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At least 505 records · Page 28Linked to original sources
PubMed1993

Regulation of substance P receptor system in rat striatum by chronic naltrexone treatment.

Chronic blockade of opioid receptors by naltrexone increases opioid peptides in the striatum, and up-regulates brain opioid receptors resulting in functional supersensitivity. Striatal SP content was increased 3.5-fold after 8 days of naltrexone treatment relative to control animals. The present study was undertaken to determine whether SP receptors in the striatum and SP receptor-coupled second messenger system are modulated by increased striatal SP content induced by chronic opioid receptor blockade. The binding affinity and capacity of SP receptors, determined using [125I]Bolton-Hunter SP ([125I]BHSP) labeled at Lys3, in striatal synaptosomal membranes were not significantly altered by chronic blockade of opioid receptors. Although the concentrations of [Sar9,Met (O2)11]SP, a NK-1 receptor-specific agonist, and SP(1-7), an aminoterminal major metabolite of SP, required to inhibit half of [125I]BHSP binding (IC50) in striatal synaptosomal membranes were significantly decreased, the IC50s for SP and an NK-2 receptor-specific agonist, [Nle10]NK A (4-10), remained unchanged by chronic naltrexone treatment. The data suggest that naltrexone which has no SP receptor antagonistic action, not only indirectly acts on SP-ergic neurons but also causes a change in the apparent affinity of NK-1 receptor (as reflected by changes in IC50 values) in the striatum. Cellular inositol-1,4,5-trisphosphate [Ins(1,4,5)P3], quantified by a highly sensitive and selective radioreceptor mass assay, was increased in the striatum by 28% relative to control levels. With [3H]Ins(1,4,5)P3 as a ligand, Scatchard analyses of the concentration-dependent saturation curves showed that the density of striatal intracellular Ins(1,4,5)P3 receptors was increased by 53%. The levels of SP and cellular Ins(1,4,5)P3, and the density of Ins(1,4,5)P3 receptors in the cerebellum, used as a positive control, were unchanged by chronic naltrexone treatment. The findings of opiate antagonist-induced increases in SP striatal content and Ins(1,4,5)P3 receptor densities, appear to support the concept of a role of endogenous opioids in the regulation of SP receptor activity. The data also suggest that inter-regulatory mechanisms exist between phospholipase C/phosphoinositide-coupled receptors such as SP receptors, and adenylate cyclase-coupled inhibitory receptors, such as opioid receptors.

Animals↗
PubMedDate not supplied

Second messenger pathways involved in up-regulation of an L-type calcium channel.

Catfish cone horizontal cells contain a voltage-gated L-type calcium channel that is modulated by activation of metabotropic glutamate receptors (mGluRs). Activation of group I mGluRs with the mGluR I agonist, (S)-3,5-dihydroxyphenylglycine [(S) 3,5-DHPG], potentiated peak calcium current amplitude, shifted the membrane potential corresponding to peak current activity, and widened the calcium current's activation range. In this study, we have examined the mechanisms linking activation of the mGluRs with "up-regulation" of calcium current activity. Under whole-cell voltage-clamp conditions favoring expression of the L-type calcium current, we provide evidence that activation of mGluRs initiate the diacylglyceral (DG) second messenger pathway to activate protein kinase C (PKC) and up-regulate calcium channel activity. This evidence was based on results using a number of PKC activators and inhibitors. PKC activators mimicked the effect of (S) 3,5-DHPG on calcium current activity. Up-regulation of the calcium channel by PKC activators or (S) 3,5-DHPG was eliminated if PKC inhibitors were present. These results also demonstrated that activation of group I mGluRs were linked to a pertussis toxin sensitive G-protein. When the GTP analog, guanosine 5-0-(3-thiotriphosphate (GTPgammaS), was allowed to diffuse into voltage-clamp cells, up-regulation of the calcium channel occurred and mimicked the effect of (S) 3,5-DHPG. However, when pertussis toxin (PTX) was allowed to diffuse into the cell along with GTPgammaS, GTPgammaS failed to modulate calcium current activity. IP3 (inositol 1,4,5 triphosphate) is a second product produced by activation of group I mGluRs. Once formed, IP3 can trigger calcium release from IP3-sensitive intracellular stores. To determine if the IP3 second messenger system was involved in up-regulation of calcium channel, (S) 3,5-DHPG was applied to voltage-clamped cone horizontal cells containing different concentrations of the calcium buffer, EGTA. Low concentrations of EGTA failed to buffer calcium released from intracellular stores. In the presence of low EGTA concentrations, (S) 3,5-DHPG's enhancement of the calcium current amplitude was reduced. Inhibition of the calcium current amplitude in low concentrations of EGTA was eliminated in the presence of the intracellular calcium store blocker, heparin. These results suggest that both the DG and IP3 second messenger pathways are involved in modulation of the voltage-gated calcium channel in catfish cone horizontal cells. The DG pathway up-regulates the voltage-gated calcium channel activity whereas calcium released from IP3 intracellular stores inhibits peak current amplitude.

