Biomedical subjects

J J Warsh

Publications and source records attributed to J J Warsh.

At least 19 recordsLinked to original sources

PubMed2000

The human nucleus accumbens is highly susceptible to G protein down-regulation by methamphetamine and heroin.

Although the nucleus accumbens is assumed to be a critical brain "pleasure center," its function in humans is unknown. As animal data suggest that a unique feature of this small brain area is its high sensitivity to down-regulation of an inhibitory G protein by drugs of abuse, we compared G protein levels in postmortem nucleus accumbens with those in seven other brain regions of chronic users of cocaine, methamphetamine, and heroin, and of matched controls. Biochemical changes were restricted to the nucleus accumbens in which concentrations of G(alpha)1 and/or G(alpha)2 were reduced by 32-49% in the methamphetamine and heroin users. This selective responsiveness to these abused drugs implies a special role for the human nucleus accumbens in mechanisms of drug reinforcement and suggests that some features of the drug-dependent state (e.g., tolerance) might be related to inhibition of G(alpha)1-linked receptor activity.

Adult↗

PubMed1999

Characterization of alpha(s)-immunoreactive ADP-ribosylated proteins in postmortem human brain.

ADP-ribosylation of the stimulatory G protein alpha subunit, alpha(s), has been demonstrated in a number of different mammalian tissues. However, little is known about the occurrence and role of this process in modifying alpha(s) levels/function in human brain. In the present study, endogenous and cholera toxin (CTX)-catalyzed [32P]ADP-ribosylated products were characterized in postmortem human temporal cortex by (1) immunoprecipitation with alpha(s) antisera (RM/1), (2) comparisons of immunoblots and autoradiograms of the [32P]ADP-ribosylated products, and (3) limited protease digestion. Of the three major endogenous [32P]ADP-ribosylated products (48, 45, and 39 kDa) in postmortem brain, the 48-kDa and 45-kDa bands were clearly identified as alpha(s-L) (long isoform) and alpha(s-S) (short isoform), respectively. RM/1 immunoprecipitated the 39-kDa [32P]ADP-ribosylated protein, and overlays of immunoblots and autoradiograms showed that this product corresponded to an alpha(s)-like-immunoreactive protein. Furthermore, limited protease digestion of the 39-kDa endogenous [32P]ADP-ribosylated band generated peptide fragments similar to both endogenous and CTX-catalyzed [32P]ADP-ribosylated alpha(s-S). Two major CTX-catalyzed [32P]ADP-ribosylated products were also identified as alpha(s-L) (52 kDa) and alpha(s-S) (45 kDa). These findings clearly demonstrate that alpha(s) is a substrate for endogenous and CTX-catalyzed [32P]ADP-ribosylation in postmortem human brain. Furthermore, a lower molecular weight alpha(s)-like immunoreactive protein is also expressed in human brain and is a substrate for endogenous but not CTX-catalyzed [32P]ADP-ribosylation.

Adenosine Diphosphate Ribose↗

PubMed1999

Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia.

We recently reported that the activity of a calcium-independent subtype of phospholipase A2 is increased in blood of patients with schizophrenia. The present investigation examined whether similar changes take place in brain of patients with this disorder, and for comparison, in patients with bipolar disorder. The activity of two classes of PLA2, calcium-stimulated and independent, were assayed in autopsied temporal, prefrontal and occipital cortices, putamen, hippocampus and thalamus of 10 patients with schizophrenia, 8 patients with bipolar disorder and 12 matched control subjects. Calcium-independent PLA2 activity was increased by 45% in the temporal cortex of patients with schizophrenia as compared with the controls but was not significantly altered in other brain areas. In contrast, calcium-stimulated PLA2 activity was decreased by 27-42% in the temporal and prefrontal cortices and putamen, with no significant alterations in other brain regions. Brain PLA2 activity was normal in patients with bipolar disorder. Calcium-stimulated PLA2 activity was normal in cortex, cerebellum and striatum of rats treated acutely or chronically with haloperidol, whereas calcium-independent PLA2 activity was decreased in striatum of chronically treated animals, indicating that altered PLA2 activity in patients with schizophrenia is unlikely to be a direct effect of medication. Studies of the cellular role played by PLA2 suggest that decreased calcium-stimulated PLA2 activity, as also occurs in striatum of chronic human cocaine users, may be due, in part, to increased dopaminergic activity in the disorder, whereas increased calcium-independent PLA2 activity may be related to abnormal fatty acid metabolism and oxidative stress in schizophrenia.

1-Acylglycerophosphocholine O-Acyltransferase↗

PubMed1999

Imaging of cAMP-specific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats.

