Caffeine withdrawal affects central adenosine receptors but not benzodiazepine receptors

Summary The effects of chronic caffeine administration on both adenosine and benzodiazepine receptors were studied in mouse brain membranes. Animals were fed on a diet enriched with caffeine (600 mg/kg diet) for 15 days and sacrificed 2, 4, 8 and 15 days after withdrawal. Compared with controls fed on a regular diet, animals receiving a caffeine-enriched diet showed an increase in the number of brain adenosine receptors labeled with [³H]-DPX in both the cerebellum and forebrain regions. This up-regulation was still significant 15 days after withdrawal in the cerebellum but not in the forebrain, where the number of adenosine receptors returned to control levels within 8 days following withdrawal. Benzodiazepine receptors labeled by [³H]-B-CCE were not influenced by chronic caffeine diet or withdrawal.Study performed when both authors were working within the Biological Psychiatry Branch. National Institute of Mental Health, Bethesda, Maryland, U.S.A.     

首发精神分裂症患者的血清甲状腺相关激素水平变化及其与临床关系对照研究

目的探讨首发精神分裂症患者血清甲状腺相关激素（Ｔ３、Ｔ４、ＴＳＨ、ＦＴ３及ＦＴ４）水平的动态变化及其与临床关系。方法４１例患者分别于疗前、疗后进行ＢＰＲＳ评定及血清Ｔ３、Ｔ４、ＴＳＨ、ＦＴ３、ＦＴ４测定，并与正常对照组作比较。结果研究组疗前血清甲状腺素（Ｔ４）显著高于对照组，并随治疗及病情改善而恢复正常。但游离甲状腺素（ＦＴ４）在疗前、疗后均低于正常对照组。患者的ＢＰＲＳ得分高低与其疗前血清Ｔ３、Ｔ４水平显著正相关（Ｐ＜０．０５）。结论精神分裂症患者血清Ｔ４、ＦＴ４水平变化可能与其疾病本身有关。血清Ｔ３，Ｔ４水平似乎可预测精神分裂症的严重度。     

Characterization of adenosine receptors in brain using N cyclohexyl [H]adenosine

The presence of distinct binding sites for adenosine in both the CNS and PNS has been proposed in numerous studies. The recent availability of stable adenosine analogues such as cyclohexyladenosine, 2-chloroadenosine and diethylphenylxanthine has made the characterization of such a receptor feasible. In the present report the binding of N⁶ cyclohexyl [³H]adenosine ([³H]CHA) to rat brain synaptosomal membranes is characterized. [³H]CHA binding is saturable and exhibits a biphasic kinetic saturation profile characteristic of 2 binding sites. The high affinity site has a K_d of 0.7 nM and the low affinity site 2.4 nM. The respective B_max values are 230 and 120 fmol/mg protein in rat forebrain. The highest density of binding sites is found in the hippocampus and subcellular distribution studies indicate that the [³H]CHA site is predominantly synaptosomal. [³H]CHA binding is highly dependent on the presence of adenosine deaminase since only 30% of the binding capacity is observed in synaptosomal membranes not treated with this enzyme. Of the many cations and anions tested only copper and zinc have effects on [³H]CHA binding. Both metals are potent inhibitors of binding with copper having an IC₅₀ of 30 μM and zinc 150 μM. Sulfhydryl reducing and alkylating agents also inhibit binding indicating that the binding site is a sulfhydryl-dependent protein.     

奥氮平对甲状腺激素水平的影响

目的：了解奥氮平对精神分裂症患者甲状腺素水平的影响。方法：随机抽取正在服用奥氮平的住院精神分裂症患者20例,分别于入组时、入组后1个月查FT3、FT4、TSH并进行比较。结果：入组时与常模比较FT3显著下降（P〈0．01）;1个月后与常模比较FT3、FT4显著下降（P〈0．01）;入组时与1个月后比较FT4显著下降（P〈0．01）;TSH与年龄、剂量、服用时间正相关（r〉0．3）;FIB、FT4、TSH与性别无相关性。结论：奥氮平可致甲状腺激素水平下降,TSH有反馈性升高趋势,但尚在正常范围内。临床或许可以通过干预甲状腺激素水平来调整精神分裂症患者的情绪障碍。     