Animals↗
PubMed1999

Hypoxia/aglycemia increases endothelial permeability: role of second messengers and cytoskeleton.

The effects of hypoxia/aglycemia on microvascular endothelial permeability were evaluated, and the second messenger systems and the cytoskeletal-junctional protein alterations in this response were also examined. Monolayers of human dermal microvascular endothelial cells on microcarrier beads were exposed to either thioglycolic acid (5 mM, an O(2) chelator), glucose-free medium, or both stresses together. Permeability measurements were performed over a 90-min time course. Although neither hypoxia alone nor aglycemia alone increased endothelial permeability significantly, the combination of both increased significantly as early as 15 min. Intracellular Ca(2+) measurements with fura 2-AM showed that hypoxia/aglycemia treatment increased Ca(2+) influx. To determine the second messengers involved in increased permeability, monolayers were incubated for 30 min with the cytosolic Ca(2+) scavenger 3,4, 5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, 0.1 mM), a classical protein kinase C (PKC) blocker, Gö-6976 (10 nM), a cGMP-dependent protein kinase (PKG) antagonist, KT-5823 (0.5 microM), or the mitogen-activated protein (MAP) kinase inhibitor PD-98059 (20 microM). Hypoxia/aglycemia-mediated permeability changes were blocked by chelating cell Ca(2+), PKC blockade, PKG blockade, and by inhibiting p38 MAP kinase-1. Finally, changes in the binding of junctional proteins to the cytoskeleton under the same conditions were assessed. The concentrations of occludin and pan-reactive cadherin binding to the cytoskeleton were significantly decreased by only both stresses together. However, these effects were also blocked by pretreatment with TMB-8, Gö-6976, KT-5823 (not in occludin), and PD-98059. These data suggest that hypoxia/aglycemia-mediated endothelial permeability may occur through PKC, PKG, MAP kinase, and Ca(2+) related to dissociation of cadherin-actin and occludin-actin junctional bonds.

Alkaloids↗
PubMed1993

Ca(2+)-induced cortisol secretion from permeabilized bovine adrenocortical cells: the roles of calmodulin, protein kinase C and cyclic AMP.

