Redundant role of OsCNGC4 and OsCNGC5 encoding cyclic nucleotide-gated channels in rice pollen germination and tube growth.

In staple crops, such as rice (Oryza sativa L.), pollen plays a crucial role in seed production. However, the molecular mechanisms underlying rice pollen germination and tube growth remain underexplored. Notably, we recently uncovered the redundant expression and mutual interaction of two rice genes encoding cyclic nucleotide-gated channels (CNGCs), OsCNGC4 and OsCNGC5, in mature pollen. Building on these findings, the current study focused on clarifying the functional roles of these two genes in pollen germination and tube growth. To overcome functional redundancy, we produced gene-edited rice plants with mutations in both genes using the CRISPR-Cas9 system. The resulting homozygous OsCNGC4 and OsCNGC5 gene-edited mutants (oscngc4/5) exhibited significantly lower pollen germination rates than the wild type (WT), along with severely reduced fertility. Transcriptome analysis of the double oscngc4/5 mutant revealed downregulation of genes related to receptor kinases, transporters, and cell wall metabolism. To identify the direct regulators of OsCNGC4, which form a heterodimer with OsCNGC5, we screened a yeast two-hybrid library containing rice cDNAs from mature anthers. Subsequently, we identified two calmodulin isoforms (CaM1-1 and CaM1-2), NETWORKED 2 A (NET2A), and proline-rich extension-like receptor kinase 13 (PERK13) proteins as interactors of OsCNGC4, suggesting its roles in regulating Ca2+ channel activity and F-actin organization. Overall, our results suggest that OsCNGC4 and OsCNGC5 may play critical roles in pollen germination and elongation by regulating the Ca2+ gradient in growing pollen tubes.

Mycobacterial phosphodiesterase Rv0805 is a virulence determinant and its cyclic nucleotide hydrolytic activity is required for propionate detoxification.

Cyclic AMP (cAMP) signaling is essential to Mycobacterium tuberculosis (Mtb) pathogenesis. However, the roles of phosphodiesterases (PDEs) Rv0805, and the recently identified Rv1339, in cAMP homeostasis and Mtb biology are unclear. We found that Rv0805 modulates Mtb growth within mice, macrophages and on host-associated carbon sources. Mycobacterium bovis BCG grown on a combination of propionate and glycerol as carbon sources showed high levels of cAMP and had a strict requirement for Rv0805 cNMP hydrolytic activity. Supplementation with vitamin B12 or spontaneous genetic mutations in the pta-ackA operon restored the growth of BCGΔRv0805 and eliminated propionate-associated cAMP increases. Surprisingly, reduction of total cAMP levels by ectopic expression of Rv1339 restored only 20% of growth, while Rv0805 complementation fully restored growth despite a smaller effect on total cAMP levels. Deletion of an Rv0805 localization domain also reduced BCG growth in the presence of propionate and glycerol. We propose that localized Rv0805 cAMP hydrolysis modulates activity of a specialized pathway associated with propionate metabolism, while Rv1339 has a broader role in cAMP homeostasis. Future studies will address the biological roles of Rv0805 and Rv1339, including their impacts on metabolism, cAMP signaling and Mtb pathogenesis.

Grafting with an invasive Xanthium strumarium improves tolerance and phytoremediation of native congener X. sibiricum to cadmium/copper/nickel tailings.

Invasive plants could play an important role in the restoration of tailings, but their invasiveness limits their practical application. In this study, the phytoremediation potentials and invasive risks of an exotic invasive plant (Xanthium strumarium, LT), a native plant (X. sibiricum, CR), and combinations of inoculations (EG, with CR as the scion and LT as the rootstock; SG, with CR as both the scion and rootstock) were evaluated on Cd/Cu/Ni tailings. LT rootstock has a stronger nutrient and metal transport capacity, compared with CR. EG not only had higher biomass and Cd/Cu/Ni accumulation, but also abundant rhizosphere microbial communities. Hydroponic and common garden experiments showed that the growth and metal enrichment characteristics of EG are not inherited by plant offspring, which reduces the risk of the biological diffusion in the process of using exotic species. Transcriptome analysis shows that a large number of differentially-expressed genes in EG leaves and roots are involved in phenylpropanoid biosynthesis, secondary metabolite generation, and signal transduction. The genes induced in EG leaves, including cyclic nucleotide-gated ion channel, calcium-binding protein, and WRKY transcription factor, were found to be differentially expressed compared to CR. The genes induced in EG roots, included phenylalanine ammonia-lyase, cinnamoyl-CoA reductase, caffeoyl-CoA O-methyltransferase, and beta-glucosidase. We speculate that lignin and glucosinolates play an important role in the metal accumulation and transportation of EG. The results demonstrate that grafting with LT not only improved CR tolerance and accumulation of Cd, Cu, and Ni, but also created a beneficial microbial environment for plants in tailings. More importantly, grafting with LT did not enhance the invasiveness of CR. Our results provide an example of the safe use of invasive plants in the restoration of Cd/Cu/Ni tailings.