抑郁症与心境恶劣障碍患者的甲状腺素水平

目的:测定抑郁症与心境恶劣障碍患者的甲状腺素水平,探讨其神经内分泌改变。方法:对抑郁症30例和心境恶劣障碍30例进行汉密尔顿抑郁量表(HAMD),艾森克人格问卷(EPQ)及生活事件量表(LES)评定。测血清三碘甲状腺原氨酸(T3)、甲状腺素(T4)及促甲状腺素(TSH)浓度。结果:两组间在HAMD总分及T4水平差异显著。抑郁症组T3与EPQ的内外向分及HAMD的迟缓因子分呈正相关;T4与HAMD总分、焦虑因子分及负性生活事件刺激量呈正相关;TSH与正性生活事件刺激量呈正相关。心境恶劣障碍组T3与认知障碍因子分呈负相关;T4与HAMD总分、负性生活事件及迟缓因子分呈正相关。结论:负性生活事件促进了抑郁发作,T4水平可预测抑郁症状的严重程度。     

Deep brain stimulation suppresses epileptic seizures in rats via inhibition of adenosine kinase and activation of adenosine A1 receptors

Aims

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus, is an effective therapy for patients with drug-resistant epilepsy, yet, its mechanism of action remains elusive. Adenosine kinase (ADK), a key negative regulator of adenosine, is a potential modulator of epileptogenesis. DBS has been shown to increase adenosine levels, which may suppress seizures via A1 receptors (A₁Rs). We investigated whether DBS could halt disease progression and the potential involvement of adenosine mechanisms.

Methods

Control group, SE (status epilepticus) group, SE-DBS group, and SE-sham-DBS group were included in this study. One week after a pilocarpine-induced status epilepticus, rats in the SE-DBS group were treated with DBS for 4 weeks. The rats were monitored by video-EEG. ADK and A₁Rs were tested with histochemistry and western blot, respectively.

Results

Compared with the SE group and SE-sham-DBS group, DBS could reduce the frequency of spontaneous recurrent seizures (SRS) and the number of interictal epileptic discharges. The DPCPX, an A₁R antagonist, reversed the effect of DBS on interictal epileptic discharges. In addition, DBS inhibited the overexpression of ADK and the downregulation of A₁Rs.

Conclusion

The findings indicate that DBS can reduce SRS in epileptic rats via inhibition of ADK and activation of A₁Rs. A₁Rs might be a potential target of DBS for the treatment of epilepsy.     

Tricyclic antidepressants do not alter thyroid hormone levels in patients suffering from a major affective disorder

Abnormalities of thyroid function have been associated with affective disorders, and treatment with thyroid hormones or drugs that alter thyroid hormone levels can change the course of an affective disorder. Therefore, we investigated the possibility that mood-altering effects of tricyclic antidepressants would be mediated by alterations in thyroid hormone (T₃ and T₄) levels. In a group of 11 patients with affective disorders, tricyclic antidepressants did not alter serum T₃ and T₄ levels. We conclude that the mood-altering potency of tricyclic antidepressants, and particularly their potency to induce rapid mood cycles, is not due to changes in total T₃ and T₄ serum levels.     

Effects of thyroid state on brain development: beta-adrenergic receptors and 5'-nucleotidase activity

The effect of thyroid status on beta-adrenergic receptor binding and 5'-nucleotidase activity was studied in the forebrain and the cerebellum of the rat during the first 5 postnatal weeks. The developmental increase in beta-adrenergic receptor binding was significantly depressed in thyroid deficiency in both the forebrain and the cerebellum. The effect was more pronounced in the cerebellum, where at day 35 the concentration and the total number of beta-adrenergic receptor sites were reduced by 35% and 50% respectively. In contrast, hyperthyroidism had no significant effect on the development of beta-adrenergic receptors in the brain. On the other hand, hyperthyroidism led to a sustained increase in the forebrain in the activity of 5'-nucleotidase, an enzyme which is also associated with plasma membranes and has been proposed to play some role in neurotransmission. In thyroid deficiency the enzyme activity was markedly depressed. The effect was significant from day 12 in the cerebellum and from day 21 in the forebrain, the maximal depression, at day 21, being 55% and 45% respectively. In comparison with these plasma membrane markers, the accretion of membranous proteins was less affected: although this was retarded in hypothyroidism and advanced in hyperthyroidism there was no residual effect at 35 days except those attributable to changes in organ size. The results indicated, therefore, that the biochemical specialization of cells, as reflected in certain plasma membrane constituents, are chatacteristically influenced in the developing brain by thyroid disorders.     