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims.

BACKGROUND: Previous studies have found altered receptor/G protein-modulated adenylyl cyclase (AC) activity in subjects with mood disorders. METHODS: To investigate whether these effects are associated with altered levels of specific isoforms of AC, we measured AC isoform I, IV and V/VI immunoreactivities in postmortem temporal cortex from nine depressed suicide victims, nine subjects with bipolar disorder (BD) and 18 age-matched non-psychiatric controls. Basal, GTPgammaS- and forskolin-stimulated AC activities were measured in the temporal cortex from the nine depressed suicide victims and their controls. RESULTS: Western blotting revealed significant reductions in immunolabeling in AC type IV (-49%; p < 0.05) in depressed suicide subjects compared to age-matched controls, but no differences were found in AC type I or type V/VI. There were no statistically significant differences in AC type I, IV or V/VI immunoreactivities between BD and matched control subjects. Functionally, there was a significant reduction in forskolin-stimulated AC activity in depressed suicide subjects compared to controls, which may be, in part, related to higher basal AC activity in the former group. LIMITATIONS: Our sample size was small with diverse subject characteristics. CONCLUSIONS: These preliminary findings suggest altered levels and/or function in AC type IV may contribute to disturbances in the postreceptor cAMP signaling cascade in depression.

Adenylyl Cyclases↗

PubMed1999

Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder.

Previous observations of reduced [3H]cyclic AMP binding in postmortem brain regions from bipolar affective disorder subjects imply cyclic AMP-dependent protein kinase function may be altered in this illness. To test this hypothesis, basal and stimulated cyclic AMP-dependent protein kinase activity was determined in cytosolic and particulate fractions of postmortem brain from bipolar disorder patients and matched controls. Maximal enzyme activity was significantly higher (104%) in temporal cortex cytosolic fractions from bipolar disorder brain compared with matched controls. In temporal cortex particulate fractions and in the cytosolic and particulate fractions of other brain regions, smaller but statistically nonsignificant increments in maximal enzyme activity were detected. Basal cyclic AMP-dependent protein kinase activity was also significantly higher (40%) in temporal cortex cytosolic fractions of bipolar disorder brain compared with controls. Estimated EC50 values for cyclic AMP activation of this kinase were significantly lower (70 and 58%, respectively) in both cytosolic and particulate fractions of temporal cortex from bipolar disorder subjects compared with controls. These findings suggest that higher cyclic AMP-dependent protein kinase activity in bipolar disorder brain may be associated with a reduction of regulatory subunits of this enzyme, reflecting a possible adaptive response of this transducing enzyme to increased cyclic AMP signaling in this disorder.

Adult↗

PubMed1998

Lithium, but not carbamazepine, potentiates hyperactivity induced by intra-accumbens cholera toxin.

Elevated G protein abundance and/or function has been implicated in the pathophysiology and pharmacotherapy of bipolar affective disorder. To test the interactions between chronic lithium and carbamazepine on behavioral changes induced by cholera toxin (CTX), which catalyzes ADP-ribosylation and constitutively activates G alphas/olf, rats were given chronic dietary lithium, carbamazepine (CBZ), or regular food (REG) and injected bilaterally in the nucleus accumbens (nACC) with CTX (400 ng/ml/side) or vehicle. Locomotor activity was tested daily for 2 weeks after the injection. CTX increased locomotor activity, but a significant interaction between drug treatment and CTX reflected a two- to threefold increase of CTX-induced hyperactivity in the lithium-treated group. In contrast, on day 1, the CBZ-CTX group was significantly more active than the the LI-CTX and REG-CTX groups, both of which had suppressed locomotor activity. There was a significant reduction in CTX-catalyzed ADP ribosylation of G alphas (52 kDa and 45 kDa) in the nucleus accumbens in all three CTX-treated groups. The potentiation of the behavioral effect of CTX by lithium supports the hypothesis that lithium interacts with G proteins; however, the mechanism of interaction appears to be more complex than direct attenuation of G alphas function, as previously suggested.

Adenosine Diphosphate Ribose↗

PubMed1997

Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder.

As disturbances in guanine nucleotide binding (G) protein-coupled phosphoinositide second messenger systems have been implicated in bipolar disorder, we examined whether the abundance of G alpha q/11 and phospholipase C (PLC)-beta 1 two key transducing proteins in this signaling pathway, are altered in this disorder. Compared with the controls, immunoreactive levels of G alpha q/11 were significantly elevated by 62% (p = .047) in occipital cortex of bipolar subjects. A similar increase (52%) in the PLC-beta 1 immunolabeling was also found in the occipital cortex of the bipolar subjects, but only reached marginal statistical significance (p = .07). In contrast, frontal and temporal cortex G alpha q/11 or PLC-beta 1 immunolabeling did not differ between bipolar and control subjects. Cerebral cortical immunoreactive levels of G beta 1 or G beta 2, included as a negative control, were not different between comparison groups. These findings support and extend earlier observations suggesting that disturbances in G protein-coupled second messenger signaling pathways may play an important role in the pathophysiology of bipolar affective disorder.