Hyperpolarization-activated cyclic nucleotide-gated 2 contributes to electroacupuncture analgesia on lumbar disc herniation-induced radicular pain through activation of microglia in spinal dorsal horn.

OBJECTIVE: To explore the mechanisms of dorsal root ganglia and spinal microglia cascade cross in electroacupuncture (EA) analgesia in the treatment of lumbar disc herniation. METHODS: A rat model of lumbar disc herniation (LDH) was established, EA was administered at Huantiao (GB30) acupoint 30 min once a day, for 3 d. Before and after modeling, and after EA, mechanical allodynia thresholds were detected. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) in dorsal root ganglia was detected by quantitative polymerase chain reaction (qPCR) and Western blot. C-X3-C motif chemokine ligand 1 (CX3CL1) and activity of microglia in spinal cord was observed separately qPCR and immunofluorescence staining. RESULTS: The mechanical allodynia threshold of the right planta of model rats was significantly reduced ( < 0.01), EA increased the mechanical pain threshold of rats ( < 0.01), and decreased HCN2 mRNA, and protein expression, reduced the expression of CX3CL1 and the activation of microglia. ZD7288 (a blocker of HCN channel) reduced the analgesic effect of EA from 1.83 ± 0.84 to 0.74 ± 0.20 ( < 0.05), and the expression of CX3CL1 in the spinal cord decreased from 0.52 ± 0.11 to 0.15 ± 0.05 ( < 0.01). CONCLUSION: EA analgesia on the radicular pain of LDH is definite. EA reduced the expression of HCN2 channel in the dorsal root ganglion, thereby decreasing the noxious stimulation entered to microglia in spinal dorsal horn. Our work supports EA is an effective treatment for radicular pain of LDH.

Modulation of pacemaker channel function in a model of thalamocortical hyperexcitability by demyelination and cytokines.

A consensus is yet to be reached regarding the exact prevalence of epileptic seizures or epilepsy in multiple sclerosis (MS). In addition, the underlying pathophysiological basis of the reciprocal interaction among neuroinflammation, demyelination, and epilepsy remains unclear. Therefore, a better understanding of cellular and network mechanisms linking these pathologies is needed. Cuprizone-induced general demyelination in rodents is a valuable model for studying MS pathologies. Here, we studied the relationship among epileptic activity, loss of myelin, and pro-inflammatory cytokines by inducing acute, generalized demyelination in a genetic mouse model of human absence epilepsy, C3H/HeJ mice. Both cellular and network mechanisms were studied using in vivo and in vitro electrophysiological techniques. We found that acute, generalized demyelination in C3H/HeJ mice resulted in a lower number of spike-wave discharges, increased cortical theta oscillations, and reduction of slow rhythmic intrathalamic burst activity. In addition, generalized demyelination resulted in a significant reduction in the amplitude of the hyperpolarization-activated inward current (Ih) in thalamic relay cells, which was accompanied by lower surface expression of hyperpolarization-activated, cyclic nucleotide-gated channels, and the phosphorylated form of TRIP8b (pS237-TRIP8b). We suggest that demyelination-related changes in thalamic Ih may be one of the factors defining the prevalence of seizures in MS.

Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

In Vitro Antiplatelet Activity of Mulberroside C through the Up-Regulation of Cyclic Nucleotide Signaling Pathways and Down-Regulation of Phosphoproteins.

Physiological agonists trigger signaling cascades, called "inside-out signaling", and activated platelets facilitate adhesion, shape change, granule release, and structural change of glycoprotein IIb/IIIa (αIIb/ß3). Activated αIIb/ß3 interacts with fibrinogen and begins second signaling cascades called "outside-in signaling". These two signaling pathways can lead to hemostasis or thrombosis. Thrombosis can occur in arterial and venous blood vessels and is a major medical problem. Platelet-mediated thrombosis is a major cause of cardiovascular disease (CVD). Therefore, controlling platelet activity is important for platelet-mediated thrombosis and cardiovascular diseases. In this study, focus on Morus Alba Linn, a popular medicinal plant, to inhibit the function of platelets and found the containing component mulberroside C. We examine the effect of mulberroside C on the regulation of phosphoproteins, platelet-activating factors, and binding molecules. Agonist-induced human platelet aggregation is dose-dependently inhibited by mulberroside C without cytotoxicity, and it decreased Ca2+ mobilization and p-selectin expression through the upregulation of inositol 1, 4, 5-triphosphate receptor I (Ser1756), and downregulation of extracellular signal-regulated kinase (ERK). In addition, mulberroside C inhibited thromboxane A2 production, fibrinogen binding, and clot retraction. Our results show antiplatelet effects and antithrombus formation of mulberroside C in human platelets. Thus, we confirm that mulberroside C could be a potential phytochemical for the prevention of thrombosis-mediated CVDs.

