A comparison between the dynamics of horizontal and vertical axis offshore floating wind turbines.

The need to further exploit offshore wind resources in deeper waters has led to a re-emerging interest in vertical axis wind turbines (VAWTs) for floating foundation applications. However, there has been little effort to systematically compare VAWTs to the more conventional horizontal axis wind turbine (HAWT). This article initiates this comparison based on prime principles, focusing on the turbine aerodynamic forces and their impact on the floating wind turbine static and dynamic responses. VAWTs generate substantially different aerodynamic forces on the support structure, in particular, a potentially lower inclining moment and a substantially higher torque than HAWTs. Considering the static stability requirements, the advantages of a lower inclining moment, a lower wind turbine mass and a lower centre of gravity are illustrated, all of which are exploitable to have a less costly support structure. Floating VAWTs experience increased motion in the frequency range surrounding the turbine [number of blades]×[rotational speed] frequency. For very large VAWTs with slower rotational speeds, this frequency range may significantly overlap with the range of wave excitation forces. Quantitative considerations are undertaken comparing the reference NREL 5 MW HAWT with the NOVA 5 MW VAWT.

Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson's disease. For comparison, parallel experiments were also performed with amantadine. First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naïve and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naïve and L-DOPA-primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3-week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B ratio at striatal synaptic membranes. Our results are in line with clinical observations suggesting that NMDA receptor blockade may only be transiently effective against LID in PD patients.

Augmented cocaine-induced accumbal dopamine efflux, motor activity and place preference in rats fed with a tryptophan-deficient diet.

In the present study we demonstrate that consumption of a tryptophan-deficient diet for a period of 14 days decreased the striatal serotonin and 5-hydroxyindolacetic acid tissue content in rats, whereas the level of dopamine remained unchanged. Under this condition of diminished serotonergic tone, a challenge dose of cocaine (10mg/kg, i.p.) significantly increased motor activity and dopamine extracellular content in the nucleus accumbens compared to rats fed with a balanced diet. We moreover found that pretreatment with cocaine (7 and 10mg/kg, i.p.) produced a significant increase in preference for a cocaine-associated environment in the tryptophan-deficient group compared to control rats. Our experiments show that a low tone of serotonergic system, augments the behavioural reinforcing effect of cocaine and that this effect may be due to a increased cocaine-induced accumbal dopamine release. These data indicate that a tryptophan-deficient diet alters the behavioural and neurochemical effect of psychostimulants, such as cocaine, and suggest an important role of serotonin in modulation of these effects.

Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats.

Vitamin A and its derivatives, retinoids, are involved in the regulation of gene expression by binding two nuclear receptor families, retinoic acid receptors and retinoid X receptors. Retinoid receptors are highly expressed in the striatum, revealing an involvement of this system in the control of movement as demonstrated by previous observations in knockout mice. To further assess the role of retinoids in adult striatal function, the present study investigated the effect of vitamin A deprivation on rat motor activity and coordination, the rate of synthesis and release of dopamine, the functioning of D1 and D2 receptors and their expression in the striatum. Moreover, the content of acetylcholine in the striatum was measured. Results show that 24 weeks of postnatal vitamin A deprivation induced severe locomotor deficits and impaired motor coordination. Vitamin A deprivation rats showed a significant hyperactivity following D1 receptor stimulation by R(+)-6-chloro-7,8-dihydroxy-1-phenyil-2,3,4,5-tetrahydro-1H-3-benzazepine or amphetamine and reduced catalepsy in response to haloperidol treatment. This different response to the above drugs is not due to a change in striatal DA release or synthesis between vitamin A deprivation and control animals. In situ hybridization experiments showed identical level of expression for the D1 and D2 receptor transcripts. On the other hand, the striatal tissue content of acetylcholine was reduced significantly by about 30% starting from the initial manifestation of motor deficits. We suggest that the locomotor impairment could be imputable to the dysfunction in striatal cholinergic interneurons. Our results stress the basic role of vitamin A in the maintenance of basal ganglia motor function in the adult rat brain.

Cell growth and cholesterol metabolism in human glucose-6-phosphate dehydrogenase deficient lymphomononuclear cells.