Adult↗

PubMed1997

The niacin challenge test: clinical manifestation of altered transmembrane signal transduction in schizophrenia?

Several lines of evidence implicate altered phospholipid-dependent signal transduction (PDST) in the pathophysiology of schizophrenia. Niacin induces vasodilation through mechanisms requiring intact PDST. Thus, an altered response to a challenge dose of niacin may reflect disturbances in these signalling processes in this disorder. In the present study, niacin-induced vasodilation was estimated quantitatively in schizophrenic and comparison bipolar affective disorder and healthy subjects using thermocouple sensors to measure the change in skin temperature relative to core body and ambient room temperature. Twelve (42.9%) of 28 schizophrenic subjects did not vasodilate in response to a 200-mg niacin challenge dose, whereas only 1 of 18 (6%) bipolar disorder subjects and none of 28 controls showed impaired response (Fisher's Exact Test, p < .0001). These findings support the notion that the schizophrenic syndromes are biochemically heterogeneous and suggest the existence of a subgroup of schizophrenic subjects in whom phospholipid-dependent signalling responses may be impaired.

Adolescent↗

PubMed1997

Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2.

BACKGROUND: Magnetic resonance spectroscopy studies have suggested above-normal turnover of membrane phospholipids in brains of patients with schizophrenia. One possible explanation for these findings is increased activity of the phospholipid-catabolizing enzyme phospholipase A2 (PLA2). However, attempts to demonstrate higher PLA2 activity in the serum of subjects with schizophrenia have led to conflicting results. We hypothesized that this was due to serum PLA2 activity consisting of a family of different enzymes, with each group of investigators measuring activity of different PLA2 forms. DESIGN: Activity of PLA2 in serum samples obtained from 24 individuals with schizophrenia was compared with serum obtained from 33 age- and sex-matched control subjects, using both fluorometric and radiometric assays with different substrates. Each method had previously yielded conflicting results concerning the status of the enzyme in schizophrenia. RESULTS: With the fluorometric assay, serum PLA2 activity in individuals with schizophrenia was markedly increased by 49% compared with control subjects (P < .001). In contrast, radiometric assay of the same serum samples resulted in PLA2 activity not significantly different between patients and control subjects. Further investigations demonstrated that, whereas the radiometric assay measured activity of a calcium-dependent enzyme, the fluorometric assay detected a calcium-insensitive enzyme possessing an acid-neutral pH optimum. CONCLUSIONS: Increased calcium-independent PLA2 activity was seen in the serum of patients with schizophrenia. This change, if present also in the brain, may well explain the increased levels of phosphodiesters observed using magnetic resonance spectroscopy and therefore may contribute to the pathophysiological features of the disorder.

Adult↗

PubMed1997

Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder.

Findings of increased Gs alpha levels and forskolin-stimulated adenylyl cyclase activity in selective cerebral cortical postmortem brain regions in bipolar affective disorder (BD) implicate increased cyclic AMP (cAMP)-mediated signaling in this illness. Accumulating evidence suggests that intracellular levels of cAMP modulate the abundance and disposition of the regulatory subunits of cAMP-dependent protein kinase (cAMP-dPK). Thus, in the present study, we tested further whether hyperfunctional Gs alpha-linked cAMP signaling occurs in BD by determining [3H]cAMP binding, a measure of the levels of regulatory subunits of cAMP-dPK, in cytosolic and membrane fractions from discrete brain regions of postmortem BD brain. Specific [3H]cAMP (5 nM) binding was determined in autopsied brain obtained from 10 patients with DSM-III-R diagnoses of BD compared with age- and postmortem delay-matched controls. [3H]cAMP binding was significantly reduced across all brain regions in cytosolic fractions of BD frontal (-22%), temporal (-23%), occipital (-22%) and parietal (-15%) cortex, cerebellum (-36%), and thalamus (-13%) compared with controls, but there were no differences in [3H]cAMP binding in the membrane fractions from these same regions. These results suggest that changes occur in the cAMP-dPK regulatory subunits in BD brain, possibly resulting from increased cAMP signaling. The possibility that antemortem lithium and/or other mood stabilizer treatment may contribute to the above changes, however, cannot be ruled out.