Inhibition of brain adenylate cyclase by A1 adenosine receptors: Pharmacological characteristics and locations

When tested under conditions reducing the endogenous production of adenosine (presence of adenosine deaminase (ADA) 1.6 IU/ml; and deoxyadenosine triphosphate (d-ATP)), and in the presence of both NaCl and GTP, the ADA-resistant analog phenylisopropyladenosine (PIA) inhibited the adenylate cyclase of several tissues. These tissues included:(1) 5 brain areas of adult rats (frontal and parietal cortex, cerebellum cortex, hippocampus and striatum) — hypothalamus and mid-brain adenylate cyclases were not inhibited by PIA; (2) astrocytes in primary cultures prepared from cerebral cortex of newborn mice; and (3) neurons in primary cultures prepared from striata of 15-day-old mouse embryos.The specificity profile of the adenosine receptor involved in the inhibition was determined in astrocytes. It was typical of an A₁ adenosine receptor (high affinity of PIA;K_aapp: 9 ± 5 × 10⁻⁹M(n= 4) compared to the affinity of 5′-N-ethylcar☐amide adenosine (NECA);K_aapp: 1.3 ± 0.6 × 10⁻⁷M (n= 3). There was an excellent correlation between the affinities of several adenosine agonists and antagonists for A₁ receptors coupled with an adenylate cyclase in astrocytes and for the receptors labeled with N⁶-cyclohexyl-[³H]adenosine in brain cortex.In adult rat striatum as well as in astrocytes and striatal neurons in culture the adenylate cyclase was inhibited by low PIA concentrations through A₁ receptors and stimulated by higher concentrations through A₂ receptors. In contrast, A₂ receptors were not detected in adult rat cerebral cortex.In adult rat striatum, A₁ and dopamine receptors coupled with an adenylate cyclase seemed to be located on different cell populations. In contrast, in astrocytes A₁ and β-adrenergic receptors coupled with adenylate cyclase were apparently located on the same cells.     

Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings

Abstract The original concept of the critical period of thyroid hormone (TH) action on brain development was proposed to identify the postnatal period during which TH supplement must be provided to a child with congenital hypothyroidism to prevent mental retardation. As neuropsychological tools have become more sensitive, it has become apparent that even mild TH insufficiency in humans can produce measurable deficits in very specific neuropsychological functions, and that the specific consequences of TH deficiency depends on the precise developmental timing of the deficiency. Models of maternal hypothyroidism, hypothyroxinaemia and congenital hyperthyroidism have provided these insights. If the TH deficiency occurs early in pregnancy, the offspring display problems in visual attention, visual processing (i.e. acuity and strabismus) and gross motor skills. If it occurs later in pregnancy, children are at additional risk of subnormal visual (i.e. contrast sensitivity) and visuospatial skills, as well as slower response speeds and fine motor deficits. Finally, if TH insufficiency occurs after birth, language and memory skills are most predominantly affected. Although the experimental literature lags behind clinical studies in providing a mechanistic explanation for each of these observations, recent studies confirm that the specific action of TH on brain development depends upon developmental timing, and studies informing us about molecular mechanisms of TH action are generating hypotheses concerning possible mechanisms to account for these pleiotropic actions.     