In order to clarify the role of intracellular second messenger systems in the cortisol secretion from bovine adrenocortical (BAC) cells, the cells were permeabilized with beta-escin and stimulated intracellularly with various compounds. When the permeabilized BAC cells were exposed to submicromolar concentrations of Ca2+, a prompt cortisol secretion was elicited in a concentration-dependent manner. As the cells were stimulated with 12-O-tetradecanoyl-phorbol-13-acetate and 1-oleoyl-2-acetyl-glycerol, slow but persistent cortisol secretion was elicited, but in the case of 4 alpha-phorbol-12,13-didecanoate, no such effect was observed. The Ca(2+)-induced cortisol secretion was inhibited by simultaneous applications of calmodulin and protein kinase C (C kinase) inhibitors, but no significant inhibition was elicited by protein kinase A (A kinase) inhibitor. The results seem to indicate that in the Ca(2+)-induced cortisol secretion calmodulin may stimulate the initial stage, while C kinase may be involved mainly in the late phase of the secretion. In addition, cyclic AMP (cAMP) was also effective in activating cortisol secretion from permeabilized BAC cells. The cAMP-induced cortisol secretion was suppressed by an A kinase inhibitor but not affected by calmodulin or C kinase inhibitor. When Ca2+ and cAMP were added simultaneously at concentrations lower than those required to induce the cortisol secretion separately, a marked cortisol secretion was elicited, suggesting that a synergic action exists between Ca(2+)- and cAMP-activated systems. The Ca(2+)-induced cortisol secretion was suppressed by ruthenium red, an inhibitor of Ca2+ transport in the mitochondria. Although both NADP+ and NADPH elicited only a transient cortisol secretion, simultaneous addition of Ca2+ with NADP+ or NADPH caused a potent and sustained cortisol secretion. The augmentation due to Ca2+ on the NADP+ (or NADPH)-induced cortisol secretion was inhibited by the addition of a calmodulin inhibitor or a C kinase inhibitor, but not such effect was caused by A kinase inhibitor. From the present investigation, it was concluded that the Ca(2+)-dependent intracellular signal transduction may simulate the cortisol synthesis systems in the mitochondria of BAC cells.

Adrenal Cortex↗
PubMed1989

[Formation of the functional synapse in the cultured nerve cell].

Recent progress concerned with the formation of the functional synapse among cultured nerve cells was reviewed. By means of newly developed techniques, such as the patch-clamp method, selective nerve-cell culture and optical measurement of the intracellular Ca concentration, our knowledge about presynaptic and postsynaptic functions markedly increased in this decade. Especially in the fields of differentiation of the neurotransmitter synthesis and releasing mechanism, neurite-outgrowth and specific cell-to-cell adhesion, identification of neurotransmitters-receptors and corresponding second messenger systems, great progress has been made. Actually functional synapses were formed between neurons cultured from spinal cord, cerebellum, hippocampus, cerebral cortex and other brain regions. Basic problems such as identification of neurotransmitters and their receptors, analysis of network functions, synchronized activities and cell death mechanism have been studied using above culture systems. Although molecular mechanism underlying the specific synapse formation has not been understood well, this problem would be resolved in the near future using the nerve cell culture.

Animals↗
PubMed2001

Bitter taste transduced by PLC-beta(2)-dependent rise in IP(3) and alpha-gustducin-dependent fall in cyclic nucleotides.

Current evidence points to the existence of multiple processes for bitter taste transduction. Previous work demonstrated involvement of the polyphosphoinositide system and an alpha-gustducin (Galpha(gust))-mediated stimulation of phosphodiesterase in bitter taste transduction. Additionally, a taste-enriched G protein gamma-subunit, Ggamma(13), colocalizes with Galpha(gust) and mediates the denatonium-stimulated production of inositol 1,4,5-trisphosphate (IP(3)). Using quench-flow techniques, we show here that the bitter stimuli, denatonium and strychnine, induce rapid (50-100 ms) and transient reductions in cAMP and cGMP and increases in IP(3) in murine taste tissue. This decrease of cyclic nucleotides is inhibited by Galpha(gust) antibodies, whereas the increase in IP(3) is not affected by antibodies to Galpha(gust). IP(3) production is inhibited by antibodies specific to phospholipase C-beta(2) (PLC-beta(2)), a PLC isoform known to be activated by Gbetagamma-subunits. Antibodies to PLC-beta(3) or to PLC-beta(4) were without effect. These data suggest a transduction mechanism for bitter taste involving the rapid and transient metabolism of dual second messenger systems, both mediated through a taste cell G protein, likely composed of Galpha(gust)/beta/gamma(13), with both systems being simultaneously activated in the same bitter-sensitive taste receptor cell.

Animals↗
PubMed1990

Ototoxic and nephrotoxic drugs inhibit agonist-induced inositol phosphate formation in rat brain synaptoneurosomes.

