Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation

BACKGROUND: Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. RESULTS: In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. CONCLUSIONS: These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.     

Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myoinositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high-resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myoinositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myoinositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI cycle.     

Effects of chronic lithium and sodium valproate on concentrations of brain amino acids.

The present study was designed to determine if the mood stabilizers, lithium and valproate, have common effects on concentrations of amino acid neurotransmitters which may be related to their mechanisms of action. Two separate groups of rats were administered therapeutic doses of lithium, sodium valproate, or saline for 2 weeks. Whole brain extracts were then examined using either high-field 1H NMR spectroscopy or HPLC. Both drugs decreased whole brain concentrations of aspartate, glutamate, and taurine while brain concentrations of gamma-aminobutyric acid (GABA) and alanine decreased following chronic sodium valproate administration but not following chronic lithium administration. These findings indicate that lithium and sodium valproate share common effects on the concentrations of certain amino acid neurotransmitters in whole brain which may be related to their mechanisms of action in bipolar disorder.     

The effect of DHEA complementary treatment on heroin addicts participating in a rehabilitation program: A preliminary study

We evaluated the effect of DHEA complementary treatment in opiate addicts undergoing detoxification. DHEA (100 mg/day) or placebo was added to the routine medication protocol in a randomized, double blind controlled study. Follow-up for 12 months was conducted. Two separate DHEA-treated subgroups were identified by the Fuzzy clustering method: one showed statistically significant improvement in the severity of withdrawal symptoms, depression and anxiety scores (n = 34; p < 0.001 for all) and the other subgroup deteriorated in all measures (n = 15). DHEA at the end of the detoxification program showed a tendency towards correlation with the duration of abstinence (r = 0.6843; p > 0.05; n = 6), while a negative correlation was obtained with the cortisol level (r = − 0.900; p = 0.005, n = 8). The completion-rate of the DHEA-improved subgroup was greater than in the DHEA-deteriorated subgroup (64.7% vs. 33.3%, respectively).

The influence of supplementary DHEA treatment was mostly effective in heroin addicts who had not previously used either cocaine or benzodiazepines and who had experienced only few withdrawal programs.     

alpha2B-adrenoceptor agonist ST-91 antagonizes beta2-adrenoceptor-mediated relaxation in rat mesenteric artery rings

We sought an isolated vascular preparation and experimental setting where the function of _2B-adrenoceptors could be demonstrated by non-recombinant technique. ST-91 (2-[2,6-diethylphenylamino]-2-imidazoline), an _2B-adrenoceptor agonist with a mixed adrenergic receptor type/subtype selection profile antagonized the relaxant effect of isoproterenol in endothelium-denuded rat mesenteric artery rings precontracted with phenylephrine. At 10^− 7 M of ST-91, the antagonism was characterized by a rightward shift of isoproterenol dose–response curve (A₅₀ = 6.81 ± 1.40 e− 7 (n = 4) vs the control 1.29 ± 0.25 e− 7 M (n = 4)) with no E_max depression. At 10^− 6 M the E_max depression was prevalent (36.1 ± 7.0% (n = 4) vs the control 79.9 ± 5.1% (n = 4)); both actions could be antagonized by the ₂-adrenoceptor antagonist yohimbine. The not subtype-selective ₂-adrenoceptor agonist xylazine (10^− 7 M) did not affect the relaxant action of isoproterenol. Present findings are discussed in the light of previously reported hemodynamic effects attributed to _2B-adrenoceptors in receptor subtype-knockout animals.     

Tetraspan protein CD151: a common target of mood stabilizing drugs?

The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have been predicted with the candidate gene approach. During the process of characterizing one of these novel genes, we have identified a cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (also known as tetraspan) protein, CD151, the expression of which was significantly decreased in rat frontal cortex following chronic (five weeks) lithium treatment. The reduction of CD151 mRNA levels was also observed following chronic administration of carbamazepine and valproate. Conversely, the expression of CD151 was not altered by short-term (one week) lithium treatment and by chronic administration of the tricyclic antidepressant, imipramine, or the typical antipsychotic, haloperidol, further demonstrating time dependence and pharmacological specificity of this effect. Our studies, thus, indicate that CD151 may represent a therapeutically relevant target common to lithium and the anticonvulsant mood stabilizing drugs, carbamazepine and valproate.     