Comparative distribution of the mammalian mediator subunit thyroid hormone receptor-associated protein (TRAP220) mRNA in developing and adult rodent brain

Disinhibition reliably induces regular synchronous bursting in networks of spinal interneurons in culture as well as in the intact spinal cord. We have combined extracellular multisite recording using multielectrode arrays with whole cell recordings to investigate the mechanisms involved in bursting in organotypic and dissociated cultures from the spinal cords of embryonic rats. Network bursts induced depolarization and spikes in single neurons, which were mediated by recurrent excitation through glutamatergic synaptic transmission. When such transmission was blocked, bursting ceased. However, tonic spiking persisted in some of the neurons. In such neurons intrinsic spiking was suppressed following the bursts and reappeared in the intervals after several seconds. The suppression of intrinsic spiking could be reproduced when, in the absence of fast synaptic transmission, bursts were mimicked by the injection of current pulses. Intrinsic spiking was also suppressed by a slight hyperpolarization. An afterhyperpolarization following the bursts was found in roughly half of the neurons. These afterhyperpolarizations were combined with a decrease in excitability. No evidence for the involvement of synaptic depletion or receptor desensitization in bursting was found, because neither the rate nor the size of spontaneous excitatory postsynaptic currents were decreased following the bursts. Extracellular stimuli paced bursts at low frequencies, but failed to induce bursts when applied too soon after the last burst. Altogether these results suggest that bursting in spinal cultures is mainly based on intrinsic spiking in some neurons, recurrent excitation of the network and auto-regulation of neuronal excitability.     

奥氮平、奎硫平与阿立哌唑对精神分裂症患者血清甲状腺激素和催乳素水平的影响

目的:探讨非典型抗精神病药奥氮平、奎硫平、阿立哌唑对精神分裂症患者血清甲状腺激素和催乳素(PRL)水平的影响方法:将150例精神分裂症患者随机分为奥氮平、奎硫平及阿立哌唑组并接受相应的药物治疗8周。治疗前后分别检测血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、总三碘甲状腺原氨酸(T3)、总甲状腺素(T4)、促甲状腺激素(TSH)及PRL水平。结果:治疗后3组血清FT4、T3、T4水平较治疗前明显下降(P均0.01);T4组间主效应有统计学意义(P0.05);治疗后奎硫平组血清T4水平较奥氮平组下降更明显(P0.05);治疗后奥氮平组血清PRL水平明显高于治疗前及奎硫平及阿立哌唑组(P均0.01),并具有交互作用(P0.01)。结论:奥氮平、奎硫平、阿立哌唑都降低甲状腺激素水平,奎硫平更易降低T4水平;奥氮平显著影响血清PRL水平。     

急性脑出血患者血清甲状腺激素水平的变化及其意义

目的探讨急性脑出血患者血清甲状腺激素水平的变化及其意义。方法 65例急性脑出血患者于入院第1 d、第3 d、第7 d、第15 d,52名正常对照者于体检日进行血清三碘甲状腺原氨酸(T3)、甲状腺素(T4)、游离T3(FT3)、游离T4(FT4)和促甲状腺激素(TSH)水平检测和比较。并对不同病情及预后的急性脑出血患者入院第3 d的血清甲状腺激素水平进行比较。结果与正常对照组比较,急性脑出血组入院第1 d、第3 d、第7 d时血清T3、FT3水平明显降低,血清T4、FT4水平明显增高(均P<0.05)。与急性脑出血轻度亚组比较,中度亚组及重度亚组血清T3、FT3水平明显降低,血清T4、FT4及TSH水平明显增高(均P<0.05);与急性脑出血中度亚组比较,重度亚组血清T3、FT3水平明显降低,血清T4、FT4及TSH水平明显增高(均P<0.05)。与急性脑出血显著进步亚组比较,进步亚组及死亡亚组血清T3、FT3水平明显降低,血清T4、FT4及TSH水平明显增高(均P<0.05);与急性脑出血进步亚组比较,死亡亚组血清T3、FT3水平明显降低,血清T4、FT4及TSH水平明显增高(均P<0.05)。结论急性脑出血...     