Neomycin (an aminoglycoside antibiotic), ethacrynate (a loop diuretic), cisplatin (an anticancer drug) and mercuric chloride are chemically unrelated drugs which present similar ototoxic and nephrotoxic properties. We have found that all these molecules inhibit inositol phosphate turnover induced by carbachol or glutamate in rat brain synaptoneurosomes. Since this second messenger system appears to be a key mechanism for cell functioning and even survival, our observations raise the possibility that the expression of the specific toxicity of these compounds may result from excessive inhibition of the phosphoinositide cascade.

Animals↗
PubMed1993

Metabotropic glutamate receptors in brain function and pathology.

Metabotropic glutamate receptors (mGluRs) are a novel family of recently cloned G protein-coupled receptors. These receptors are heterogeneous and coupled to multiple second messenger systems that include increases in phosphoinositide hydrolysis, activation of phospholipase D, decreases in cAMP formation, increases in cAMP formation, and changes in ion channel function. Using the selective mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid (1s,3R-ACPD), considerable progress has been made towards understanding the role of this glutamate receptor class in the central nervous system. This article reviews the molecular aspects and pharmacology of mGluRs, and recent studies elucidating their role in brain function and pathology.

Animals↗
PubMed1997

Expression of a functional tagged human thyrotropin receptor in HeLa cells using recombinant vaccinia virus.

We report a new effective system for expression of FLAG and six histidine tagged TSH receptor in mammalian cells using recombinant vaccinia virus. HeLa cells infected with recombinant virus produced large amounts of human TSH receptor of approximately 150,000 functional molecules per cell. This value is one to two orders of magnitude higher than those in thyroid cells and is comparable with receptor number of the best stably transfected mammalian cell clones previously described. Vaccinia virus produced TSH receptor was able to bind TSH (Kd of 2.1 +/- 0.1 x 10(-10) M) and Graves'disease autoantibodies. TSH caused an increase of the intracellular cAMP level in infected HeLa cells in a concentration-dependent manner, demonstrating the coupling of expressed recombinant TSH receptor to the cAMP second messenger system of the cells. 6His-tagged recombinant TSH receptor was immobilized on Ni2+ nitrilotriacetic acid-agarose. Bound receptor was fully functional, interacting with both TSH and Graves' disease autoantibodies in patient sera. The solid phase bound TSH receptor technique provides a new and simple method for the diagnosis of autoimmune diseases.

Autoantibodies↗
PubMed1992

[Mechanism of suppressed prolactin secretion due to medium hyperosmolarity--the importance of Ca2+ influx].

It is still unknown how extracellular hyperosmolarity suppresses exocytosis. To evaluate the possibility that extracellular hyperosmolarity affects one of the most important second messenger system, Ca2+ signal, we evaluated the effect of hyperosmolarity on the thyrotropin releasing hormone (TRH)-induced changes in both intracellular Ca2+ concentration ([Ca2+]i) and prolactin (PRL) secretion in GH4C1 cells. TRH caused two phases of [Ca2+]i: an initial high-amplitude phase (first phase), which was not inhibited by Ca2+ free medium, and a sustained low-amplitude phase (second phase), which was abolished by Ca2+ free medium. Medium hyperosmolarity (isotonic = 300mOsm, hypertonic = 338, 375, 450, and 600mOsm) suppressed both TRH-induced phases of [Ca2+]i in a dose dependent manner, however, the suppressive effect was clearly stronger in the second phase of [Ca2+]i than in the first phase of [Ca2+]i. Low doses of medium hyperosmolarity (338 and 375mOsm) suppressed PRL secretion, which was dependent on Ca2+ influx. However, high doses of medium hyperosmolarity (450 and 600mOsm) also blocked PRL secretion, which was dependent on Ca2+ mobilized from cytosolic Ca2+ pools. These data indicate that in GH4C1 cells medium hyperosmolarity may inhibit PRL secretion by both blocking Ca2+ influx and a mechanism unrelated to Ca2+.

Calcium↗
PubMed2002

Stimulation of L-type Ca(2+) channels by increase of intracellular InsP3 in rat retinal pigment epithelial cells.