Disulfiram enhances subjective effects of dextroamphetamine in humans

Disulfiram has shown promise in several clinical trials for cocaine addiction, but its potential utility in the treatment of amphetamine addiction has not been examined. The goal of this study was to determine the effects of disulfiram on acute physiological and subjective responses to dextroamphetamine in healthy volunteers. Five male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects were randomly assigned to a sequence of disulfiram (250 mg/day) or placebo treatments each lasting for 4 days. Day four of each treatment period was the experimental session, in which subjects orally ingested a single dose of dextroamphetamine (20 mg/70 kg). Outcome measures included heart rate, blood pressure, plasma cortisol and prolactin, subjective and performance on the Sustained Attention to Response Test (SART). Disulfiram did not affect dextroamphetamine-induced increases in heart rate, blood pressure, cortisol, or prolactin. Disulfiram did enhance some of the subjective effects of dextroamphetamine including ratings of "high," "anxious," "bad drug effects," "want more drug" and "drug liking" and was also associated with decreased performance in the SART test. How these enhanced subjective amphetamine responses affect cocaine use behavior remains to be determined in future clinical trials.     

Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.     

Evidence of excessive concentrations of 5-flucytosine in children aged below 12 years: a 12-year review of serum concentrations from a UK clinical assay reference laboratory

5-Flucytosine (5-FC) is an antifungal drug used for the treatment of serious infections caused by Candida or Cryptococcus spp. In the UK, the recommended pre- and post-dose serum therapeutic ranges are 30–40 mg/L and 70–80 mg/L, respectively. A 12-year retrospective review of serum concentrations of 5-FC in three groups of children aged 1–30 days (n = 167), 31–60 days (n = 102) and 91 days to 12 years (n = 122) was conducted. In these three age groups, 65.1%, 44.4% and 21.3% of pre-dose samples and 39.3%, 29.2% and 19.7% of post-dose samples were above the recommended ranges. Both the mean concentration and the percentage of concentrations above the recommended ranges were significantly higher in the youngest age group (1–30 days old), suggesting that the standard dose of 100 mg/kg daily may not be an appropriate dose in this age group.     

Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium

This study tested if sodium valproate or lithium, two agents used to treat bipolar mood disorder, altered the regulatory phosphorylations of Akt or glycogen synthase kinase-3beta (GSK3beta) in human neuroblastoma SH-SY5Y cells. Treatment with sodium valproate caused a gradual but relatively large increase in the activation-associated phosphorylation of Akt on Ser-473, and a similarly gradual but more modest increase in the inhibition-associated phosphorylation of GSK3beta on Ser-9. Two other inhibitors of histone deacetylase, a recently identified target of sodium valproate, also caused gradual increases in the phosphorylation of Akt and GSK3beta. Lithium treatment increased the Ser-9 phosphorylation of GSK3beta both in cells and in mouse brain after chronic administration, but did not alter the phosphorylation of Akt. These results identify novel effects of sodium valproate on the Akt/GSK3beta signaling pathway, indicating that histone deacetylase inhibition is linked to activation of Akt, and show that two anti-bipolar agents have a common action, the increased inhibitory phosphorylation of Ser-9-GSK3beta. The latter finding, along with previous reports that lithium directly inhibits GSK3beta, reveals the possibly unique situation where a single target, GSK3beta, is inhibited by two independent mechanisms, directly and by phosphorylation following lithium administration, and further, that two mood stabilizers have inhibitory effects on GSK3beta.     

Discriminative stimulus properties of pizotifen maleate (BC105): a putative serotonin antagonist

The neurochemical specificity of physiological, biochemical, and psychological responses to dextroamphetamine was tested by pretreating volunteers with haloperidol (0.014 mg/kg IM), proparonol (0.1 mg/kg IV), thymoxamine (0.1 mg/kg IV), or placebo prior to 0.3 mg/kg IV amphetamine. Healthy volunteers (N=12) participated in the studies, but not all volunteers received each drug combination. Haloperidol prevented dextroamphetamine-induced behavioral excitation, but did not significantly affect plasma norepinephrine or pressor responses, whereas propranolol inhibited norepinephrine and pressor responses without influencing excitation or other behavioral responses. Thymoxamine did not affect any of the responses measured. None of the agents significantly affected plasma cortisol or growth hormone responses. The prolactin rise following dextroamphetamine was potentiated by haloperidol. The results are consistent with the hypothesis that behavioral excitation after dextroamphetamine occurs through a dopaminergic mechanism, and pressor responses through a noradrenergic mechanism.     

A new hydrogel for the extended and complete prednisolone release in the GI tract