Development of Phosphodiesterase-Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity.

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE-PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE-PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems-cAMP-specific PDE8-PKAR, cGMP-specific PDE5-PKG, and dual-specificity RegA-RD complexes-and ranked inhibitors according to their inhibition potency. Targeting PDE-PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.

Bee Bread Ameliorates Vascular Inflammation and Impaired Vasorelaxation in Obesity-Induced Vascular Damage Rat Model: The Role of eNOS/NO/cGMP-Signaling Pathway.

Obesity and hyperlipidemia are major risk factors for developing vascular diseases. Bee bread (BB) has been reported to exhibit some biological actions, including anti-obesity and anti-hyperlipidemic. This study aims to investigate whether bee bread can ameliorate vascular inflammation and impaired vasorelaxation activity through eNOS/NO/cGMP pathway in obese rats. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10/group), namely: control (normal group), obese rats (OB group), obese rats treated with bee bread (0.5 g/kg/day, OB/BB group) and obese rats treated with orlistat (10 mg/kg/day, OB/OR group). The latter three groups were given a high-fat diet (HFD) for 6 weeks to induced obesity before being administered with their respective treatments for another 6 weeks. After 12 weeks of the total experimental period, rats in the OB group demonstrated significantly higher Lee obesity index, lipid profile (total cholesterol, triglyceride, low-density lipoprotein), aortic proinflammatory markers (tumor necrosis factor-α, nuclear factor-κß), aortic structural damage and impairment in vasorelaxation response to acetylcholine (ACh). Bee bread significantly ameliorated the obesity-induced vascular damage manifested by improvements in the lipid profile, aortic inflammatory markers, and the impaired vasorelaxation activity by significantly enhancing nitric oxide release, promoting endothelial nitric oxide synthase (eNOS) and cyclic guanosine monophosphate (cGMP) immunoexpression. These findings suggest that the administration of bee bread ameliorates the impaired vasorelaxation response to ACh by improving eNOS/NO/cGMP-signaling pathway in obese rats, suggesting its vascular therapeutic role.

Banxia Xiexin Decoction () Treats Diabetic Gastroparesis through PLC-IP3-Ca2+/NO-cGMP-PKG Signal Pathway.

OBJECTIVE: To test the effect of Banxia Xiexin Decoction (, BXD) on the contraction and relaxation of gastric smooth muscle (SM) in diabetic gastroparesis (DGP) model rats, and to explore the mechanism of BXD in the prevention and treatment of DGP through experiments of signal pathway both in vivo and in vitro. METHODS: Sixty Sprague-Dawley rats were divided into 6 groups according to a random number table: control group, model group, high-, medium- and low-dose BXD groups (9.2, 4.6 and 1.8 g/(kg·d), respectively), and domperidone group (10 mg/(kg·d)), 10 rats per group. DGP model was established initially by a single intraperitoneal injection of streptozotocin (STZ), and was confirmed by recording gastric emptying, intestinal transport velocity and gastric myoelectric activity of rats after 2 months. Each group was treated with a corresponding drug for 4 weeks. The mRNA and protein expressions of phospholipase C (PLC), inositol triphosphate (IP3), neuronal nitric oxide synthase (nNOS), and cyclic guanosine monophosphate (cGMP) dependent protein kinase G (PKG) were detected by reverse transcription-polymerase chain reaction and Western blot, respectively, while nitric oxide (NO) and cGMP expressions were detected by enzyme-linked immunosorbent assay. Gastric tissues were obtained from rats for primary cell culture preparation. Gastric SM cells were treated with 0.8 µmol/L of STZ or STZ plus 1,000, 500 and 200 µg/mL of BXD or STZ plus 2.5 µmol/mL of domperidone for 24, 48, 72 or 96 h, respectively. The length of gastric SM cells and intracellular Ca2+ concentration ([Ca2+]i) before and after BXD treatment was measured. RESULTS: Compared with the model group, high- and medium-dose BXD and domperidone significantly increased the expressions of PLC, IP3, NO, nNOS, cGMP and PKG in rat's gastric tissue (P<0.01). Gastric SM cells treated with BXD showed a time- and dose-dependent increase in cell viability (P<0.01). The treatment with high- and medium-dose BXD and domperidone inhibited the increase in gastric SM cells length and increased [Ca2+]i compared with the model cells (P<0.01). CONCLUSIONS: Treatment with high- and medium-dose BXD significantly attenuated STZ-induced experimental DGP in rats. The therapeutic effect of BXD on DGP rats might be associated with the PLC-IP3-Ca2+/NO-cGMP-PKG signal pathway.