Adult↗

PubMed1997

High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder.

OBJECTIVE: Higher basal concentrations of intracellular calcium Ca2+ in platelets and lymphocytes from subjects with bipolar affective disorder than in unipolar depressed and healthy subjects implicate abnormal intracellular Ca2+ signaling in bipolar disorder. The purpose of this study was to clarify whether these intracellular Ca2+ abnormalities are trait related. METHOD: Basal Ca2+ concentration was measured by using ratiometric fluorescence assay with fura-2 for T lymphocytes and Epstein-Barr-virus-immortalized B lymphoblasts from physically healthy subjects with DSM-IV diagnoses of bipolar mood disorder (bipolar I, N = 28; bipolar II, N = 11) or major depressive disorder (N = 14), mixed psychiatric patients with non-mood disorders (N = 14), and health subjects (N = 20). Phytohemagglutinin-stimulated (10 micrograms/ml) intracellular Ca2+ levels were also determined in T lymphocytes. RESULTS: The basal Ca2+ concentration was significantly higher in the B lymphoblasts from patients with bipolar I disorder, but not bipolar II disorder or major depression, than in healthy subjects or psychiatric patients with nonmood disorders. There was a significant interaction between gender and diagnosis in the effect on basal Ca2+ levels in T lymphocytes. Contrasts of diagnoses within gender revealed significantly higher basal Ca2+ concentrations in T lymphocytes in male bipolar I patients, but not mean with bipolar II disorder or major depression, than in healthy male comparison subjects. Phytohemagglutinin-stimulated Ca2+ concentrations did not differ among groups, but the percent differences from basal Ca2+ levels were lower in bipolar I and depressed patients than in healthy subjects. CONCLUSIONS: These findings support the occurrence of abnormal calcium homeostasis in bipolar disorder and suggest that trait-dependent factors account, at least partly, for the higher basal lymphocyte Ca2+ concentration in bipolar I subjects.

Adult↗

PubMed1996

Genetic variant near cytosolic phospholipase A2 associated with schizophrenia.

Two studies were undertaken to determine a possible genetic basis for alterations in phospholipid metabolism in schizophrenia. Initial results demonstrated an association in 65 schizophrenics compared with a matched normal control population. A follow-up haplotype relative risk study of 44 triads (mother, father, affected offspring), confirmed the results seen in the association study. Results suggest that a genetic variant near the promotor region of the gene for cytosolic phospholipase A2, the rate-limiting enzyme in the synthesis of prostaglandins from arachindonic acid, is associated with schizophrenia.

Female↗

PubMed1996

Lack of effect of antidepressants on mononuclear leukocyte G-protein levels or function in depressed outpatients.

Evidence from studies in animal and cultured cell models suggests that antidepressants (ADs) may enhance postreceptor signalling through the G protein coupled adenylyl cyclase (AC) pathways. To test whether this also occurs in patients receiving AD treatment, G-protein-activated-AC activity and the levels of alpha s and alpha i were measured in mononuclear leukocytes (MNLs) from 12 subjects with major depressive disorder (MDD) at baseline and after a 5 week trial of AD treatment. Although no differences were found in GTP gamma S-and forskolin-stimulated AC activity or the levels of alpha s and alpha i in MDD subjects compared with age- and sex-matched healthy subjects, pretreatment basal AC activity was significantly lower in treatment responders compared with healthy subjects. No significant changes were evident in any of these biochemical measures following 5 weeks of AD treatment in the patient group as a whole or stratified by response. These findings do not support an effect of ADs on the G-protein AC pathway, at least in MNLs. Lower pretreatment basal AC activity in responders suggests some change(s) in post-receptor signalling processes may be associated with an increased likelihood of therapeutic response to ADs.

Adenylyl Cyclases↗

PubMed1996

Brain region-specific and time-dependent decreases of G alpha i2 in amygdala-kindled rats.

Immunoreactivity levels of G protein alpha-subunits, Galphas (45 and 52 kDa), Galphai1, and Galphai2, were determined in plasma membranes prepared from ipsilateral amygdala-pyriform cortex (AM/PC), contralateral AM/PC, dorsal hippocampus (DH), and ventral hippocampus (VH) in amygdala-kindled rats 24 h, 1 month, and 3 months after the last seizure. Relative to sham controls, immunoreactivity levels of Galphai2 were significantly reduced in ipsilateral AM/PC and DH, with maximal decreases observed, respectively, at 24 h (26% form control levels) and 1 month (18% from control levels) postseizure. No significant alterations in the levels of Galphai1 or either of the Galphas isoforms were observed. The reduction in Galphai2 levels was, however, not accompanied by measurable changes in Galphai-mediated inhibition of adenylyl cyclase, as estimated by GppNHp modulation of forskolin-activated adenylyl cyclase activity. The present findings add support to the hypothesis that long-term changes in brain functioning following kindling may involve altered expression and/or function of components of the transmembrane signalling cascade, including G proteins.