Atherosclerosis is an inflammatory-fibroproliferative response of the arterial wall involving a complex set of interconnected events where cell proliferation (lymphomonocytes, and endothelial and smooth-muscle cells) and substantial perturbations of intracellular cholesterol metabolism are considered to be among the main features. Glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the hexose-monophosphate shunt pathway, is an essential enzyme involved in both cell growth and cholesterol metabolism, raising the question as to whether G6PD deficiency may have metabolic and growth implications in a deficient population. In the present study, we investigated cell growth and cholesterol metabolism in peripheral blood lymphomononuclear cells (PBMC) from G6PD-normal (n = 5) and -deficient (n = 5) subjects stimulated with lectins (phytohaemoagglutinin and Concanavalin A). G6PD activity, DNA ([3H]-thymidine incorporation) cholesterol synthesis and esterification ([14C]-acetate and [14C]-oleate incorporation), and G6PD, HMGCoA reductase and low density lipoprotein (LDL) receptor mRNA levels (RT-PCR) all increased following lectin stimulation in both normal and G6PD-deficient cells. However, these parameters were significantly lower in G6PD-deficient cells (P < 0.05). It is of interest that G6PD-deficient PBMC, which showed lower expression of G6PD and higher expression of the LDL receptor gene than normal PBMC under basal conditions, exhibited an opposite pattern after stimulation: G6PD and HMGCoA reductase being expressed at significantly higher levels in deficient than in normal cells (P < 0.05). We conclude that the reduced capability of G6PD-deficient cells to respond to mitogenic stimuli and to synthesize cholesterol esters may represent favourable conditions for reducing the risk of cardiovascular diseases.

Early exposure to restraint stress enhances chemical carcinogenesis in rat liver.

This study examines the effect of a stress-associated condition on chemical hepatocarcinogenesis in the rat. Rats were given diethylnitrosamine (200 mg/kg. b.w., i.p.), followed, 1 week later, by three cycles of immobilization at room temperature. Two weeks after the last cycle they were treated according to the resistant hepatocyte protocol. At 4 weeks after selection, mean size of glutathione-S-transferase 7-7 positive foci/nodules was increased in the immobilized group (0.82+/-0.22 vs. 0.25+/-0.04 mm(2) in controls). Furthermore, at the end of 1 year 10/13 animals (77%) developed hepatocellular carcinoma in the former group, while only 6/14 (43%) incidence of cancer was found in controls. These results indicate that exposure to restraint stress early during carcinogenesis enhances the development of chemically-induced hepatocellular carcinoma in the rat.

The role of dopamine in the mechanism of action of antidepressant drugs.

The present paper reviews evidence on the effect of antidepressant treatments on dopamine transmission. Chronic treatment with antidepressant drugs potentiates the behavioural stimulant responses elicited by the stimulation of dopamine receptors, including reward-related behaviours. Moreover, antidepressants affect dopamine release in several brain areas. The reviewed literature is discussed in terms of the possible mechanisms underlying antidepressant-induced supersensitivity to dopamine-mediated behavioural responses, and of the possible implications for the therapeutic effect of these drugs. It is concluded that the potentiation of dopaminergic neurotransmission induced by chronic antidepressant treatments might contribute to their therapeutic effect.

Chronic lithium chloride fails to prevent imipramine-induced sensitization to the dopamine D(2)-like receptor agonist quinpirole.

Lithium salts, an effective antimanic treatment, are able to prevent the development of the dopaminergic behavioural supersensitivity induced by chronic treatment with neuroleptics, by denervation of the dopaminergic terminal fields and by rapid eye movements (REM) sleep deprivation, which is considered a model of mania. We have studied the effect of a lithium (LiCl) diet, inducing a lithium serum level in the range of therapeutic efficacy, on the development of the supersensitivity to the locomotor effect of the dopamine D(2)-like receptor agonist, quinpirole, induced by chronic treatment with the antidepressant drug, imipramine. The results show that lithium is not able to prevent the development of such behavioural supersensitivity. The present data suggest that antidepressant-induced dopaminergic supersensitivity might provide a useful model of those manic states induced by (or subsequent to) antidepressant treatments. Moreover, the finding is consistent with the view that antidepressant-induced dopaminergic supersensitivity might play a role in the therapeutic effect of these drugs (which is known to be augmented by lithium, and not antagonised). Finally, the results show that the dopaminergic supersensitivity induced by imipramine is qualitatively different from that induced by neuroleptics or denervation of the dopaminergic terminal fields.

Dizocilpine prevents the enhanced locomotor response to quinpirole induced by repeated electroconvulsive shock.