The purpose of this study was to investigate the role of voltage-dependent L-type Ca(2+)channels in intracellular Ca(2+)signaling of the retinal pigment epithelium (RPE). Patch-clamp techniques in conjunction with measurements of the intracellular free Ca(2+)using the Ca(2+)-sensitive fluorescence dye fura-2 were performed using cultured rat RPE cells. Intracellular application of inositol-1,4,5-trisphosphate (InsP3; 10 microM) via the patch-pipette during the whole-cell configuration led to an increase in the intracellular free Ca(2+)([Ca(2+)](i)). This effect could be reduced by the L-type Ca(2+)channel blocker nifedipine (2 microM). At the moment of the maximal rise in [Ca(2+)](i)L-type currents displayed an increase in the current density and shifts in the activation curve and of the steady-state inactivation. Comparable changes of L-type channel activity could be observed by induction of capacitative Ca(2+)entry, a maneuver to release Ca(2+)from intracellular Ca(2+)stores independently from InsP3. The increase in L-type Ca(2+)channel activity and [Ca(2+)](i)by intracellular application of InsP3 or induction of capacitative Ca(2+)entry could be inhibited by blocking tyrosine kinase activity using genistein (5 microM) or tyrphostin 51 (10 microM). It is concluded that L-type Ca(2+)channels are involved in the Ca(2+)/InsP3 second messenger system by generating an influx of extracellular Ca(2+)into the cell. This is enabled by depletion of cytosolic Ca(2+)stores and tyrosine kinase-dependent activation of L-type channels.

Animals↗
PubMed2001

Structure-activity and possible mode of action of S-Iamide neuropeptides on identified central neurons of Helix aspersa.

Intracellular recordings were made from identified neurons from the suboesophageal ganglia of Helix aspersa. The inhibitory action of nine S-Iamide peptides was investigated. Structure-activity studies suggest that all act through a common receptor, which normally requires FVRIamide at the C terminal, with a preferred length of seven amino acids. Substitution at the N-terminal with alanine (A), threonine (T), proline (P) or leucine (L) results in little change in potency, suggesting the N-terminal requirements are relatively flexible. Ion substitution experiments suggest that potassium is the main ion involved in the inhibitory response to S-Iamide application. Studies using a range of compounds, which modify second messenger systems, would suggest that S-Iamide peptides may interact with adenylate cyclase. No evidence was found for an interaction with either guanylate cyclase or nitric oxide synthase.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Pavlovian conditioning of Hermissenda: current cellular, molecular, and circuit perspectives.

The less-complex central nervous system of many invertebrates make them attractive for not only the molecular analysis of the associative learning and memory, but also in determining how neural circuits are modified by learning to generate changes in behavior. The nudibranch mollusk Hermissenda crassicornis is a preparation that has contributed to an understanding of cellular and molecular mechanisms of Pavlovian conditioning. Identified neurons in the conditioned stimulus (CS) pathway have been studied in detail using biophysical, biochemical, and molecular techniques. These studies have resulted in the identification and characterization of specific membrane conductances contributing to enhanced excitability and synaptic facilitation in the CS pathway of conditioned animals. Second-messenger systems activated by the CS and US have been examined, and proteins that are regulated by one-trial and multi-trial Pavlovian conditioning have been identified in the CS pathway. The recent progress that has been made in the identification of the neural circuitry supporting the unconditioned response (UR) and conditioned response (CR) now provides for the opportunity to understand how Pavlovian conditioning is expressed in behavior.

Animals↗
PubMed1996

Nongenomic actions of estrogen in the brain: physiological significance and cellular mechanisms.

Estrogen regulates neuroendocrine, reproductive, and behavioral functions of the brain by utilizing a number of diverse cellular mechanisms. In the classical genomic mechanism of steroids, estrogen induces relatively long-term actions on neurons by activating specific intracellular receptors that modulate transcription and protein synthesis. In addition, estrogen can also exert very rapid effects in the brain that cannot be attributed to genomic mechanisms. These nongenomic actions of estrogen influence a variety of neuronal properties, including electrical excitability, synaptic functioning, and morphological features, and are involved in many of the physiological functions and clinical effects of estrogen in the brain. Recently the specific cellular and molecular mechanisms underlying the nongenomic actions of estrogen have begun to be elucidated. Estrogen may utilize direct membrane mechanisms, such as activation of ligand-gated ion channels and G-protein-coupled second messenger systems and regulation of neurotransmitter transporters. Additionally the membrane and genomic actions of estrogen have the potential to interact, producing synergistic effects and dependence between the two types of mechanisms. The combination of nongenomic and genomic mechanisms endows estrogen with considerable diversity, range, and power in regulating neural function.