Activation of adenosine A3 receptors reduces ischemic brain injury in rodents

Adenosine A3 receptor (A3R) agonists have been shown to reduce cardiac and lung injury, but the protective roles of A3R agonists in the CNS are not well characterized. The protective effect of selective A3R agonist chloro-N(6)-(3-iodo-benzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) was first examined in primary cortical cultures. In cortical culture, Cl-IB-MECA pretreatment antagonized the hypoxia-mediated decrease in cell viability. In vivo, Cl-IB-MECA or vehicle was given intracerebroventricularly or intravenously to anesthetized rats. Animals were subjected to focal cerebral ischemia induced by transient middle cerebral artery (MCA) ligation. Intracerebroventricular or repeated intravenous administration (i.e., at 165 min and 15 min before MCA ligation) of Cl-IB-MECA did not alter blood pressure during ischemia but increased locomotor activity and decreased cerebral infarction 2 days after. In these animals, Cl-IB-MECA also reduced the density of TUNEL labeling in the lesioned cortex. The possibility of endogeneous neuroprotection was further examined in A3R knockout mice. After MCA ligation, an increase in cerebral infarction was found in the A3R knockouts compared with the A3R wild-type controls, suggesting that A3Rs are tonically activated during ischemia. Additionally, intracerebroventricular pretreatment with Cl-IB-MECA decreased the size of infarction in the wild-type controls, but not in the A3R knockout animals, suggesting that Cl-IB-MECA-induced protection was mediated through the A3 receptors. Collectively, these data suggest that Cl-IB-MECA reduced cerebral infarction through the activation of A3Rs and suppression of apoptosis.     

Coexpression of thyroid hormone receptor isoforms in mouse oligodendrocytes.

Double and triple immunocytochemistry with stage-specific markers and specific antireceptor antibodies was used to study expression of nuclear thyroid hormone receptor (TR) isoforms in cultured mouse oligodendrocytes. To evaluate the coexpression of each TR isoform, antibodies were raised in rabbits and mice against specific regions of alpha1-TR and alpha2-TR common to both alpha isoforms and beta1-TR. Their specificities were assessed by Western blotting and by immunocytochemistry on rat hepatocytes. Oligodendrocyte subpopulations were found to coexpress the alpha- and beta1-TR epitopes at defined developmental stages. Both alpha- and beta1-TR isoforms are colocalized in oligodendrocytes during an early stage identified by the marker OL-1, before 2',3'-cyclic nucleotide 3'-phosphohydrolase is expressed. Expression of beta1-TR varies during maturation, and that of alpha-TR decreases during terminal maturation.     

Phobic anxiety does not affect plasma levels of thyroid stimulating hormone in man

(1) The effect of anxiety on plasma levels of thyroid stimulating hormone (TSH) is not clear, despite a number of relevant studies. (2) Nine human subjects with severe phobias had blood samples taken for TSH assay every 20 min during five sessions of 3-hr duration each. (3) Severe anxiety, induced by treating the subject's phobia with in vivo flooding, did not influence plasma TSH levels in any consistent way, nor could a specific TSH response to anxiety be identified in any individual subject.     

Cobalt ion enhancement of 2-chloro[H]adenosine binding to a novel class of adenosine receptors in brain: antagonism by calcium

We have recently reported the identification of a novel class of micromolar-affinity adenosine binding sites in rat brain membranes using the adenosine agonist 2-chloro[³H]adenosine (Cl[³H]Ado). These binding sites are distinguishable from the A1 and A2 adenosine receptors by a number of pharmacological criteria, and we have designated this new class of binding sites as the A3 adenosine binding sites. In the present study, the effects of a wide range of divalent and trivalent cations on micromolar Cl[³H]Ado binding to brain membranes were examined. Co²⁺, Ni²⁺ and La³⁺ markedly stimulated specific Cl[³H]Ado binding by 45–150% above control when tested at concentrations of 1–10 mM. Ca²⁺ had no significant effect on binding except at high concentrations where it depressed binding slightly. Ca²⁺, however, completely prevented the stimulation of Cl[³H]Ado binding by Co²⁺. These findings further distinguish the A3 class of adenosine binding sites from the previously characterized adenosine receptors and suggest that the A3 binding sites are associated with calcium systems in brain.