Repeated administration of electroconvulsive shock, as expected, potentiated the locomotor stimulant response to quinpirole (0.3 mg/kg s.c.), a dopamine D2-like receptor agonist. Chronic, but not acute, treatment with the NMDA receptor non-competitive antagonist dizocilpine (0.3 mg/kg i.p.) prevented electroconvulsive shock-induced potentiation of quinpirole locomotor response. These results suggest that NMDA receptor activation is necessary for the development of supersensitivity to dopamine receptor agonists produced by repeated electroconvulsive shock. The relevance of this observation in regard to the mechanism of electroconvulsive shock therapeutic effect is discussed.

Behavioural sensitization of mesolimbic dopamine D2 receptors in chronic fluoxetine-treated rats.

A common action of chronic antidepressant treatments is the potentiation of dopaminergic transmission in the limbic system. We now report that chronic, but not acute, treatment with fluoxetine (2.5 mg/kg by intragastric gavage once a day for 21 days) potentiates the locomotor stimulant effect of quinpirole, a selective dopamine D2/D3 receptor agonist. However, neither quinpirole-induced stereotypies nor the sedative effects elicited by low doses of this dopamine receptor agonist are influenced by chronic fluoxetine. These results suggest that fluoxetine, as well as classical antidepressants, sensitize postsynaptic dopamine D2/D3 receptors in the mesolimbic system.

Role of D1 and alpha1 receptors in the enhanced locomotor response to dopamine D2-like receptor stimulation induced by repeated electroconvulsive shock.

We previously reported that, in rats chronically treated with the antidepressant drug imipramine, the enhanced locomotor response to the D2-like receptor agonist quinpirole became less sensitive to the inhibitory effect of the D1 receptor antagonist SCH 23390 and more sensitive to the inhibitory effect of the alpha1 receptor antagonist prazosin. In this study, we show that in electroconvulsive shock-treated rats these antagonists behave in the opposite manner to that observed in imipramine-treated rats, with SCH 23390 being highly effective and prazosin ineffective in antagonizing the locomotor response to quinpirole. The possibility that these differences may reflect some of the clinical characteristics of these antidepressant treatments is discussed.

Chronic administration of l-sulpiride at low doses reduces A10 but not A9 somatodentritic dopamine autoreceptor sensitivity.

The effect of chronic treatment (twice daily for 21 days) with low doses of l-sulpiride (2 mg/kg i.p.) on the apomorphine-induced inhibition of A10 and A9 dopaminergic neurons was compared with the effect of chronic administration of the classic antidepressant desipramine (20 mg/kg i.p. daily for 21 days). Intravenous administration of apomorphine (0.01-0.04 mg/kg), to rats treated chronically with l-sulpiride, produced a reduction of the spontaneous firing rate of A9 dopaminergic neurons not significantly different from that observed in control (saline-treated) rats. In contrast, apomorphine at the same doses was more potent in inhibiting A10 firing in control rats than in l-sulpiride-treated subjects. On the other hand, desipramine-treated rats were found normosensitive (as compared to saline-treated rats) to the inhibitory properties of apomorphine in both A9 and A10 dopaminergic neurons. It is suggested that chronic l-sulpiride-induced reduction of autoreceptor sensitivity in the A10 region may contribute to its clinical antidepressant effect.

Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine.

Acute intoxication and chronic therapy with the alcohol consumption deterrent dithiocarbamate disulfiram have been associated with several neurological complications perhaps involving the impairment of neurotransmitter pathways. In this study we have tested the hypothesis that dopaminergic malfunction is a critical component in disulfiram-evoked neurotoxicity. Disulfiram antagonized the in vitro striatal binding of [3H]tyramine, a putative marker of the vesicular transporter for dopamine, and the uptake of [3H]dopamine into striatal synaptic vesicles, with inhibitory constants (Ki) in the range of reported blood dithiocarbamate levels in treated alcoholics. Furthermore, disulfiram provoked a loss of radioactivity from [3H]dopamine-preloaded striatal vesicles, when added directly to the incubation mixture. Several metal-containing fungicide analogs were also potent displacers of specifically bound [3H]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injection of a high dose of disulfiram and DDC into rats, mimicking acute intoxication, induced in vivo overflow of striatal dopamine from both a reserpine-sensitive (vesicular) and an alpha-methyl-p-tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine release resulted mainly from a direct activity of disulfiram, on the organelles (interaction with the carrier for dopamine plus membrane permeabilization) and indirectly through the mediation of serotonergic 5-HT3 receptors. DDC acted poorly at the vesicle membrane, and the in vivo releasing effect of dopamine was only partially prevented by the inhibition of 5-HT3 receptors, thus suggesting the role of additional mechanisms. It is concluded that disulfiram intoxication may acutely disrupt dopamine balance, an effect probably underlying some of the central neurotoxic, extrapyramidal symptoms associated with dithiocarbamate overdose.