Animals↗
PubMed1998

Novel therapeutic approaches beyond the serotonin receptor.

The influence of serotonin (5-HT) on neuronal function is mediated by regulation of receptor-coupled intracellular signal transduction pathways, and the therapeutic action of 5-HT selective reuptake inhibitors (SSRIs), as well as other types of antidepressants, most likely involves regulation of these intracellular pathways. The cyclic adenosine monophosphate (cAMP) second messenger system is one pathway that could be involved in antidepressant action. Chronic administration of antidepressants, including SSRIs, up-regulates the cAMP pathway at several levels, including increased expression of the cAMP response element binding protein (CREB). Among the multiple target genes that could be regulated by CREB and that could be involved in antidepressant actions and the pathophysiology of depression in brain-derived neurotrophic factor (BDNF). Stress decreases the expression of BDNF, and reduce levels of this neurotrophic factor could contribute to the atrophy and decreased function of stress-vulnerable hippocampal neurons. In contrast, antidepressant treatment increases the expression of BDNF in hippocampus, and could thereby reverse the stress-induced atrophy of neurons or protect these neurons from further damage. Up-regulation of the cAMP and BDNF systems has resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic agents.

Adenylyl Cyclases↗
PubMed1991

The role of immediate early genes in the stabilization of long-term potentiation.

Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesis-independent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory. Long-term potentiation (LTP) is a persistent, activity-dependent form of synaptic plasticity that stands as a good candidate for the mechanism of associative memory. A number of IEGs coding for transcription factors have been shown to transiently increase transcription in the dentate gyrus of rats following LTP-inducing afferent stimulation. These include zif/268 (also termed NGFI-A, Krox-24, TIS-8, and egr-l), c-fos-related genes, c-jun, junB, and junD. Of these, zif/268 appears to be the most specifically related to LTP since it is evoked under virtually all LTP-inducing situations and shows a remarkably high correlation with the duration of LTP. There are a number of outstanding questions regarding the role of zif/268 and other IEGs in LTP, including which second messenger systems are important for activating them, which "late effector" genes are regulated by them, and the exact role these genes play, if any, in the stabilization and maintenance of LTP.

Animals↗
PubMed2005

Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-2 on platelet aggregation.

OBJECTIVE: Platelets contain and release some matrix metalloproteinases (MMPs), enzymes involved in the degradation of extracellular matrix, and one of these (MMP-2) exerts a proaggregatory effect. We explored the signal transduction mechanisms activated by MMP-2 in human blood platelets. METHODS AND RESULTS: Recombinant, human MMP-2, added before stimulation with subthreshold doses of different agonists, potentiated platelet activation, calcium influx, IP3 formation, and pleckstrin phosphorylation. Wortmannin and LY29400, two PI3-K inhibitors, suppressed the potentiating effects of MMP-2 and preincubation with MMP-2 enhanced the thrombin-induced association of the p85alpha PI3-K subunit with the cytoskeleton and increased the phosphorylation of PKB. Protein tyrosine kinase inhibitors, MAP kinase inhibitors, PLA2 inhibitors, cyclooxygenase inhibitors and antagonists of the P2Y1 and P2Y12 receptors did not affect the potentiating activity of MMP-2 on platelets. CONCLUSION: Our data show that MMP-2, at a concentration released by activated platelets, facilitates platelet activation acting at the level of a second messenger system common to different agonists and related to the activation of PI3-K. Platelet-released MMP-2 may contribute to platelet activation in vivo.

Androstadienes↗
PubMed1999

Kindling and second messengers: an approach to the neurobiology of recurrence in bipolar disorder.

Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse--through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

Acetylcholine↗