Adenylyl Cyclases↗

PubMed1996

Lack of effect of chronic antidepressant treatment on Gs and Gi alpha-subunit protein and mRNA levels in the rat cerebral cortex.

Experimental evidence indicates that chronic antidepressant treatment in rats modifies the central nervous system beta-adrenoceptor signaling pathway at multiple sites including receptor, G-protein, adenylyl cyclase, and protein kinase A. In the present study, we examined the postreceptor effect of antidepressant treatment on the protein and mRNA levels of stimulatory and inhibitory C protein alpha-subunits (G alpha s and G alpha i) and beta-subunits in rats infused continuously with various antidepressants for 21 days. Chronic treatment with tricylic (desipramine and amitriptyline) and monoamine oxidase inhibiting (tranylcypromine) antidepressants did not significantly affect the immunoreactivity levels of G alpha s (both 45- and 52-kDa species), G alpha i1, G alpha i2, G beta 36, and beta 35 in rat cerebral cortex. Similarly, the levels of mRNA encoding these G protein subunits remained unchanged subsequent to these drug treatments. In contrast, cortical beta-adrenoceptor number was significantly decreased by these treatments. These results suggest that the adaptive changes of rat cerebral cortical beta-adrenoceptor-adenylyl cyclase system often seen after chronic antidepressant treatment are not accompanied by changes in the abundance and gene expression of G alpha s, G alpha i, or G beta proteins.

Analysis of Variance↗

PubMed1996

Stimulatory G-protein alpha-subunit mRNA levels are not increased in autopsied cerebral cortex from patients with bipolar disorder.

Increased alpha-subunit (alpha s) levels of both the 45- and 52-kDa isoforms of the stimulatory guanine nucleotide binding protein (G-protein), have been found in postmortem brain and mononuclear leukocytes from patients with bipolar disorder (BD). The pathophysiological mechanism responsible for increased alpha s protein levels is unknown, however, it may involve increased expression of the gene encoding this protein. To assess this possibility, alpha s mRNA levels were determined by RT-PCR in postmortem brain from 10 subjects with an antemortem diagnosis of BD and age- and sex-matched control subjects in whom we had previously reported increased alpha s protein levels. There were no significant differences in alpha s mRNA levels in frontal, temporal, or occipital cortex between BD and control subjects. Cerebral cortex alpha s mRNA levels did not correlate with age or postmortem interval. These findings do not support the notion that higher alpha s levels found in BD postmortem brain are a result of increased gene expression.

Adult↗

PubMed1996

The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain.

The function of the phosphoinositide second messenger system was assessed in occipital, temporal, and frontal cortex obtained postmortem from subjects with bipolar affective disorder and matched controls by measuring the hydrolysis of [3H]phosphatidylinositol ([3H]PI) incubated with membrane preparations and several different stimulatory agents. Phospholipase C activity, measured in the presence of 0.1 mM Ca2+ to stimulate the enzyme, was not different in bipolar and control samples. G proteins coupled to phospholipase C were concentration-dependently activated by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and by NaF. GTP gamma S-stimulated [3H]Pl hydrolysis was markedly lower (50%) at all tested concentrations (0.3-10 microM GTP gamma S) in occipital cortical membranes from bipolar compared with control subjects. Responses to GTP gamma S in temporal and frontal cortical membranes were similar in bipolars and controls, as were responses to NaF in all three regions. Brain lithium concentrations correlated directly with GTP gamma S-stimulated [3H]Pl hydrolysis in bipolar occipital, but not temporal or frontal, cortex. Carbachol, histamine, trans-1-aminocyclopentyl-1,3-dicarboxylic acid, serotonin, and ATP each activated [3H]Pl hydrolysis above that obtained with GTP gamma S alone, and these responses were similar in bipolars and controls except for deficits in the responses to carbachol and serotonin in the occipital cortex, which were equivalent to the deficit detected with GTP gamma S alone. Thus, among the three cortical regions examined there was a selective impairment in G protein-stimulated [3H]Pl hydrolysis in occipital cortical membranes from bipolar compared with control subjects. These results directly demonstrate decreased activity of the phosphoinositide signal transduction system in specific brain regions in bipolar affective disorder.

Adenosine Triphosphate↗