Structure, dynamics and implied gating mechanism of a human cyclic nucleotide-gated channel.

Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucleotide-binding domains. Mutations in these channels result in severe, degenerative retinal diseases, which remain untreatable. The lack of structural information on CNG channels has prevented mechanistic understanding of disease-causing mutations, precluded structure-based drug design, and hampered in silico investigation of the gating mechanism. To address this, we built a 3D model of the cone tetrameric CNG channel, based on homology to two distinct templates with known structures: the transmembrane (TM) domain of a bacterial channel, and the cyclic nucleotide-binding domain of the mouse HCN2 channel. Since the TM-domain template had low sequence-similarity to the TM domains of the CNG channels, and to reconcile conflicts between the two templates, we developed a novel, hybrid approach, combining homology modeling with evolutionary coupling constraints. Next, we used elastic network analysis of the model structure to investigate global motions of the channel and to elucidate its gating mechanism. We found the following: (i) In the main mode of motion, the TM and cytosolic domains counter-rotated around the membrane normal. We related this motion to gating, a proposition that is supported by previous experimental data, and by comparison to the known gating mechanism of the bacterial KirBac channel. (ii) The VSDs could facilitate gating (supplementing the pore gate), explaining their presence in such 'voltage-insensitive' channels. (iii) Our elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently, but are coupled to each other allosterically.

The low-dose combination preparation Vertigoheel activates cyclic nucleotide pathways and stimulates vasorelaxation.

Vertigo of various and often unknown aetiologies has been associated with and attributed to impaired microvascular perfusion in the inner ear or the vertebrobasilar system. Vertigoheel is a low-dose combination preparation of proven value in the symptomatic treatment of vertigo. In the present study we tested the hypothesis that Vertigoheel's anti-vertiginous properties may in part be due to a vasodilatory effect exerted via stimulation of the adenylate and/or guanylate cyclase pathways. Thus, the influence of Vertigoheel or its single constituents on synthesis and degradation of cyclic nucleotides was measured. Furthermore, vessel myography was used to observe the effect of Vertigoheel on the vasoreactivity of rat carotid arteries. Vertigoheel and one of its constituents, Anamirta cocculus, stimulated adenylate cyclase activity, while another constituent, Conium maculatum, inhibited phosphodiesterase 5, suggesting that the individual constituents of Vertigoheel contribute differentially to a synergistic stimulation of cyclic nucleotide signalling pathways. In rat carotid artery rings, Vertigoheel counteracted phenylephrine-induced tonic vasoconstriction. The present data demonstrate a vasorelaxant effect of Vertigoheel that goes along with a synergistic stimulation of cyclic nucleotide pathways and may provide a mechanistic basis for the documented anti-vertiginous effects of this combination preparation.

Dietary fatty acids and allergy.

The increase in the prevalence of atopic diseases has recently been linked to altered consumption of polyunsaturated fatty acids (PUFAs). As typical Western diets contain almost 10 times more linoleic acid (18:2 omega-6) than alpha-linolenic acid (18:3 omega-3), it is the metabolism of the former that predominates. Subsequently produced arachidonic acid-derived eicosanoids alter the balance of T-helper cells type 1 and type 2 thus favouring the production of immunoglobulin (Ig)E. In atopic subjects, the impact of this excessive eicosanoid production may be further strengthened as a result of changes in cyclic nucleotide metabolism exacerbated by substrate availability. Dietary omega-3 fatty acids can have marked influence on both specific and nonspecific immune responses in modifying eicosanoid production and replacing omega-6 fatty acids in cell membranes. Therefore, it is concluded that careful manipulation of dietary PUFAs may play a key role in the successful management of inflammation associated with atopic diseases.

Molecular cloning and expression of the Modulatory subunit of the cyclic nucleotide-gated cation channel.