The issue of incomplete release of poorly soluble drugs from sustained-release oral formulations is addressed using prednisolone (PDS) as the model drug and a novel highly swelling hydrogel as the rate-controlling material. The hydrogel was formed by heating N-carboxymethylchitosan (CMC) to 80 °C for 24 h. Swelling, alkalimetry, FTIR, DSC, and solid-state NMR studies showed that the treatment produced physical crosslinking, i.e., polymer chain entanglement. A controlled-release system was prepared by coating an inert compacted support of ethylcellulose (50 mg; diameter, 6 mm) with a CMC layer containing dispersed PDS powder (10–50 μm). The system was heated to crosslink the CMC coating, then drug release to simulated GI fluids was studied in vitro. The drug release pattern and term were modulated via the layer mass (LM) (10 or 14 mg cm⁻²) and/or the drug–polymer wt ratio (D/P) (1:5 or 2:5). The rate parameter, K, and the time exponent, n, of the Peppas equation were: K = 26.6 ± 0.3 h⁻ⁿ, n = 0.78 ± 0.02 (LM, 10 mg cm⁻²; D/P, 1:5); K = 24.7 ± 0.7 h⁻ⁿ, n = 0.56 ± 0.02 (LM, 14 mg cm⁻²; D/P, 1:5); K = 20.7 ± 0.3 h⁻ⁿ, n = 0.76 ± 0.01 (LM, 10 mg cm⁻²; D/P, 2:5). Hydrogel swelling was faster than drug release. This was controlled, in a first stage, by drug dissolution–diffusion in the swollen gel, and subsequently, by diffusion. The drug release rate was unaffected by the GI pH variations, and slightly affected by the environmental hydrodynamics. The system promises an extended and complete release of poorly soluble drugs in the GI tract.     

A simple formula for individualising ceftazidime dosage administered by continuous infusion in patients with haematological malignancies

A formula is proposed for individualising ceftazidime dosage administered by continuous infusion in patients with haematological malignancies. Sixty patients were retrospectively randomised into Group A (n = 30) to establish the formula and Group B (n = 30) to evaluate this formula. Individual ceftazidime clearances were estimated from the ratio between the rate of infusion and plasma concentration at steady state. In Group A, ceftazidime clearance was significantly correlated with creatinine clearance. From this result, a formula (rate of infusion (g/day) = 0.00133 × [creatinine clearance (mL/min)] × [target concentration at steady state (mg/L)]) is proposed. This formula provided consistent estimations of ceftazidime plasma concentrations in Group B and should help clinicians to define the optimum ceftazidime dosage, particularly in patients with disturbed renal function.     

Effects of chronic valproate treatment on reproductive endocrine hormones in female and male Wistar rats

Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in humans. There is sparse information regarding the mechanisms behind these disturbances. By using an animal model, we wanted to study the effect of valproate on hormonal function in non-epileptic rats. Female rats were given 0 (vehicle control, n=15), 200 mg/kg (n=15), or 300 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4–6 h after the last dose given. Serum testosterone concentrations remained unchanged, while estradiol levels were significantly reduced in both treatment groups, leading to significantly increased testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained unaltered in valproate treated rats, whereas the luteinizing hormone (LH) concentrations were reduced at the lowest valproate dose. Male rats received 0 (vehicle control, n=15), 200 mg/kg (n=15), or 400 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4–6 h after the last dose. Serum testosterone levels were not significantly changed, but there was a highly significant increase in FSH and LH concentrations at the high dose. In conclusion, the study demonstrates a drug-induced effect of valproate on endocrine function in both male and female rats. The results indicate that the drug exerts its effect primarily at the gonadal level, although a centrally mediated effect cannot be ruled out.     

Repeated exposure to Delta(9)-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

The present study examined the effect of chronic exposure to Δ⁹-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (n = 60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups (n = 12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (n = 6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naïve rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the Edinger–Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.     

Homocysteine levels in adolescent schizophrenia patients

Homocysteine is a sulfur containing amino acid that has been widely investigated for its putative role in cardiovascular and neuropsychiatric disorders. It has been suggested that homocysteine has implications especially in young, male schizophrenia patients. In this prospective case-control study, we compared plasma homocysteine levels in a group of adolescent schizophrenia inpatients (aged 14–21 years; n = 23) to normal healthy controls (n = 51). Mean plasma homocysteine levels were significantly higher in the patient group than in the control group (15.40 ± 2.00 and 9.78 ± 0.33 μmol/L, respectively, p < 0.032). The difference was almost entirely attributable to the male schizophrenia subgroup (18.18 ± 5.65 in male patients vs. 10.31 ± 5.33 μmol/L in female patients). The group × sex interaction was statistically significant (p = 0.0035). These data indicate that a subgroup of male adolescent schizophrenia patients has high homocysteine blood levels. The role of homocysteine in the pathophysiology of adolescent-onset schizophrenia merits further investigation.     

Gas chromatographic-mass spectrometric analysis of d-limonene in human plasma

d-Limonene shows carminative and cholagogue effects and is used in treatment of gallstone, cholecystitis and angiocholitis. A simple method was developed to determine the concentration of d-limonene in human plasma. d-Limonene and internal standard (naphthalane, C₁₀H₁₈) were extracted with n-hexane and then injected to GC–MS. Calibration curves were linear (r = 0.9990, n = 6) in the range of 2–500 ng/ml for d-limonene in human plasma. Limit of detection and quantification were 0.5 and 2 ng/ml, respectively. This rapid and specific method was applied to the clinical pharmacokinetic investigation of d-limonene.