Dopaminergic correlates of motivated behavior: importance of drive.

In vivo brain microdialysis was used to monitor changes in dopamine (DA) release in the nucleus accumbens (NAc) during anticipatory and consummatory components of feeding behavior. During 10 daily training sessions, rats were first confined to one compartment of a testing chamber for 10 minutes. During this period (anticipatory phase) they were prevented from gaining access to a highly palatable liquid meal by a wire mesh screen. The screen was then removed and the animals were permitted to consume the meal for 20 min (consummatory phase). On removal of the screen, the latency to begin drinking decreased and the amount consumed increased as a function of days of training, both measures reaching asymptotic levels by day 7. Trained animals were implanted with dialysis probes in the NAc on day 10, and on day 12 DA release was monitored during the feeding session. Compared to controls, trained animals failed to show significantly greater increases in accumbal DA release during the anticipatory phase, all groups showing small (approximately 10%) increases on being placed in the test chamber. In contrast, compared to controls, DA release increased significantly in the NAc during consumption of the palatable meal. The magnitude of this increase was significantly enhanced (30% vs 71% peak increase) in animals that were 20 hr food deprived at the time of testing. The latter animals also showed a statistically significant increase (24%) in DA release during the anticipatory phase. A subsequent experiment in which consumption of the palatable liquid was limited to 5 ml in deprived and nondeprived animals indicated that only part of the deprivation-induced potentiation of accumbal DA release could be attributed to the larger volume consumed by the deprived animals. That is, the same volume and rate of consumption of a small amount of the liquid diet produced a significantly greater increase in accumbal DA release in deprived than in nondeprived animals (42% vs 23% peak increase). Feeding-induced increases in accumbal DA release were not due to postingestional factors as direct injections of the liquid diet into the stomach by gavage failed to produce this effect. The results of these experiments indicate (1) that consummatory rather than anticipatory aspects of feeding are robustly associated with increases in DA release in the NAc, and (2) that motivational state can influence the magnitude of the neurochemical events that are associated with goal-directed behaviors.

Biochemical and electrophysiological effects of 7-OH-DPAT on the mesolimbic dopaminergic system.

Systemic administration of the putative selective D3 receptor agonist 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) consistently decreased extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and dopaminergic neuronal activity in the ventral tegmental area. 7-OH-DPAT inhibited dopamine release in the nucleus accumbens also when locally perfused through the dialysis probe. The results suggest the possibility that stimulation of dopamine D3 receptors with 7-OH-DPAT mimic biochemical and electrophysiological actions previously ascribed to D2 autoreceptor stimulation; however the lack of selective D3 antagonist precludes any firm conclusion in this sense.

Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression.

We compared the effect of two selective dopamine D1 receptor agonists, SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl) and A68930 ((1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman.HCl), and that of imipramine in the behavioural despair model of depression. The dopamine D1 receptor agonists and imipramine showed an anti-immobility effect. Moreover we found that the 'antidepressant' effect of imipramine in the behavioural despair test was antagonized by SCH 23390, a selective dopamine D1 receptor blocker. The results further support the hypothesis that dopamine D1 receptor stimulation plays an important role in the mechanism of action of antidepressants and suggest that dopamine D1 receptor agonists might be considered as potential antidepressant drugs.

TRH activates mesolimbic dopamine system: behavioural evidence.

The effect of TRH pretreatment on locomotor activity and stereotypy induced by d-amphetamine was examined in rats. The results show that TRH potentiates d-amphetamine-induced locomotor activity, but not d-amphetamine-induced stereotypy, suggesting that this neuropeptide selectively activates the mesolimbic dopamine system.

Haloperidol-induced vacuous chewing in rats: suppression by alpha-methyl-tyrosine.

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movements (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administration of the specific dopamine D1, receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were totally suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, alpha-methyl-tyrosine (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D1 agonist, SKF 38393. The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon D1 receptors.