The cDNA of three variants of a cyclic nucleotide-gated (CNG) channel modulatory subunit (CNG4c-CNG4e) has been cloned. CNG4c, CNG4d, and CNG4e differ slightly from each other within an amino-terminal sequence that was originally reported as part of the bovine retinal glutamic acid-rich protein (GARP). The core region of CNG4 is homologous to the second subunit of the human rod photoreceptor channel (hRCNC2b), suggesting that both proteins are alternatively spliced products of the bovine and human homologue of the same gene. CNG4 transcripts are present in retina, testis, kidney, heart, and brain. Expression of CNG4 in HEK293 cells did not lead to detectable currents. Coexpression of CNG4 with the principal subunit of the bovine testis CNG channel (CNG3) resulted in currents which differed in several aspects from that induced by CNG3 alone. The heterooligomeric CNG3/CNG4 and the homooligomeric CNG3 channels were modified by Ca2+-calmodulin and some calmodulin antagonists. The results suggest that CNG4 forms functional heterooligomeric channels with CNG3 in vitro and probably also in intact tissues.

[Cardioprotective effects of adaptogens of plant origin]. / Kardioprotektornye éffekty adaptogenov rastitel'nogo proiskhozhdeniia.

The experiments performed on emotional--painful stress model in rats demonstrated cardioprotective activity of adaptogens of vegetable origin (rodiolae, eleutherococcus, levsea, p-tyrosol). Preliminary injection of rodiolae extract was found to prevent stress--induced increase in cAMP level and cGMP content decrease in heart. We can conclude that adaptogens cardioprotective effect may be the drugs to prevent stressor change in cyclic nucleotides level in myocardium.

Rapid purification and N-terminal sequencing of a potato tuber cyclic nucleotide binding phosphatase.

A high affinity cyclic nucleotide binding phosphatase was purified to homogeneity from potato tubers by a rapid procedure involving batchwise elution from carboxymethylcellulose and gel filtration. The phosphatase has a molecular weight of 28,000 as estimated from both SDS-PAGE and gel filtration. The phosphatase binds to Con A-agarose and is eluted by 0.5 M alpha-methylglucoside. The phosphatase catalyses the hydrolysis of nucleoside monophosphates, p-nitrophenylphosphate and O-phospho-L-tyrosine, but not of O-phospho-L-serine or O-phospho-L-threonine. N-terminal sequencing of the phosphatase has revealed significant homology with two similar-size soybean leaf and stem storage glycoproteins.

Investigations on pharmacological and immunological properties of imuthiol.

An observation was made that imuthiol exerts inhibitory effect on hemolysins forming cells (PFC) and on NK cells activity. It also reduces the number of T lymphocytes (in vitro), increases the activity of interleukin-1 and of the lymph node permeability factor. Well recognized is also its protective effect on thymocytes against hydrocortisone. Imuthiol was found to enhance rosette formation and to stimulate stem cells and partly suppressor cells. It reduces the level of cAMP. Its effect on the circulatory system is negligible.

[Effect of gamma-oxybutyrate on energy metabolism and the cyclic nucleotide level in nerve tissue in experimental intracerebral hemorrhage]. / Vliianie gamma-oksibutirata na énergeticheskii metabolizm i uroven' tsiklicheskikh nukleotidov v nervnoi tkani pri éksperimental'nom vnutrimozgovom krovoizliianii.

Experimental intracerebral hemorrhage (EICH) was shown to cause a disorder of the functional state of the brain mitochondria. The rate of oxidation of NAD- and FAD-linked substrates in 3 and 4 states decreased 1 and 24 hours after hemorrhage. An injection of gamma-hydroxybutyrate 1 hour before decapitation increased the rate of mitochondrial respiration. EICH was found to increase cGMP level and to decrease cAMP level. A combined action of hemorrhage and gamma-hydroxybutyrate produced a greater lowering of cAMP level and an elevation of cGMP level.

[Enkephalin and cyclic nucleotide content in the brain structures of rats at different stages of the formation and development of alcoholic dependence]. / Soderzhanie énkefalinov i tsiklicheskikh nukleotidov v strukturakh mozga krys v razlichnye stadii formirovaniia i razvitiia alkogol'noi zavisimosti.

Rats with increased alcohol motivation have been found to have a rise in enkephalin levels in limbic cortex and a decrease in met-enkephalin levels in the brain basal ganglia. Reduction of met-enkephalin to leu-enkephalin ratio in basal ganglia, limbic cortex and hypothalamus may serve as an index of increased inclination to ethanol in these animals. Alcohol dependence is characterized by reduced cAMP content in the majority of brain structures studied, sharply decreased met-enkephalin levels in limbic cortex and hypothalamus, and diminished cAMP and cGMP content in hypothalamus. In the third stage of experimental alcoholism the partial normalization of met-enkephalin and cAMP levels is observed in brain structures, with cGMP content increased in hypothalamus and considerably reduced in basal ganglia.