tf) subtypes were determined by isoelectric focusing and polyacrylamide gelelectrophoresis on samples from 380 unrelated individuals. The following gene frequencies were observed: Tf^C1 0.7816, Tf^C2 0.1355, Tf^C3 0.0711, and Tf^B 0.0118.Progress reports on this work were presented at the First International Anthropological Poster Conference, September 8–11, 1980, Zagreb, Yugoslavia     

Should bipolar disorder be viewed as manic disorder? Implications for bipolar depression

This paper proposes that the syndrome of mania rather than mood swings is the central distinguishing feature of bipolar disorder, which may be more appropriately viewed as manic disorder. The theoretical consequence of this change in perspective is to regard the depressive mood states as being a co-morbid condition. This may lead to a more profound and broader understanding of the variety of states of depression that complicate manic disorder. The paper also reviews diagnostic issues relating to bipolar depression. A broader approach may extend therapeutic choices, and open innovative research avenues.     

Effect of M4-Cholinoceptor Blockade on Haloperidol-Produced Catatonic Syndrome in Rats

We studied the relationship between the efficiency of muscarinic receptor antagonists in preventing haloperidol-induced catatonia and their activity in tests for the interaction of ligands with various subtypes of muscarinic receptors (M1-M4) in rats. Mathematical modeling showed that affinity of the ligand for M4 receptors positively affects its ability to correct extrapyramidal disorders (catatonic syndrome) produced by haloperidol, while affinity for M2 receptors had a negative effect on this characteristic.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

3H-noradrenaline release from mouse iris–ciliary body: role of presynaptic muscarinic heteroreceptors

Sympathetic neurotransmitter release and its modulation by presynaptic muscarinic heteroreceptors were studied in mouse iris–ciliary bodies. Tissue preparations were preincubated with ³H-noradrenaline and then superfused and stimulated electrically. Firstly, experimental conditions were defined, allowing study of presynaptic sympathetic inhibition in mouse iris–ciliary body. If tissue was stimulated four times with 36 pulses/3 Hz, tritium overflow peaks were reliably and reproducibly measured. As expected, these stimulation conditions led to marked ₂-autoinhibition as indicated by the release-enhancing effect of the ₂-antagonists phentolamine and rauwolscine. To ensure autoinhibition-free ³H-noradrenaline release, which is optimal for studying presynaptic sympathetic inhibition, ₂-receptors were blocked in all subsequent experiments. Under these conditions, evoked tritium overflow was almost completely abolished in the presence of the sodium channel blocker tetrodotoxin, indicating a neuronal origin of ³H-noradrenaline release. Secondly, muscarinic inhibition of ³H-noradrenaline release was characterized using the conditions described above (36 pulses/3 Hz; phentolamine 1 M and rauwolscine 1 M throughout). The muscarinic receptor agonist oxotremorine M decreased evoked tritium overflow in a concentration-dependent manner with an IC₅₀ of 0.33 M and maximal inhibition of 51%. The concentration–response curve of oxotremorine M was shifted to the right by the muscarinic antagonists ipratropium and methoctramine, whereas pirenzepine was ineffective. The observed rank order of antagonist potencies, ipratropium > methoctramine > pirenzepine, which is typical for the M₂ subtype, indicates that presynaptic muscarinic receptors on sympathetic axons of mouse iris–ciliary bodies are predominantly M₂. Finally, inhibition of ³H-noradrenaline release by endogenously secreted acetylcholine was investigated. Longer pulse trains, 120 pulses/3 Hz and 600 pulses/5 Hz, were used and the cholinesterase inhibitor physostigmine was added to the superfusion medium to increase synaptic levels of endogenous acetylcholine. Under these conditions, ipratropium approximately doubled the evoked overflow of tritium, indicating that endogenously released acetylcholine can activate presynaptic muscarinic heteroreceptors. In conclusion, the present experiments establish measurement of the electrically induced release of ³H-noradrenaline from mouse iris–ciliary bodies. As in other species, noradrenaline release in this preparation was subject to presynaptic muscarinic inhibition. Our results also indicate that the presynaptic muscarinic receptors on sympathetic axons in mouse iris–ciliary body are predominantly M₂. Moreover, these receptors can be activated by both exogenous agonists and endogenously released acetylcholine and, hence, may operate physiologically in the interplay between the parasympathetic and sympathetic nervous system.     

Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America

Alpha-1-antitrypsin deficiency (AAT deficiency) is one of the most common serious hereditary disorders in the world, as its affects all major racial subgroups worldwide, and there are an estimated 120.5 million carriers and deficient subjects worldwide. This genetic disease is related to susceptibility for development of jaundice in infants, liver disease in children and adults and pulmonary emphysema in adults. Moreover, AAT deficiency carrier phenotypes (PiMS and PiMZ) and deficiency allele phenotypes (PiSS, PiSZ and PiZZ) are suspected to predispose subjects to a variety of other adverse health effects. Because there is a limited database on the number of individuals affected by this disease worldwide, we have collected data on control cohorts in genetic epidemiological studies published on case-control studies in the peer-reviewed literature worldwide. Based on these data, we estimated the numbers of carriers and deficiency allele combinations for the two most common defective alleles, namely PiS and PiZ in 58 countries worldwide. The present paper focuses on the distribution of the PiS and PiZ deficiency alleles in Australia, Canada, New Zealand and the United States of America. A total of 31,042,232 individuals at risk for adverse health effects have been calculated in these four countries: 2,144,158 in Australia, 3,258,564 in Canada, 430,922 in New Zealand and 24,909,548 in the United States of America. The prevalences for all five phenotypic classes of AAT deficiency in each of these countries is as follows: Australia 1 out of 8.9, Canada 1 out of 9.8, New Zealand 1 out of 8.5 and the United States of America 1 out of 11.3. The geographical distribution of individual control cohorts and estimates of the numbers of carriers and deficiency allele phenotypes in each of these four countries are given in individual tables.     

Development of ovine fetal ileal motility: role of muscarinic receptor subtypes

OBJECTIVE: In the preterm human fetus, immaturity of gastrointestinal (GI) motility contributes to impairment of oral feeding and an increased risk of necrotizing enterocolitis. In view of the limited knowledge of fetal GI motility development, and the primary role of the muscarinic system in adult GI motility, we examined the development of GI muscarinic receptor subtypes associated with ileal motility. STUDY DESIGN: Ovine term fetal, newborn, and pregnant adult ileal longitudinal muscle contractile responses to muscarinic agonists (bethanechol) and muscarinic nonspecific (atropine) and subtype specific-antagonists (M1-M4) were examined in organ baths. Immunohistochemical analysis of ileal muscle muscarinic receptor subtypes was correlated with contractile responses. RESULTS: Bethanechol induced a concentration-dependent ileal contraction at all 3 age groups. Adult ileal maximal tension was 2-fold higher than that of the fetus and newborn, while 50% effective concentration (EC(50)) was similar at all ages. Atropine (10(-6)mol/L) inhibited contractility in fetal (67%+/-7%), newborn (82%+/-5%), and adult (97%+/-2%) in an age-dependent manner. The M3 antagonist exhibited robust inhibition at all age groups while the M2 antagonist demonstrated enhanced inhibition in the fetus. Immunohistochemical analysis indicated coexpression of subtype receptors in fetal, newborn, and adult ileal smooth muscle with increasing expression with advancing age. CONCLUSION: These results demonstrate a specific developmental pattern of muscarinic receptor subtype expression. Knowledge and/or alterations of GI motility regulation may aid in the treatment of the preterm fetus or newborn.